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PURPOSE Proteasome inhibitors are effective in Waldenström's macroglobulinemia (WM) but require parenteral administration and are associated with polyneuropathy. We investigated efficacy and toxicity of the less neurotoxic oral proteasome inhibitor ixazomib combined with rituximab, in patients with relapsed WM. METHODS We conducted a multicenter phase I/II trial with ixazomib, rituximab, and dexamethasone (IRD). Induction consisted of eight cycles IRD wherein rituximab was started in cycle 3, followed by rituximab maintenance. Phase I showed feasibility of 4 mg ixazomib. Primary end point for phase II was overall response rate (ORR [≥ minimal response]) after induction. RESULTS A total of 59 patients were enrolled (median age, 69 years; range, 46-91 years). Median number of prior treatments was 2 (range, 1-7); 70% had an intermediate or high WM-IPSS (International Prognostic Scoring System for WM) score. After eight cycles, ORR was 71% (42 out of 59) (14% very good partial response [PR], 37% PR, and 20% minor response). Depth of response improved until month 12 (best ORR 85% [50 out of 59]: 15% very good PR, 46% PR, and 24% minor response). Median duration of response was 36 months. The average hematocrit level increased significantly (0.33-0.38 L/L) after induction ( P < .001). After two cycles of ixazomib and dexamethasone, immunoglobulin M levels decreased significantly (median 3,700-2,700 mg/dL, P < .0001). Median time to first response was 4 months. Median progression-free survival and overall survival were not reached. After median follow-up of 24 months (range, 7.4-54.3 months), progression-free survival and overall survival were 56% and 88%, respectively. Toxicity included mostly grade 2 or 3 cytopenias, grade 1 or 2 neurotoxicity, and grade 2 or 3 infections. No infusion-related reactions or immunoglobulin M flare occurred with use of subcutaneous rituximab. Quality of life improved significantly after induction. In total, 48 patients (81%) completed at least six cycles of IRD. CONCLUSION Combination of IRD shows promising efficacy with manageable toxicity in patients with relapsed or refractory WM.

Background NJLCG1402 was a phase I/II trial investigating biweekly nanoparticle albumin‐bound paclitaxel (nab‐PTX) in patients with advanced non‐small cell lung cancer (NSCLC). Methods The study included patients aged ≥20 years with previously treated NSCLC. Nab‐PTX (100–150 mg/m2) was administered biweekly in a 28‐day cycle. The phase I portion was performed to determine the recommended phase II dose of nab‐PTX. In the phase II portion, the primary endpoint was the objective response rate. Secondary endpoints were disease control rate, progression‐free survival, overall survival, and safety. Results A total of 15 patients received biweekly nab‐PTX (100–150 mg/m2) and 12 patients in phase II were treated with 150 mg/m2. In the phase I portion, 150 mg/m2 was determined as the recommended dose. Among those treated with 150 mg/m2, the objective response rate was 22%, and the median progression‐free and overall survival was 3.6 and 11.2 months, respectively. Adverse events grade ≥3 were observed in 39% of patients. Conclusions Biweekly nab‐PTX monotherapy was well tolerated and exhibited favorable antitumor activity in patients with previously treated NSCLC., We conducted the first prospective multicenter phase I/II trial to evaluate the efficacy and safety of biweekly nab‐PTX treatment in patients with previously treated advanced NSCLC. In phase I portion, 150 mg/m2 was determined as the recommended dose. Among those treated with 150 mg/m2, the objective response rate was 22%; median progression‐free and overall survival was 3.6 and 11.2 months, respectively.

Immunotherapy is an innovative treatment approach that harnesses a patient’s immune system to treat cancer. It has provided an alternative and complementary treatment modality to conventional chemotherapy. Combining immunotherapy with cytotoxic chemotherapy agent has become the leading trend and the most active research field in oncology. To accommodate this growing trend, we propose a Bayesian phase I/II dose-finding design to identify the optimal biological dose combination (OBDC), defined as the dose combination with the highest desirability in the risk-benefit trade-off. We propose new statistical models to describe the relationship between the doses and treatment outcomes, including immune response, toxicity and progression-free survival (PFS). During the trial, based on accrued data, we continuously update model estimates and adaptively assign patients to dose combinations with high desirability. The simulation study shows that our design has desirable operating characteristics.

Pre-clinical evidence suggests bevacizumab (BV) depletes the GBM peri-vascular cancer-stem cell niche. This phase I/II study assesses the safety and efficacy of repeated doses of superselective intra-arterial cerebral infusion (SIACI) of BV after blood–brain barrier disruption (BBBD). Date of surgery was day 0. Evaluated patients received repeated SIACI bevacizumab (15 mg/kg) with BBBD at days 30 ± 7, 120 ± 7, and 210 ± 7 along with 6 weeks of standard chemoradiation. Response assessment in neuro-oncology criteria and the Kaplan–Meier product-limit method was used to evaluate progression free and overall survival (PFS and OS, respectively). Twenty-three patients with a median age of 60.5 years (SD = 12.6; 24.7–78.3) were included. Isocitrate dehydrogenase mutation was found in 1/23 (4%) patients. MGMT status was available for 11/23 patients (7 unmethylated; 3 methylated; 1 inconclusive). Median tumor volume was 24.0 cm3 (SD = 31.1, 1.7–48.3 cm3). Median PFS was 11.5 months (95% CI 7.7–25.9) with 6, 12, 24 and 60 month PFS estimated to be 91.3% (95% CI 69.5–97.8), 47.4% (26.3–65.9), 32.5% (14.4–52.2) and 5.4% (0.4–21.8), respectively. Median OS was 23.1 months (95% CI 12.2–36.9) with 12, 24, and 36 month OS as 77.3% (95% CI 53.6–89.9), 45.0% (22.3–65.3) and 32.1% (12.5–53.8), respectively. Repeated dosing of IA BV after BBBD offers an encouraging outcome in terms of PFS and OS. Phase III trials are warranted to determine whether repeated IA BV combined with Stupp protocol is superior to Stupp protocol alone for newly diagnosed GBM.

OBJECTIVES We investigated differences in quality of life (QoL) in patients enrolled on a phase I/II dose-escalation study of 3-fraction resection cavity stereotactic radiosurgery (SRS) for large brain metastases. METHODS Eligible patients had 1 to 4 brain metastases, one of which was a resection cavity 4.2 to 33.5 cm3. European Organization for Research and Treatment of Cancer (EORTC) quality of life questionnaires core-30 (QLQ-30) and brain cancer specific module (QLQ-BN20) were obtained before SRS and at each follow-up. Nine scales were analyzed (global health status; physical, social, and emotional functioning; motor dysfunction, communication deficit, fatigue, insomnia, and future uncertainty). QoL was assessed with mixed effects models. Differences ≥10 points with q-value (adjusted P-value to account for multiplicity of testing)

PURPOSE This phase I/II study evaluated tremelimumab (anticytotoxic T-lymphocyte–associated antigen-4 monoclonal antibody) and durvalumab (antiprogrammed death ligand-1 monoclonal antibody) as monotherapies and in combination for patients with unresectable hepatocellular carcinoma (HCC), including a novel regimen featuring a single, priming dose of tremelimumab (ClinicalTrials.gov identifier: NCT02519348 ). PATIENTS AND METHODS Patients with HCC who had progressed on, were intolerant to, or refused sorafenib were randomly assigned to receive T300 + D (tremelimumab 300 mg plus durvalumab 1,500 mg [one dose each during the first cycle] followed by durvalumab 1,500 mg once every 4 weeks), durvalumab monotherapy (1,500 mg once every 4 weeks), tremelimumab monotherapy (750 mg once every 4 weeks [seven doses] and then once every 12 weeks), or T75 + D (tremelimumab 75 mg once every 4 weeks plus durvalumab 1,500 mg once every 4 weeks [four doses] followed by durvalumab 1,500 mg once every 4 weeks). Safety was the primary end point. Secondary end points included objective response rate (ORR) by Response Evaluation Criteria in Solid Tumors v1.1 and overall survival; exploratory end points included circulating lymphocyte profiles. RESULTS A total of 332 patients were enrolled (T300 + D, n = 75; durvalumab, n = 104; tremelimumab, n = 69; and T75 + D, n = 84). Tolerability was acceptable across arms, with grade ≥ 3 treatment-related adverse events occurring in 37.8%, 20.8%, 43.5%, and 24.4%, respectively. Confirmed ORRs (95% CI) were 24.0% (14.9 to 35.3), 10.6% (5.4 to 18.1), 7.2% (2.4 to 16.1), and 9.5% (4.2 to 17.9), respectively. An early expansion of CD8+ lymphocytes was associated with response across arms, with highest proliferating CD8+ lymphocyte levels occurring in the T300 + D arm. The median (95% CI) overall survival was 18.7 (10.8 to 27.3), 13.6 (8.7 to 17.6), 15.1 (11.3 to 20.5), and 11.3 (8.4 to 15.0) months in the T300 + D, durvalumab, tremelimumab, and T75 + D arms, respectively. CONCLUSION All regimens were found to be tolerable and clinically active; however, the T300 + D regimen demonstrated the most encouraging benefit-risk profile. The unique pharmacodynamic activity and association with ORR of the T300 + D regimen further support its continued evaluation in HCC.

Myeloid-derived suppressor cells (MDSCs) are potent suppressors of antitumor immunity and are commonly associated with poor outcomes in melanoma patients treated with immune checkpoint inhibitors. Inducing the differentiation of MDSCs using all-trans retinoic acid (ATRA) alters their activity and reduces MDSC frequency. This trial seeks to assess the safety and efficacy of combining ATRA and pembrolizumab in metastatic melanoma patients. In 24 stage IV melanoma patients, treatment with pembrolizumab Q3W plus the supplemental treatment of ATRA orally for three days surrounding each of the first four pembrolizumab infusions effectively lowered the frequency of circulating PMN-MDSCs and enhanced melanoma-specific T cell activity. The combination was well tolerated. Median progression free survival was 20.3 months, and the overall response rate was 71%, with 50% of patients experiencing a complete response. Targeting MDSCs remains a promising mechanism to enhance the efficacy of anti-PD-1 therapies and this combination merits further investigation.

In the decommissioning phase of oilfield facility lifecycles, focus pivots from positive net present value to executing the care and preservation, then decommissioning in the safest and most environmentally sensitive manor, and at the lowest total cost of ownership. Asset Retirement Obligation (ARO) is a long-term liability carried on the balance sheet, as a provision for the cost to return a wellsite to pre-exploration condition. The reduction of abandonment and decommissioning expenditure (ABEX) in executing compliant operations is a key business performance factor, and critical in executing higher volumes of wells earlier than planned. In doing so maximizing value to company shareholders, residents, industries and government level stakeholders. In the case study, an offline pre-abandonment and Phase I primary reservoir isolation project is presented, which seeks to maximize net project efficiency via offline wellbore intervention, executing the primary reservoir isolation of the wellbore via rigless techniques. This approach contributed to ABEX reductions by up to 40% per well vs the planned approval for expenditure (AFE) provisions taken for the operations. The project execution structure utilized offline intervention and Phase I primary reservoir isolation of 81 wellbores, across 5 wellhead platforms and 47 days continuous operations. Operations were part of a simultaneous operation (SIMOPS) project, as an offline work front located on the wellhead platform (WHP) weather deck. A second work front for Phase II and Phase III well abandonment operations, is executed concurrently, from the jack-up rig cantilever above the WHP. Live well operations are conducted concurrently by both work fronts, through the Christmas Tree (XT) and pressure control equipment in Phase I, and through the drilling riser and blowout preventor for Phase II and Phase III, to maximize productivity when the rig is on location. The scope of operations included wellhead qualification, wellbore access and preparation, well kill, injectivity testing, various wellbore preparation and cement placement techniques, pressure testing and lubrication of the wellbore. The operator's system engineering, design of operations and planning agility are key to its success. Acute focus was given to the batching of operations and delivery of these in a phased approach to increase productivity and maintain high service delivery through repetition of tasks. The project successfully executed Incident Free Operations (IFO) with 100% productive time and facilitated combined project performance, which delivered wells up to 44% ahead of the planned AFE. To enable this, over 4.19 million feet of slickline was run, conveying 428 bottom hole assemblies (BHAs), preparing the wellbores to isolate 804 primary reservoirs, and 2 intermediate reservoirs.

BACKGROUND The blood brain barrier (BBB) remains a potential barrier to central nervous system (CNS) penetration of novel immunotherapies in recurrent glioblastoma (rGBM). Laser interstitial thermal therapy (LITT) was recently demonstrated to induce BBB disruption. When combined with anti-PD1 blockade, LITT may therefore potentiate host T-cell mediated cytotoxicity. This phase I/II study aims to evaluate the safety and efficacy of combining LITT and the PD-1 inhibitor pembrolizumab for rGBM. METHODS Phase I treated eligible bevacizumab-naïve high grade glioma patients with LITT and the anti-PD1 inhibitor pembrolizumab at 3 dose levels (100, 150, and 200 mg IV Q3W; 3 patients at each level), while phase II was restricted to rGBM patients only with the recommended phase II dose (RP2D) of pembrolizumab. Phase II was initially designed to randomize rGBM to either pembrolizumab or pembrolizumab+LITT but was later amended to receive only pembrolizumab+LITT after 16 patients were randomized (10 pembrolizumab+LITT arm, 6 pembrolizumab-alone arm). Progression-free survival (PFS) and overall survival (OS) were evaluated using the Kaplan Meier method, and adverse events (AE) documented. RESULTS Phase I enrolled 9 patients (7 rGBM and 2 anaplastic astrocytomas, 33% IDH-mut, 44% MGMTp-methylated) with no dose limiting toxicities (DLT), prompting selection of 200mg Q3W as the RP2D. Phase II interim analysis included 34 rGBM patients (9% IDH-mut, 50% MGMTp-methylated; 6 receiving pembrolizumab alone and 28 pembrolizumab+LITT) plus two Phase I rGBM patients who received RP2D. On per-protocol analysis, pembrolizumab+LITT cohort had improved PFS (median PFS 10.5 months vs 2.1 months) and OS (median OS 11.4 months vs 5.2 months) than pembrolizumab alone. A single treatment-related grade 3 AE was noted (respiratory infection). CONCLUSION: LITT may be safely combined with pembrolizumab for rGBM with promising clinical outcomes on interim analysis. Enrollment for Phase II, correlative studies, and continued AE documentation are ongoing. Clinical Trial ID NCT02311582.

BackgroundMalignant pleural mesothelioma (MPM) is an aggressive malignancy without curative treatment. Standard of care (SOC) include pemetrexed/cisplatin and nivolumab/ipilimumab with median overall survival in unresectable disease of 12.1 months and 18.1 months respectively.1 2 ONCOS-102 is a granulocyte-macrophage colony stimulating factor (GM-CSF) expressing oncolytic adenovirus (Ad5/3-D24-GMCSF) with a unique ability to both prime and boost immune responses. The aim of the study was to assess efficacy and safety of ONCOS-102 in combination with SOC chemotherapy in 1st and 2nd line unresectable MPM.MethodsTwenty patients (experimental arm) were allocated to receive ONCOS-102 given intratumorally under CT or US guidance at a dose of 3 x 1011 VP on Day 1, 4, 8, 36, 78 and 120 plus six cycles of SOC starting on Day 22. Eleven patients (control group) received SOC. Imaging was done at baseline, Day 43–64 and 127–148 with regular monitoring of blood and biopsy based immune markers. Primary objective was safety and tolerability. Secondary objectives were ORR, PFS and OS as well as immunological activation. An analysis of 24 month survival data compared randomised only patients excluding six patients in the single-arm safety lead-in.Results24-month survival rate for 1st line pts was 50% in the experimental group and 0% in the control group with mOS of 25.0 months and 13.5 months respectively (N.S). Based on censoring, mOS in the experimental group will be within 21.9 – 25.0 months range. mOS across both 1st and 2nd line was 19.3 and 18.3 months for experimental and control patients (N.S). mPFS was 9.8 months in the experimental group and 7.6 in the control group (N.S.).ConclusionsThe survival rate of patients receiving ONCOS-102 in combination with SOC was seen to be numerically higher than previously reported for SOC or nivolumab/ipilimumab. Improved survival was associated with ONCOS-102 induced immune activation with a favourable TME modulation providing scientific rationale for combination with check point inhibition.Trial RegistrationClinicalTrials.gov NCT02879669ReferencesVogelzang, et al, Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma. J Clin Oncol 2003;21: 2636–44.Baas P, et al, First-line nivolumab plus ipilimumab in unresectable pleural mesothelioma (CheckMate 743): a multicentre, randomised, open-label, phase 3 trial. The Lancet 2021; 397: 375–386.Ethics ApprovalThis study was approved by the IRBs of all the participating sites in Madrid, Barcelona, Rennes and Poitiers.

BackgroundT-cell redirecting bispecific antibodies (bsAbs) are therapeutics that recognize two distinct antigens: a tumor-associated antigen on tumor cells to promote recruitment of T-cells to the tumor, and a receptor on T-cells to potentiate anti-tumor activity. REGN7075 is a human immunoglobulin G4-based costimulatory bsAb designed to bridge epidermal growth factor receptor (EGFR) positive tumor cells with CD28 positive T-cells and to provide amplified T-cell receptor-CD3 complex-mediated T-cell activation within the tumor, through the activation of CD28 co-stimulation. In genetically humanized immunocompetent mouse models, REGN7075 in combination with anti–PD-1 (antibody directed against programmed cell death-1 receptor) improved anti-tumor activity compared with either single agent alone.1MethodsThis is an open label, Phase I/II, first-in-human study evaluating the safety, tolerability, pharmacokinetics, and preliminary anti-tumor activity of REGN7075 (EGFRxCD28) alone and in combination with cemiplimab in patients with advanced solid tumors (NCT04626635). Patients must have a protocol-defined advanced solid tumor, be ≥18 years of age (≥20 years in Japan), have an Eastern Cooperative Oncology Group performance status of 0 or 1, and be naïve to anti–PD-1/anti–PD-ligand(L)1.This study includes dose escalation (a 4+3 design modified from 3+3; Part 1) and expansion phases (Part 2). In Part 1, patients will receive a lead-in of REGN7075 monotherapy for 3 weeks followed by combination therapy with cemiplimab 350 mg every 3 weeks. Study therapies are administered until disease progression, intolerable adverse events, withdrawal of consent, or other stopping criterion is met. Once a recommended Phase 2 dose is determined in Part 1, four tumor-specific expansion cohorts will be opened: non-small cell lung cancer (PD-L1 ≥50%), triple-negative breast cancer, colorectal cancer (microsatellite stable), and cutaneous squamous cell carcinoma. Primary endpoints are safety and tolerability of REGN7075 alone or in combination with cemiplimab for Part 1, and objective response rate per Response Evaluation Criteria in Solid Tumors version 1.1 for Part 2. This study is currently open to enrollment.Trial RegistrationClinicalTrials.gov identifier NCT04626635.ReferencesWaite JC, Wang B, Haber L, et al. Tumor-targeted CD28 bispecific antibodies enhance the antitumor efficacy of PD-1 immunotherapy. Sci Transl Med 2020;12:2325.Ethics ApprovalThis study was conducted in accordance with the principles of the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice guidelines. The study protocol and all amendments were approved by the institutional review board/ethics committee at each participating study site.ConsentAll patients provided written informed consent.

Pulmonary arterial hypertension is an unmet clinical need. Imatinib, a tyrosine kinase inhibitor, 200 to 400 mg daily reduces pulmonary artery pressure and increases functional capacity in this patient group, but is generally poorly tolerated at the higher dose. We have designed an open-label, single-arm clinical study to investigate whether there is a tolerated dose of imatinib that can be better targeted to patients who will benefit. The study consists of two parts. Part 1 seeks to identify the best tolerated dose of Imatinib in the range from 100 and up to 400 mg using a Bayesian Continuous Reassessment Method. Part 2 will measure efficacy after 24 weeks treatment with the best tolerated dose using a Simon's two-stage design. The primary efficacy endpoint is a binary variable. For patients with a baseline pulmonary vascular resistance (PVR) >1000 dynes �� s �� cm-5, success is defined by an absolute reduction in PVR of ���300 dynes �� s �� cm-5 at 24 weeks. For patients with a baseline PVR ���1000 dynes �� s �� cm-5, success is a 30% reduction in PVR at 24 weeks. PVR will also be evaluated as a continuous variable by genotype as an exploratory analysis. Evaluating the response to that dose by genotype may inform a prospective biomarker-driven study.

There is a growing trend to combine a new targeted or immunotherapy agent with the cancer-specific standard of care to treat different types of cancers. We propose a master-protocol-based, Bayesian phase I/II platform design to co-develop combination (BPCC) therapies in multiple indications. Under the BPCC design, only a single master protocol is needed, and the combined drug is evaluated in different indications in a concurrent or staggered fashion. For each indication, we jointly model dose-toxicity and -efficacy relationships and employ Bayesian hierarchical models to borrow information across them for more efficient indication-specific decision-making. To account for the characteristic of targeted or immunotherapy agents that their efficacy may not monotonically increase with the dose, and often plateau at high doses, we use the utility to quantify the risk-benefit tradeoff of the treatment. At each interim, we update the toxicity and efficacy model, as well as the estimate of the utility, based on the observed data across indications to inform the indication-specific decision of dose escalation and de-escalation and identify the optimal biological dose for each indication. Simulation study shows that the BPCC design has desirable operating characteristics, and that it provides an efficient approach to accelerate the development of combination therapies.

A Bayesian biomarker-based phase I/II design (BIPSE) is presented for immunotherapy trials with a progression-free survival endpoint. The objective is to identify the subgroup-specific optimal dose, defined as the dose with the best risk-benefit tradeoff in each biomarker subgroup. We jointly model the immune response, toxicity outcome, and progression-free survival with information borrowing across subgroups. A plateau model is used to describe the marginal distribution of the immune response. Conditional on the immune response, we model toxicity using probit regression and model progression-free survival using the mixture cure rate model. During the trial, based on the accumulating data, we continuously update model estimates and adaptively randomize patients to doses with high desirability within each subgroup. Simulation studies show that the BIPSE design has desirable operating characteristics in selecting the subgroup-specific optimal doses and allocating patients to those optimal doses, and outperforms conventional designs.

Background: Desmoplasia is a central feature of the tumor microenvironment in pancreatic ductal adenocarcinoma (PDAC). LDE225 is a pharmacological Hedgehog signaling pathway inhibitor and is thought to specifically target tumor stroma. We investigated the combined use of LDE225 and chemotherapy to treat PDAC patients. Methods: This was a multi-center, phase I/II study for patients with metastatic PDAC establishing the maximum tolerated dose of LDE225 co-administered with gemcitabine and nab-paclitaxel (phase I) and evaluating the efficacy and safety of the treatment combination after prior FOLFIRINOX treatment (phase II). Tumor microenvironment assessment was performed with quantitative MRI using intra-voxel incoherent motion diffusion weighted MRI (IVIM-DWI) and dynamic contrast-enhanced (DCE) MRI. Results: The MTD of LDE225 was 200 mg once daily co-administered with gemcitabine 1000 mg/m2 and nab-paclitaxel 125 mg/m2. In phase II, six therapy-related grade 4 adverse events (AE) and three grade 5 were observed. In 24 patients, the target lesion response was evaluable. Three patients had partial response (13%), 14 patients showed stable disease (58%), and 7 patients had progressive disease (29%). Median overall survival (OS) was 6 months (IQR 3.9–8.1). Blood plasma fraction (DCE) and diffusion coefficient (IVIM-DWI) significantly increased during treatment. Baseline perfusion fraction could predict OS (&gt, 222 days) with 80% sensitivity and 85% specificity. Conclusion: LDE225 in combination with gemcitabine and nab-paclitaxel was well-tolerated in patients with metastatic PDAC and has promising efficacy after prior treatment with FOLFIRINOX. Quantitative MRI suggested that LDE225 causes increased tumor diffusion and works particularly well in patients with poor baseline tumor perfusion.

BackgroundType-1 diabetes (T1D) occurs following autoimmune-induced pancreatic beta cells death. Among several treatment modalities, Mesenchymal Stem Cells (MSCs) transplantation is promising for autoimmune disorders due to immunomodulation, regeneration, and migration to damaged tissue upon systemic injection. This study assessed the safety and efficacy of intravenous injection of autologous bone marrow-derived MSCs in newly diagnosed T1D patients. MethodsAfter receiving informed consent, 21 patients who met the study criteria were enrolled and randomly assigned to receive either MSCs or placebo. Each patient in the experimental group received two doses of MSCs and followed for at least one year post-transplantation. ResultsThe results have shown that this transplantation is safe and significantly reduces the number of hypoglycemic episodes. MSCs transplantation improved glycated hemoglobin (HbA1c), shifted serum cytokine patterns from pro-inflammatory to anti-inflammatory, increased the number of regulatory T-cells in the peripheral blood, and improved quality of life. Early transplantation of MSCs significantly improved HbA1c and C-peptide levels and shifted pro-inflammatory cytokines to anti-inflammatory cytokines. Also, exercise combined with MSCs transplantation improved glycemic and immunologic indices. ConclusionsIn conclusion, autologous MSC transplantation is safe and effective, and its early transplantation is a promising treatment in newly-diagnosed T1D children suffering from hypoglycemic episodes. Trial registrationThis clinical trial was registered at the Iranian Registry of Clinical Trials (IRCT) with the identifier IRCT ID: IRCT2016070428786N1 registered on August 20, 2016 (Retrospectively registered) (https://en.irct.ir/trial/23256) and at the U.S. National Institutes of Health (ClinicalTrials.gov) with the related identifier NCT04078308 registered on September 6, 2019 (Retrospectively registered). (https://clinicaltrials.gov/ct2/show/NCT04078308)

Purpose: Overexperssion of Gastrin-releasing-peptide receptor (GRPr) in prostate carcinoma (PCa) suggests new means in the detection of prostate cancer foci. The bombesin derivative RM2 (DOTA-4-amino-1-carboxy­methyl­piperidine-D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2) is a GRPr antagonist with strong binding affinity. Based on promising results from a first-in-man study on PCa detection in patients with local disease, a Phase I/II study was initiated and the ability of [68Ga]Ga-RM2 PET/CT to detect PCa lesions was compared with [18F]fluoromethylcholine ([18F]FCH) PET/CT and multiparameteric prostate Magnetic Resonance Imaging (mpMRI).Methods: This Phase I/II study was conductedwith a pre-specified interim analysis following the enrollment of 30 biopsy-positive PCa subjects, stratified into low, intermediate and high pretreatment risk of extra-glandular metastases with reference to NCCN criteria. Each subject had PCa detected by transrectal ultrasound guided prostate biopsy and subjects were scheduled to undergo prostatectomy with pelvic lymph node (LN) dissection in intermediate and high risk patients. Following administration of an intravenous dose of 140 MBq of [68Ga]Ga-RM2,imaging was conducted at 60 min. p.i.. Twenty-five (25/30) subjects had concomitant [18F]FCH PET/CT imaging. All patients underwent mpMRI. Intra-prostatic and pelvic nodal PET/CT findings were correlated with histopathologic results.Results: High uptake of [68Ga]Ga-RM2 was seen in pancreas and the urinary system with very low background uptake in the rest of the abdomen or thorax. Despite of high bladder activity, focal intraprostatic uptake was readily well detectable. Of overall 312 analyzed regions, 120 regions (4 to 8 lesions per-patient) showed abnormal finding in the prostate gland. In a region-based analysis overall sensitivity and specificity of [68Ga]Ga-RM2 PET/CT in the detection of primary tumor were 74% and 90%, respectively; while it was 60% and 80% for [18F]FCH PET/CT and 72% and 89% for mpMRI. Although, the overall sensitivity of [68Ga]Ga-RM2 PET/CT was higher comparing to [18F]FCH PET/CT and mpMRI; however, the statistical analysis showed only significant difference between [68Ga]Ga-RM2 PET/CT and [18F]FCH PET/CT in intermediate-risk group (P=0.01) and [68Ga]Ga-RM2 PET/CT and mpMRT in high-risk group (p=0.03). [68Ga]Ga-RM2 PET/CT correctly detected 2 histopathologically verified LN metastases in 2 high risk patients; while 18F-FCH PET/CT only identified the LN lesion in 1 patient.Conclusion: [68Ga]Ga-RM2 is a promising new PET-tracer with a high detection rate for intraprostatic PCa. While index lesion detection rates were similar in both PET/CT studies, the improved specificity of [68Ga]Ga-RM2 for canver versus BPH renders it notably better than [18F]FCH in the detection of intraprostatic lesions. In addition, GRP-R-based imaging seems to play a complementary role to Choline-based imaging for full characterization of PCa extent, biopsy guidance in low and intermediate metastatic risk PCa patients and has the potential to discriminate them from whom of those at higher risks.Trial Registeration number: EudraCT-Nr.: 2014-003027-21, Date: 10 June, 2014

Background and Aim Mesenchymal stem cells [MSCs] have anti-inflammatory and anti-fibrotic properties and could be a potential therapy for Crohn’s disease [CD] strictures. In this phase I–II pilot trial, we assessed safety and efficacy of local MSC injection to treat CD strictures. Methods CD patients with a short [less than 5 cm in length] non-passable stricture accessible by ileocolonoscopy were included. Allogenic bone-marrow derived MSCs were injected in the four quadrants of the stricture. Adverse events and clinical scores were evaluated at each follow-up visit and endoscopy and magnetic resonance enterography were performed at baseline, Week [W]12 and W48. The main judgement criterion for efficacy was the complete [defined by the ability to pass the ileocolonoscope] or partial [defined by a diameter increase] resolution of the stricture at W12. Second efficacy criteria included assessment of the stricture at W48 and evolution of clinical scores at W12 and W48. Results We performed 11 MSC injections in 10 CD patients [three primary and seven anastomotic strictures; one stricture injected twice]. MSC injections were well tolerated but four hospitalisations for occlusion were reported. At W12, five patients presented a complete or partial resolution of the stricture [two complete and three partial]. Seven patients were re-evaluated at W48 [one dilated, one operated, and one lost to follow-up] and four patients had a complete resolution. The evolution of clinical scores between W0, W12, and W48 was not statistically significant. Conclusions MSCs injection in CD stricture was well tolerated and may offer a benefit.

Treatment options for recurrent glioblastoma are limited and there is a need for novel effective therapies. We previously demonstrated encouraging anti-tumor activity with the targeted delivery of tumor necrosis factor a (TNF) in preclinical orthotopic glioma models. TNF- a is a potent pro-inflammatory cytokine which may trigger strong anti-tumor immunity. However, its systemic administration at therapeutically active doses is hampered by toxic side effects. L19TNF is a fully human antibody-cytokine fusion protein, comprising TNF- a fused to the antibody L19 that binds a tumor-specific epitope of the extracellular matrix protein fibronectin. This allows a targeted delivery of therapeutically relevant doses of TNF to the tumor site upon intravenous administration while sparing healthy tissues. In this phase I/II open label, non-randomized, monocentric study, we investigated the safety and preliminary activity of L19TNF for patients with isocitrate dehydrogenase (IDH) wildtype World Health Organization (WHO) grade III / IV glioma at first relapse. Twenty patients were enrolled from 2019-2020 and treated with intravenous infusions of L19TNF. In the phase I part of the study, 6 patients were assigned to two different dose levels of L19TNF and a dose of 13 µg/kg was established as the recommended dose. In the phase II part 14 patients were treated at the recommended dose. No dose-limiting toxicities were observed and survival follow-up is ongoing. In almost all patients, we observed treatment-associated emerging tumor necrosis. For patients that had re-surgery at progression on or after treatment with L19TNF, we demonstrated increased numbers of tumor-infiltrating lymphocytes compared to the tumor tissue obtained at primary diagnosis. Translational studies to better understand the effects of L19TNF on a molecular and immunophenotypic level are ongoing. ClinicalTrials.gov Identifier: NCT 03779230

BACKGROUND Recurrent glioblastoma (rGBM) has poor response rate and survival. Laser Interstitial Thermotherapy (LITT), a minimally invasive approach, improves survival but is not curative alone. Previous studies of LITT suggested the possibility of an abscopal effect. Indeed, GBM are known to harbor elevated levels of immunosuppressive cells such as Treg, M2 macrophages and MDSC both in the tumor microenvironment as well as in the systemic circulation. Checkpoint inhibition (CPI) immunotherapy has proven highly effective for some solid tumors. CPI in newly diagnosed GBM demonstrated safety in phase I trials (NRG BN-002). Further, preclinical studies targeting PD-1 with concurrent RT appears to be synergistic and improve survival. We hypothesized that LITT would block tumor-induced immunosuppression and introduce tumor neoantigens. However, there was no data regarding safety of pembrolizumab combined with LITT. We thus conducted a phase I/II study of LITT + pembrolizumab starting at three times relative to LITT. METHODS This is a three armed Phase I/II study based on timing of pembrolizumab (200 mg q 21 days) relative to LITT at 35d or 14d post-op, or 7d pre-op, with an expansion cohort phase II arm conducted at the earliest tolerated time of CPI administration. Adults with proven supratentorial rGBM with KPS >=70 and RESULTS Arm 1-2 of the phase I trial demonstrated no SAEs grade II or greater, but limited evidence of response. Arm 3 (neoadjuvant) pembrolizumab appears to be equally safe and has been expanded to phase II, demonstrating at least two CR among the first 3 patients (66.6%) with >= 9 month follow-up and patients remain clinically stable at 10 and 15 months post-op. CONCLUSIONS Neoadjuvant pembrolizumab combined with LITT for rGBM appears to be safe in this phase I trial, and demonstrates early evidence of response. The phase II trial is ongoing.

Standard of care for patients with glioblastoma (GBM) includes resection with concurrent temozolomide (TMZ) and radiotherapy, with inevitable disease recurrence. Upon recurrence, tumors are often resistant to first-line therapies and/or have infiltrated eloquent or deep brain regions, precluding repeat resection. There is currently no standard of care for recurrent GBM and patients succumb to their disease burden within 12- 15 months of their initial diagnosis of recurrence, exposing an unmet need to find novel therapies to treat recurrent disease. Bromodomain and extraterminal (BET) proteins are chromatin readers that affect transcription of genes. The oral BET inhibitor (BETi) OTX-015 has shown promise in a dose-escalation, phase I study in patients with acute leukemia and other BET inhibitors are currently in phase I studies for the treatment of primary brain tumors. We have recently shown that BET inhibition increases DNA damage and mitotic catastrophe in oncogenic cells by increasing transcription-replication conflicts and downregulating expression of key DNA damage checkpoint proteins, and have also shown its efficacy in decreasing tumor burden and improving survival when combined with TMZ in intracranial mouse models of glioma. We have also demonstrated that BETi's synergize with Olaparib by downregulating expression of the BRCA-driven DNA damage repair pathway and further leverages additive effects when triply combined with other DNA damaging agents such as Lomustine to decrease tumor burden and improve survival in patient-derived mouse models of GBM and medulloblastoma. We therefore hypothesize that the synergistic and additive effects of this triple combination seen in our preclinical studies will achieve therapeutic benefits in patients with recurrent GBM.

Background: Gilteritinib improves response rates and overall survival (OS) compared with chemotherapy in patients (pts) with relapsed/refractory (R/R) FLT3-mutated acute myeloid leukemia (AML). For older pts with newly diagnosed (ND) FLT3-mutated AML who are unfit for intensive chemotherapy, azacitidine plus venetoclax is the current standard of care, although remission durations are relatively short, largely due to FLT3-driven relapses. We therefore sought to evaluate the triplet regimen of azacitidine, venetoclax and gilteritinib for older pts with ND FLT3-mutated AML, as well as for those of all ages with R/R FLT3-mutated AML. Methods: In this phase I/II study, pts with either R/R FLT3-mutated AML or high-risk MDS/CMML or pts with ND FLT3-mutated AML who were unsuitable for intensive chemotherapy were eligible. FLT3-ITD and/or TKD mutations were allowed. Pts were required to have a performance status ≤3, total bilirubin ≤2.5 x ULN, ALT/AST ≤3 x ULN, and creatinine clearance ≥30 mL/min. In cycle 1, pts received azacitidine 75 mg/m 2 SC/IV on days 1-7, venetoclax on days 1-28, and gilteritinib on days 1-28. Gilteritinib dose ranged from 80mg to 120mg daily during the phase I dose escalation (3+3 design). Bone marrow was performed on day 14 and if blasts Results: Between 12/2019 and 7/2021, 26 pts were treated (11 ND pts and 15 R/R pts). Baseline characteristics are shown in Table 1. The median age for the ND and R/R cohorts were 71 years (range, 61-79) and 68 years (range, 19-90), respectively. In the ND cohort, 9 (82%) had a FLT3-ITD and 2 (18%) had a FLT3 TKD mutation; in the R/R cohort, 7 (47%) had a FLT3-ITD, 5 (33%) had a FLT3-TKD, and 3 (20%) had both mutations. Among pts in the R/R cohort, the median number of prior therapies was 2 (range, 1-5), 6 (40%) had poor risk cytogenetics, 5 (33%) had undergone prior hematopoietic stem cell transplant (HSCT), and 5 (33%) had received prior FLT3 inhibitor (including 1 pt who had received prior gilteritinib). Ten R/R pts were treated in the phase I cohort (6 at 80mg of gilteritinib and 4 at 120mg). No DLTs were observed at the 80mg daily dosing. Among 3 pts in the 120mg cohort who were evaluable for DLTs, 1 achieved MLFS but had prolonged grade 4 myelosuppression that met DLT criteria. Due to good clinical activity and superior count recovery observed with the 80mg dosing (with 3 of 6 pts [50%] in the phase I cohort achieving CR/CRp), the 80mg daily dose was chosen as the phase II dose for further study. In the entire R/R cohort, the median number of cycles received was 2 (range, 1-4). The overall response rate (CR+CRi+MLFS) was 67%. One pt (7%) achieved CR as best response, 3 (20%) achieved CRi, and 6 (40%) achieved MLFS. An additional pt with extramedullary-only disease achieved PR. Four pts (27% of the entire R/R cohort, 44% of responding pts) proceeded to HSCT. Among the 10 responding pts, 4 have relapsed (1 of whom was FLT3 negative), 2 died in morphologic remission, and 4 are still alive without relapse. The 30-day and 60-day mortality rates were 0% and 13%, respectively. With a median follow-up of 9.9 months in the R/R cohort, the median duration of response was 9.0 months and the median OS was 10.5 months (Figure 1A). In the ND cohort, the median number of cycles received was 2 (range, 1-6). All pts responded and all achieved marrow remission by day 14. Eight pts (73%) achieved CR as best response, 1 (9%) achieved CRi, and 2 (18%) achieved MLFS; the 3 pts with CRi/MLFS are still recovering from cycle 1 at the time of this report. Two pts (18%) proceeded to HSCT. With a median follow-up of 3.8 months (range, 0.5-8.7 months), no pts have relapsed and 1 pt died (Figure 1B). This pt achieved MRD-negative CR and died 9 weeks into therapy due to sepsis. Conclusions: The combination of azacitidine, venetoclax and gilteritinib was effective in pts with FLT3-mutated AML. Gilteritinib dosing at 80mg daily was associated with a better safety/efficacy profile and was selected for future study; however, even with this lower dose myelosuppression was common and required attenuation of azacitidine and venetoclax. This combination appears particularly encouraging in the frontline setting where the response rate was 100% with no relapses observed to date. Figure 1 Figure 1. Disclosures Short: Astellas: Research Funding; AstraZeneca: Consultancy; Novartis: Honoraria; Jazz Pharmaceuticals: Consultancy; NGMBio: Consultancy; Takeda Oncology: Consultancy, Research Funding; Amgen: Consultancy, Honoraria. DiNardo: Celgene, a Bristol Myers Squibb company: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Forma: Honoraria, Research Funding; AbbVie: Consultancy, Research Funding; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Foghorn: Honoraria, Research Funding; Notable Labs: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; ImmuneOnc: Honoraria, Research Funding; Agios/Servier: Consultancy, Honoraria, Research Funding; Takeda: Honoraria; Novartis: Honoraria. Daver: Amgen: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; FATE Therapeutics: Research Funding; Hanmi: Research Funding; Genentech: Consultancy, Research Funding; Trovagene: Consultancy, Research Funding; Glycomimetics: Research Funding; Sevier: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Novimmune: Research Funding; Abbvie: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Gilead Sciences, Inc.: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Trillium: Consultancy, Research Funding; ImmunoGen: Consultancy, Research Funding; Novartis: Consultancy; Jazz Pharmaceuticals: Consultancy, Other: Data Monitoring Committee member; Dava Oncology (Arog): Consultancy; Celgene: Consultancy; Syndax: Consultancy; Shattuck Labs: Consultancy; Agios: Consultancy; Kite Pharmaceuticals: Consultancy; SOBI: Consultancy; STAR Therapeutics: Consultancy; Karyopharm: Research Funding; Newave: Research Funding. Yilmaz: Daiichi-Sankyo: Research Funding; Pfizer: Research Funding. Kadia: Genfleet: Other; Astellas: Other; AstraZeneca: Other; Cellonkos: Other; Sanofi-Aventis: Consultancy; Pulmotech: Other; Pfizer: Consultancy, Other; Liberum: Consultancy; BMS: Other: Grant/research support; Jazz: Consultancy; Genentech: Consultancy, Other: Grant/research support; Cure: Speakers Bureau; Ascentage: Other; Novartis: Consultancy; AbbVie: Consultancy, Other: Grant/research support; Aglos: Consultancy; Dalichi Sankyo: Consultancy; Amgen: Other: Grant/research support. Issa: Novartis: Consultancy, Research Funding; Syndax Pharmaceuticals: Research Funding; Kura Oncology: Consultancy, Research Funding. Sasaki: Novartis: Consultancy, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees. Borthakur: Takeda: Membership on an entity's Board of Directors or advisory committees; ArgenX: Membership on an entity's Board of Directors or advisory committees; Ryvu: Research Funding; Astex: Research Funding; University of Texas MD Anderson Cancer Center: Current Employment; Protagonist: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy. Jabbour: Amgen, AbbVie, Spectrum, BMS, Takeda, Pfizer, Adaptive, Genentech: Research Funding. Konopleva: F. Hoffmann-La Roche: Consultancy, Honoraria, Other: grant support; Forty Seven: Other: grant support, Research Funding; Calithera: Other: grant support, Research Funding; Genentech: Consultancy, Honoraria, Other: grant support, Research Funding; Reata Pharmaceuticals: Current holder of stock options in a privately-held company, Patents & Royalties: intellectual property rights; Novartis: Other: research funding pending, Patents & Royalties: intellectual property rights; Rafael Pharmaceuticals: Other: grant support, Research Funding; AstraZeneca: Other: grant support, Research Funding; Stemline Therapeutics: Research Funding; Eli Lilly: Patents & Royalties: intellectual property rights, Research Funding; KisoJi: Research Funding; Sanofi: Other: grant support, Research Funding; AbbVie: Consultancy, Honoraria, Other: Grant Support, Research Funding; Agios: Other: grant support, Research Funding; Ascentage: Other: grant support, Research Funding; Ablynx: Other: grant support, Research Funding; Cellectis: Other: grant support. Kantarjian: Ipsen Pharmaceuticals: Honoraria; NOVA Research: Honoraria; Amgen: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Ascentage: Research Funding; BMS: Research Funding; Daiichi-Sankyo: Research Funding; Immunogen: Research Funding; Jazz: Research Funding; Pfizer: Honoraria, Research Funding; KAHR Medical Ltd: Honoraria; Astra Zeneca: Honoraria; Astellas Health: Honoraria; Novartis: Honoraria, Research Funding; Aptitude Health: Honoraria; Precision Biosciences: Honoraria; Taiho Pharmaceutical Canada: Honoraria. Ravandi: Agios: Honoraria, Research Funding; Astex: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Prelude: Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Honoraria; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Xencor: Honoraria, Research Funding; Taiho: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Novartis: Honoraria; Syros Pharmaceuticals: Consultancy, Honoraria, Research Funding. OffLabel Disclosure: Gilteritinib for frontline treatment of FLT3-mutated AML

Introduction: FMS-like tyrosine kinase 3 (FLT3) mutations occur in about 1% of patients with newly diagnosed myelodysplastic syndrome (MDS) and up to 19% at time of failure of hypomethylating agent (HMA). In addition, Casitas B-lineage Lymphoma mutations (CBL) are observed in 10% of patients with MDS/MPN and up to 13-15% of patients with CMML (mainly proliferative type). Preclinical studies suggest that CBL-mutant cells are dependent on FLT3 signaling. Specific targeting of FLT3 and CBL mutations in MDS and MDS/MPN has not been thoroughly evaluated. Methods: We designed a phase I/II clinical trial of Azacitidine in Combination with quizartinib for newly diagnosed patients with MDS and MDS/MPN with detectable FLT3 mutation and/or CBL exon 8 or 9 deletions or point mutations Mutation on patients that are HMA naïve or had prior treatment with HMA. The study included phase I dose escalation portion, following 3+3 design, followed by phase II dose expansion portion. Dose escalation included 3 dose levels of quizartinib on days 1-28 of every cycle: 30, 40 and 60 mg in the addition to azacitidine (75 mg/m 2/day) on days 1-5 each 28-day cycle. The phase II/expansion phase will include two cohorts, Cohort A hypomethylating agent naïve patients and cohort B patients with prior hypomethylating agent. The primary objective of this study is to determine the safety, tolerability and maximum tolerable dose (MTD) of quizartinib. Secondary objectives include evaluation of overall response per IWG 2006 criteria, in addition to overall survival (OS), duration of response, leukemia-free survival (LFS), relapse-free survival (RFS). Results: At the end date of July 30 th 2021, a total of 6 patients have been enrolled: 4 patients with CMML, one with MDS excess blast and one with atypical Chronic myeloid leukemia (aCML). A total of 5 patients (83%) had normal karyotype and one patient (17%) had complex karyotype. Four patients were enrolled due to FLT3 mutations and 2 due to CBL mutations. Patients characteristics are summarized in Figure 1a. Median number of cycles administered was 3.5 (range 1-6). All patients have achieved response so far with a total of 5 patients (67%) having achieved marrow CR (mCR) including HI in 1 patient, 1 patient had hematologic improvement-erythropoietic (HI-E) with control of leukocytosis and thrombocytosis to normal levels. Response dynamics and clonal changes through the course of therapy are shown in Figure 1b. Reduction of clearance of FLT3-ITD or other FLT3 mutations was observed in all evaluable FLT3-mutant patients with no significant changes in CBL mutant variant allele frequencies observed thus far. With a median follow up of 3.1 months (range 1-12 months), the median response duration is 2.1 months (range 0.5-6.3 months) and the median OS has not been reached with all patients alive at the time of evaluation. A total of 3 patients (50%) have stopped the treatment: 1 patient due to disease relapse, 1 due to progression and the other to proceed to allogenic stem cell transplantation after achieving response to therapy. No dose limiting toxicities (DLT) have been observed to date up to the maximum dose of 40 mg of quizartinib. One patient required dose reductions due to cytopenias with the rest of the patients having recovery of counts to pre-treatment levels. Regarding the grade 3 or more adverse events (AEs): Two patients (33%) had skin infection, one patient (17%) had cardiac arrythmia with Mobitz II AV block and one patient (17%) had lumbar epidural lesion most likely of infectious origin. Conclusion: Preliminary data suggest azacitidine in combination with quizartinib for patients with MDS and MDS/MPN with FLT3 or CBL mutations have acceptable toxicity profile and associated with promising responses. Further follow up with a larger patient cohort are required to emphasize the safety and efficacy of this combination and evaluate depth and duration of response. Figure 1 Figure 1. Disclosures Jabbour: Amgen, AbbVie, Spectrum, BMS, Takeda, Pfizer, Adaptive, Genentech: Research Funding. Short: Astellas: Research Funding; Jazz Pharmaceuticals: Consultancy; NGMBio: Consultancy; Novartis: Honoraria; AstraZeneca: Consultancy; Takeda Oncology: Consultancy, Research Funding; Amgen: Consultancy, Honoraria. Konopleva: Ablynx: Other: grant support, Research Funding; Ascentage: Other: grant support, Research Funding; Agios: Other: grant support, Research Funding; AstraZeneca: Other: grant support, Research Funding; Eli Lilly: Patents & Royalties: intellectual property rights, Research Funding; KisoJi: Research Funding; Cellectis: Other: grant support; Genentech: Consultancy, Honoraria, Other: grant support, Research Funding; Sanofi: Other: grant support, Research Funding; Forty Seven: Other: grant support, Research Funding; F. Hoffmann-La Roche: Consultancy, Honoraria, Other: grant support; Reata Pharmaceuticals: Current holder of stock options in a privately-held company, Patents & Royalties: intellectual property rights; Novartis: Other: research funding pending, Patents & Royalties: intellectual property rights; Stemline Therapeutics: Research Funding; AbbVie: Consultancy, Honoraria, Other: Grant Support, Research Funding; Calithera: Other: grant support, Research Funding; Rafael Pharmaceuticals: Other: grant support, Research Funding. Daver: Amgen: Consultancy, Research Funding; Novimmune: Research Funding; Hanmi: Research Funding; Astellas: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Trovagene: Consultancy, Research Funding; Glycomimetics: Research Funding; FATE Therapeutics: Research Funding; Novartis: Consultancy; Trillium: Consultancy, Research Funding; ImmunoGen: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Sevier: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Gilead Sciences, Inc.: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Other: Data Monitoring Committee member; Dava Oncology (Arog): Consultancy; Celgene: Consultancy; Syndax: Consultancy; Shattuck Labs: Consultancy; Agios: Consultancy; Kite Pharmaceuticals: Consultancy; SOBI: Consultancy; STAR Therapeutics: Consultancy; Karyopharm: Research Funding; Newave: Research Funding. Kantarjian: Aptitude Health: Honoraria; Jazz: Research Funding; KAHR Medical Ltd: Honoraria; Pfizer: Honoraria, Research Funding; Ipsen Pharmaceuticals: Honoraria; Novartis: Honoraria, Research Funding; NOVA Research: Honoraria; Precision Biosciences: Honoraria; Astra Zeneca: Honoraria; Astellas Health: Honoraria; Immunogen: Research Funding; Daiichi-Sankyo: Research Funding; BMS: Research Funding; Ascentage: Research Funding; Amgen: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Taiho Pharmaceutical Canada: Honoraria.

Introduction: In spite of frontline response rates of 65-70% with AZA-VEN a majority of pts relapse, with only 35-40% alive at 3+ years. Outcomes in R/R AML are poor with median overall survival (mOS) 5 - 7months (m). Magro, an anti-CD47 antibody that blocks the "don't eat me signal" on macrophages, demonstrated efficacy with AZA in ND TP53wt (ORR: 63%, mOS 18.9m) and TP53mut AML (ORR 69%, mOS 12.9m). Combined blockade of CD47-SIRPa axis by Magro with AZA-VEN increased phagocytosis in AML cell lines in vitro regardless of TP53 mut status, and prolonged survival in vivo in both AZA-VEN sensitive and refractory AML PDXs (Jia Y et al, ASH 2021). We designed a phase Ib/II trial to evaluate this triplet (NCT04435691). Methods: Pts ≥18 years with ECOG PS ≤2 and WBC Pts received AZA 75 mg/m 2 on D1-7, VEN 400 mg (or equivalent per VEN label) on D1-28. Magro was dosed on cycle 1 D1, 4, 8, 11, 15, 22; weekly in cycle 2, and every 2 weeks in cycle 3+ (Fig. 1). At the end of the phase Ib (n=6 pts) no DLTs were noted and the Magro RP2D dose was established as 1 mg/kg on C1D1 and C1D4, 15 mg/kg on C1D8, and 30 mg/kg on C1D11 and subsequent doses. Primary objective were safety, maximum tolerated dose (MTD), and RP2D of the triplet. Secondary objectives included CR/CRi rate, DOR and OS. Responses were per ELN2017. Results: Between Aug 2020 and July 1 2021 38 pts with newly diagnosed (ND) (n=17), R/R VEN-naïve (n=8), and R/R-post-VEN failure (n=13) were enrolled. An additional 6 ND pts were enrolled after July 1. Pt characteristics are in Table 1. In the ND pts the median (med) age was 70 yrs (range 33 - 84). Most pts had high-risk features: 14 (82%) pts ELN adverse risk, 45% ECOG PS≥2, and 8 (47%) were TP53m (VAF med 32%, range 5 - 94%). Pts were evaluated for response and toxicity per intent to treat. 1 pt was still in cycle 1 and too early. The CR/CRi rate in the remaining ND pts was 94% (15/16) with a CR rate of 81% (Table 2). The 8-week mortality was 0. All pts achieved response after cycle 1. The med time to ANC recovery >0.5 and platelet recovery >50 among the CR/CRi pts was 28 (range 20 - 41) days and 24 (range 18- 41) days, respectively. Complete cytogenetic CR was achieved in 9 of 12 (75%) evaluable and MRD negativity by MFC In R/R prior VEN-naïve AML the CR/CRi rate was 63% (5/8) with med OS not reached (range 1.2-9.7). In R/R prior VEN failure AML the CR/CRi rate was 27% (3/13) with med OS 3.1 (range 0.9-6.5; Table 2). Among all 38 pts the 4 wk and 8 wk mortality were 0 and 9.7% (n=4): these 4 deaths occurred in R/R pts. Frequent treatment-emergent non-hematologic adverse events regardless of attribution, of all grades included hypokalemia (58%), hypophosphatemia (55%), hyperbilirubinemia (53%), hyponatremia (53%) and sinus tachycardia (47%), and of Grade 3/4 included pneumonia (32%), febrile neutropenia (32%), hyperbilirubinemia (11%), elevated ALT (11), and skin infection (11%). Among 17 ND AML the med hemoglobin drop after magro 1 st dose was 1.1 g/dL (0.0 - 3.9) and after 2 nd dose was 0.8 g/dL (0.0 - 2.0). With close monitoring anemia was manageable with no SAEs, treatment interruptions or discontinuations due to anemia. 5 pts, all ND AML, have transitioned to allo-SCT and are alive. Conclusion: The combination of AZA VEN Magro was safe. High CR/CRi (94%) rates and CR rates (81%) were noted in ND pts, with majority (82%) ELN adverse risk. ANC and platelet recovery were robust ( Figure 1 Figure 1. Disclosures Daver: Sevier: Consultancy, Research Funding; FATE Therapeutics: Research Funding; Astellas: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; ImmunoGen: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Hanmi: Research Funding; Gilead Sciences, Inc.: Consultancy, Research Funding; Trillium: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Trovagene: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Glycomimetics: Research Funding; Novartis: Consultancy; Novimmune: Research Funding; Jazz Pharmaceuticals: Consultancy, Other: Data Monitoring Committee member; Dava Oncology (Arog): Consultancy; Celgene: Consultancy; Syndax: Consultancy; Shattuck Labs: Consultancy; Agios: Consultancy; Kite Pharmaceuticals: Consultancy; SOBI: Consultancy; STAR Therapeutics: Consultancy; Karyopharm: Research Funding; Newave: Research Funding. Konopleva: KisoJi: Research Funding; Calithera: Other: grant support, Research Funding; Stemline Therapeutics: Research Funding; Ablynx: Other: grant support, Research Funding; Agios: Other: grant support, Research Funding; Ascentage: Other: grant support, Research Funding; Rafael Pharmaceuticals: Other: grant support, Research Funding; F. Hoffmann-La Roche: Consultancy, Honoraria, Other: grant support; Sanofi: Other: grant support, Research Funding; Reata Pharmaceuticals: Current holder of stock options in a privately-held company, Patents & Royalties: intellectual property rights; Eli Lilly: Patents & Royalties: intellectual property rights, Research Funding; AbbVie: Consultancy, Honoraria, Other: Grant Support, Research Funding; Genentech: Consultancy, Honoraria, Other: grant support, Research Funding; Novartis: Other: research funding pending, Patents & Royalties: intellectual property rights; AstraZeneca: Other: grant support, Research Funding; Cellectis: Other: grant support; Forty Seven: Other: grant support, Research Funding. Kadia: Amgen: Other: Grant/research support; Pfizer: Consultancy, Other; Novartis: Consultancy; Liberum: Consultancy; Astellas: Other; Sanofi-Aventis: Consultancy; Pulmotech: Other; Jazz: Consultancy; Genentech: Consultancy, Other: Grant/research support; BMS: Other: Grant/research support; Cure: Speakers Bureau; AstraZeneca: Other; AbbVie: Consultancy, Other: Grant/research support; Dalichi Sankyo: Consultancy; Cellonkos: Other; Genfleet: Other; Ascentage: Other; Aglos: Consultancy. DiNardo: Novartis: Honoraria; AbbVie: Consultancy, Research Funding; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria, Research Funding; Agios/Servier: Consultancy, Honoraria, Research Funding; Takeda: Honoraria; Notable Labs: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; ImmuneOnc: Honoraria, Research Funding; Forma: Honoraria, Research Funding; Foghorn: Honoraria, Research Funding; Celgene, a Bristol Myers Squibb company: Honoraria, Research Funding. Loghavi: Abbvie: Current equity holder in publicly-traded company; Curio Sciences: Honoraria; Gerson Lehrman Group: Consultancy; Guidepoint: Consultancy; Peerview: Honoraria; Qualworld: Consultancy. Pemmaraju: Springer Science + Business Media: Other; Daiichi Sankyo, Inc.: Other, Research Funding; Affymetrix: Consultancy, Research Funding; Samus: Other, Research Funding; Dan's House of Hope: Membership on an entity's Board of Directors or advisory committees; Roche Diagnostics: Consultancy; Celgene Corporation: Consultancy; Cellectis S.A. ADR: Other, Research Funding; Novartis Pharmaceuticals: Consultancy, Other: Research Support, Research Funding; MustangBio: Consultancy, Other; Sager Strong Foundation: Other; Plexxicon: Other, Research Funding; Clearview Healthcare Partners: Consultancy; Protagonist Therapeutics, Inc.: Consultancy; DAVA Oncology: Consultancy; Abbvie Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; CareDx, Inc.: Consultancy; ASCO Leukemia Advisory Panel: Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy; LFB Biotechnologies: Consultancy; Blueprint Medicines: Consultancy; Stemline Therapeutics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Aptitude Health: Consultancy; ASH Communications Committee: Membership on an entity's Board of Directors or advisory committees; HemOnc Times/Oncology Times: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb Co.: Consultancy; ImmunoGen, Inc: Consultancy; Pacylex Pharmaceuticals: Consultancy. Jabbour: Amgen, AbbVie, Spectrum, BMS, Takeda, Pfizer, Adaptive, Genentech: Research Funding. Sasaki: Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees. Borthakur: University of Texas MD Anderson Cancer Center: Current Employment; GSK: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astex: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; ArgenX: Membership on an entity's Board of Directors or advisory committees; Protagonist: Consultancy; Ryvu: Research Funding. Yilmaz: Daiichi-Sankyo: Research Funding; Pfizer: Research Funding. Ravandi: Syros Pharmaceuticals: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Taiho: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Xencor: Honoraria, Research Funding; Novartis: Honoraria; AbbVie: Honoraria, Research Funding; Prelude: Research Funding; Agios: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; AstraZeneca: Honoraria; Astex: Honoraria, Research Funding. Kantarjian: Pfizer: Honoraria, Research Funding; Astellas Health: Honoraria; Astra Zeneca: Honoraria; Aptitude Health: Honoraria; Amgen: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Jazz: Research Funding; Immunogen: Research Funding; Daiichi-Sankyo: Research Funding; BMS: Research Funding; Ascentage: Research Funding; Ipsen Pharmaceuticals: Honoraria; KAHR Medical Ltd: Honoraria; NOVA Research: Honoraria; Precision Biosciences: Honoraria; Taiho Pharmaceutical Canada: Honoraria. OffLabel Disclosure: Venetoclax used in salvage setting. Magrolimab is not yet licensed for use in any indication.

KC and ML are co-first authors. Background: Follicular lymphoma (FL) is the most common indolent B-cell lymphoma and has a relapsing and remitting course with risk of transformation to aggressive disease. Long-term toxicity can accumulate with repeated exposure to palliative cytotoxic chemotherapy. Rationally targeted agents have demonstrated disease control with limited toxicity in hematologic malignancies, representing a potential chemotherapy-sparing option. BCL2 rearrangements leading to overexpression are nearly universal in FL, but BCL2 inhibition monotherapy has disappointing efficacy in FL. Potential reasons include known resistance mechanisms, such as MCL-1 overexpression, or redundant survival pathways. Founder mutations in FL often involve epigenetic regulation, and BCL2 rearrangements are necessary but not sufficient for FL lymphomagenesis. In patients with FL, abnormal DNA methylation programming cooperates with somatic mutations to drive lymphomagenesis. The resulting epigenetic deregulation may be targetable by hypomethylating agents, including azacitadine (AZA). There are no published studies of venetoclax and AZA in preclinical models of FL, but there are extensive preclinical data in acute myeloid leukemia. AZA is an epigenetic modulator with synergistic anti-leukemic effect when paired with venetoclax. Treatment with AZA results in MCL-1 downregulation, which may abrogate FL resistance to BCL2 inhibition. AZA also induces re-expression of CD20 and re-sensitizes FL patients to anti-CD20 therapy. In lymphoma xenograft models, the combination of obinutuzumab and venetoclax causes more tumor growth inhibition compared to rituximab with venetoclax, possibly from more potent direct cytotoxicity. These preclinical studies suggest that epigenetic modulation of FL cells with AZA may increase the sensitivity to BCL2 inhibition and anti-CD20 therapy. The foundational position of epigenetic dysregulation in the clonal evolution of FL suggests the optimal time for this strategy may be early in the course of the disease. We hypothesize that a safe and tolerable dose of venetoclax, CC-486 (oral AZA), and obinutuzumab can be found with treatment efficacy equal to or better than other non-chemotherapy agents in the frontline treatment of FL. We present a dose-finding and efficacy trial of venetoclax, CC-486, and obinutuzumab in minimally pre-treated FL patients. Study Design: This is a single arm, multi-center phase I/II clinical trial (Figure 1). The dose finding phase is a 3+3 design with 3 escalating dose levels and two optional de-escalation levels (12-18 patients). Venetoclax (400-800mg) will be given days 1-28 of each 28 day cycle; CC-486 (150-200mg) will be given days 1-14; and obinutuzumab will be given at a fixed dose of 1000mg on days 1, 8, and 15 of cycle 1 and then day 1 of each subsequent cycle. Venetoclax and CC-486 will be given up to 12 cycles and obinutuzumab for a total of 9 cycles. Once the recommended phase 2 dose (RP2D) is identified, the study will proceed to a Simon two-stage expansion cohort. In this cohort, a three month "window" of the doublet venetoclax and CC-486 prior to introduction of obinutuzumab at cycle 4 will allow an assessment of activity of the two-drug combination. Obinutuzumab is given on days 1, 8, and 15 of cycle 4, and day 1 of each subsequent cycle. Key inclusion criteria are: age ≥ 18, ECOG ≤2; adequate kidney/liver function; and grade 1-3a FL with an indication for treatment who are either untreated or have ≤2 courses (16 doses) of lifetime anti-CD20 therapy. Patients with clinical or histologic evidence of FL transformation are excluded. Up to 32 patients will be enrolled to test the null hypothesis of a 30% CR rate against a 50% alternative (80% power, one-sided alpha=0.10). The primary objectives are the RP2D and safety based on adverse events for the dose-finding cohort, and the CR rate by PET in the expansion cohort. Secondary objectives include progression free survival, overall survival, effect of 3 cycles of venetoclax/CC-486 in the window design of the expansion cohort, and CR rate at 30 months post-treatment with PET. Exploratory objectives include pre-treatment mutation biomarkers, minimal residual disease by circulating tumor DNA, and circulating cell-free DNA methylation patterns. This trial design was reviewed and revised at ASH CRTI. Recruitment is ongoing and this trial is registered with ClinicalTrials.gov: NCT04722601. Figure 1 Figure 1. Disclosures Kline: Kite/Gilead: Speakers Bureau; Seagen: Membership on an entity's Board of Directors or advisory committees; Regeneron: Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Research Funding; Verastem: Research Funding; SecuraBio: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Morphosys: Consultancy, Membership on an entity's Board of Directors or advisory committees. Smith: Celgene, Genetech, AbbVie: Consultancy; Alexion, AstraZeneca Rare Disease: Other: Study investigator.

Background: Cytokine release syndrome (CRS) is a potentially serious complication of T-cell engaging immunotherapy. Effective measures are needed to reduce the rate and severity. In a multicenter Phase I/II study (NCT02500407), the CD20xCD3 bispecific antibody mosunetuzumab (Mosun) showed durable complete responses (CR) and had manageable safety in patients (pts) with late-line R/R B-NHL (Schuster et al. ASH 2019). IV administration with Cycle (C) 1 step-up dosing was an effective strategy for mitigating CRS during C1 (Bartlett et al. ASCO 2019). Fixed-dose SC administration was also a viable strategy for CRS mitigation, owing to the slower rate of Mosun absorption compared with IV (Matasar et al. ASH 2020). A combination of both strategies could further improve the CRS profile. We present safety and efficacy data from the initial cohorts investigating SC Mosun administration with C1 step-up dosing in the Phase I/II study. Methods: All pts had R/R B-NHL with ≥1 prior line of systemic therapy and ECOG PS ≤1. SC Mosun was given in 21-day cycles using two step-up dosing schedules (C1 day [D]1/C1D8/C1D15 and D1 of subsequent cycles: 5/15/45mg or 5/45/45mg). Mosun was discontinued after C8 in pts who achieved a CR, while pts with a partial response or stable disease continued Mosun for a total of 17 cycles, unless progressive disease or unacceptable toxicity occurred. Primary objectives included evaluation of safety, tolerability, and pharmacokinetics (PK). Responses were evaluated by investigator-assessment of PET/CT scans using Cheson 2007 criteria. CRS is reported using ASTCT criteria (Lee et al. Biol Blood Marrow Transplant 2019). Results: As of June 21, 2021, 74 pts had been enrolled (5/15/45mg: 38 pts; 5/45/45mg: 36 pts). Median age was 67.0 years (range: 41-88). The most common NHL subtypes were DLBCL (31 pts), FL (21), transformed (tr) FL (10), and MCL (3). 70.0% of pts had Ann Arbor stage III or IV disease. Median number of prior lines of therapy was 3 (range: 1-9). 79.5% of pts were refractory to prior anti-CD20 therapy and 82.4% were refractory to their last prior therapy. Median follow-up for safety was 2.5 months (range: 0.2-7.2). No dose-limiting toxicities were observed during dose-escalation. Common all-Grade (Gr) adverse events (AEs; ≥10% of pts) were injection site reaction (52.7%; Gr 1: 47.3%; Gr 2: 5.4%), CRS (24.3%), fatigue (21.6%), headache (17.6%), rash (13.5%), and pyrexia (10.8%). CRS mostly occurred in C1 and was low Gr in all pts (Gr 1: 17.6%; Gr 2: 6.8%); no Gr ≥3 CRS occurred. Gr 2 CRS occurred with a similar frequency in the 5/15/45mg and 5/45/45mg cohorts (7.9% vs 5.6% of pts, respectively). In the 5/15/45mg cohort, the 3 Gr 2 CRS events occurred after each of the C1 doses, while in the 5/45/45mg cohort, the 2 Gr 2 CRS events occurred after the first 45mg dose. Median duration of CRS was 2 days (range: 1-6) and all events resolved without sequelae. Neutropenia occurred in 12.2% of pts (Gr 2: 2.7%; Gr 3: 6.8%; Gr 4: 2.7%). Febrile neutropenia occurred in only 1 pt (Gr 3). Serious infections occurred in 3 pts (2 pneumonia, both resolved; 1 COVID-19, fatal outcome). No Mosun-related Gr 5 (fatal) AEs or Mosun-related AEs leading to Mosun discontinuation occurred. The PK profile of SC Mosun was consistent with that previously reported, with high bioavailability (>85%), a slow absorption rate, and a blunted C max. IL-6 and IFN-y kinetics in plasma were similar in both SC cohorts, with modest and delayed increases observed after the initial dose, contrasting with the more marked and rapid increases observed with IV dosing, and consistent with the low frequency and severity of CRS observed. At data cut-off, 38 pts were efficacy evaluable. Responses were observed in 19 pts across all histologies, including 8/10 (80%) pts with R/R FL and 6/17 (35.3%) pts with R/R DLBCL/trFL. Conclusions: SC Mosun administration with C1 step-up dosing has a favorable safety profile in pts with late-line and highly refractory B-NHL, enabling an outpatient treatment schedule without mandatory hospitalizations. Encouragingly, the 5/45/45mg schedule had a low rate of CRS that was similar to the 5/15/45mg schedule, allowing the target dose to be reached earlier. Early response data suggest that the efficacy of Mosun is not compromised by SC dosing. Compared with IV, SC Mosun is likely to improve convenience for pts and efficiency for healthcare providers. Updated efficacy data with longer follow up and depth of response will be presented. Disclosures Bartlett: Affimed: Research Funding; Autolus: Research Funding; Bristol-Myers Squibb: Research Funding; Celgene: Research Funding; Forty Seven: Research Funding; Janssen: Research Funding; Kite Pharma: Research Funding; Merck: Research Funding; Millennium: Research Funding; Pharmacyclics: Research Funding; Genentech, Inc./F. Hoffmann-La Roche Ltd: Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Washington University School of Medicine: Current Employment. Giri: Royal Adelaide Hospital: Current Employment. Budde: Genentech, Inc.: Consultancy; Merck, Inc: Research Funding; Amgen: Research Funding; AstraZeneca: Research Funding; Mustang Bio: Research Funding; Novartis: Consultancy; Gilead: Consultancy; Roche: Consultancy; Beigene: Consultancy. Schuster: Celgene: Consultancy, Honoraria, Research Funding; Nordic Nanovector: Consultancy; Novartis: Consultancy, Honoraria, Patents & Royalties, Research Funding; Abbvie: Consultancy, Research Funding; Acerta Pharma/AstraZeneca: Consultancy; Alimera Sciences: Consultancy; BeiGene: Consultancy; Juno Theraputics: Consultancy, Research Funding; Loxo Oncology: Consultancy; Tessa Theraputics: Consultancy; Genentech/Roche: Consultancy, Research Funding; Pharmaclyclics: Research Funding; Adaptive Biotechnologies: Research Funding; Merck: Research Funding; Incyte: Research Funding; TG Theraputics: Research Funding; DTRM: Research Funding. Assouline: Johnson&Johnson: Current equity holder in publicly-traded company; Gilead: Speakers Bureau; Amgen: Current equity holder in publicly-traded company, Research Funding; Novartis: Honoraria, Research Funding; Eli Lilly: Research Funding; Roche/Genentech: Research Funding; Jewish General Hospital, Montreal, Quebec: Current Employment; Takeda: Research Funding; BeiGene: Consultancy, Honoraria, Research Funding; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. Matasar: Merck Sharp & Dohme: Current holder of individual stocks in a privately-held company; Juno Therapeutics: Consultancy; Janssen: Honoraria, Research Funding; Daiichi Sankyo: Consultancy; Genentech, Inc.: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Research Funding; Merck: Consultancy; Teva: Consultancy; TG Therapeutics: Consultancy, Honoraria; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; GlaxoSmithKline: Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Memorial Sloan Kettering Cancer Center: Current Employment; IGM Biosciences: Research Funding; Pharmacyclics: Honoraria, Research Funding; Rocket Medical: Consultancy, Research Funding; ImmunoVaccine Technologies: Consultancy, Honoraria, Research Funding. Canales: Takeda: Consultancy, Honoraria, Speakers Bureau; Incyte: Consultancy; Sandoz: Honoraria, Speakers Bureau; iQone: Honoraria; Sanofi: Consultancy; Novartis: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Eusa Pharma: Consultancy, Honoraria; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria; Gilead/Kite: Consultancy, Honoraria; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau. Fay: St Vincent's Hosptial, Sydney, Australia: Current Employment. Cheah: BMS: Consultancy, Research Funding; Abbvie: Research Funding; Janssen: Consultancy, Honoraria; MSD: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Ascentage Pharma: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria; Lilly: Consultancy, Honoraria; TG therapeutics: Consultancy, Honoraria; Beigene: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Other: travel, Research Funding. Marlton: BeiGene: Honoraria, Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Queensland Health: Current Employment; Jazz: Honoraria, Membership on an entity's Board of Directors or advisory committees. Wiebking: Genentech, Inc.: Current Employment, Current equity holder in publicly-traded company; F. Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company. Yin: Genentech, Inc.: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months. To: Genentech, Inc.: Current Employment, Current equity holder in publicly-traded company. Li: Genentech, Inc.: Current Employment, Current holder of individual stocks in a privately-held company. Huang: F. Hoffmann-La Roche Ltd: Current Employment. Zhou: Fibrogen China: Ended employment in the past 24 months; Roche Pharma Product Development: Current Employment. Penuel: Genentech, Inc.: Current Employment, Current equity holder in publicly-traded company. O'Hear: Genentech, Inc.: Current Employment; F. Hoffmann-La Roche Ltd: Current holder of individual stocks in a privately-held company. Sehn: Novartis: Consultancy; Debiopharm: Consultancy; Genmab: Consultancy. OffLabel Disclosure: Mosunetuzumab is a CD20xCD3 bispecific antibody that redirects T cells to engage and eliminate malignant B cells. Mosunetuzumab is an investigational agent.

Background: Sapacitabine is a novel, orally bioavailable, cytosine nucleoside analogue with a unique mechanism that generates single-stranded DNA breaks which are converted into double-stranded DNA breaks resulting in cell death. Previous studies of sapacitabine alone and alternating with decitabine (DAC) have demonstrated activity in acute myeloid leukemia (AML). Preclinical studies have suggested synergy with the combination of sapacitabine and a BCL-2 inhibitor. We conducted a study investigating the combination of sapacitabine and venetoclax (VEN) as an entirely oral regimen for patients with relapsed/refractory (R/R) AML. Methods: This is a phase I/II study for patients ≥ 18 years with R/R AML or MDS with blasts ≥10% investigating the safety and efficacy of escalating doses of sapacitabine combined with VEN. Eligibility included ECOG performance status ≤ 2 and adequate organ function. Two cohorts were investigated: Cohort 1 studied sapacitabine given PO BID on D1-5; Cohort 2 studied sapacitabine given PO BID on D1-3 and D8-10 of each cycle, which was defined as 4 weeks. Sapacitabine was escalated from a starting dose of 250mg. VEN was given to a target dose of 400mg PO on D1-14 of each cycle. VEN ramp-up was utilized, starting at 100mg on D1, 200mg on D2, and 400mg on days 3 through 14. Adjustments to the VEN dose were made based on concomitant CYP3A inhibitors. Results: Between 03/2020 and 03/2021, 13 pts were enrolled in the study. Baseline characteristics are shown in table 1. The median age was 70 years (range, 30-82) and 8 pts (62%) were aged ≥ 70 years. One pt (7%%) had favorable risk, 3 (23%) had intermediate risk, and 9 (70%) had adverse risk karyotype; 5 pts (38%) had a complex karyotype. The most common mutations detected by next-generation sequencing were: TET2 (46%), ASXL1 (30%), NRAS (30%), and WT1 (23%%). One patient (8%) had a TP53 mutation. This was a heavily pretreated population, having received a median of 2 prior therapies (1 - 9), including 6 patients (46%) having received prior intensive chemotherapy and 4 patients (30%) with prior allogeneic SCT. Six patients (46%) had received prior VEN-based therapy. Among 13 evaluable patients, there was 1 (8%) complete response with incomplete platelet recovery (CRp). Patients received a median of 1 cycle (1-9) on protocol. Five patients (38%) were able to remain on protocol without a protocol defined response, but with clinical benefit and good tolerability, for ≥2 cycles. With a median follow up of 14.61 months (1-16), the median overall survival (OS) was 3.8 months with a 60-day survival rate of 76% (Figure 1). There was no significant difference in OS between the two dosing schedules. The median OS among patients that had and had not received prior VEN was 3.32 months and 4.5 months, respectively (P=0.25). The patient that achieved a CRi had secondary AML with 7q deletion, an ASXL1 mutation, and only single-agent DAC as prior therapy. The oral chemotherapy combination was well tolerated, with 4- and 8-week mortality of 8% and 15%, respectively. The most common grade 3/4 non-hematologic adverse events regardless of attribution were: febrile neutropenia (31%), cellulitis (23%) pneumonia (15%), hypophosphatemia (8%), hypokalemia (8%). Two patients (15%) had grade 5 sepsis on study in the setting of active AML. Conclusion: In a heavily pretreated population of patients with R/R AML, the combination of sapacitabine and VEN was well tolerated and feasible to be administered as a completely oral, outpatient regimen. Most patients had multiple prior cycles of nucleoside analogue containing regimens and the only notable responder had only prior DAC. Further study of this well-tolerated combination in less heavily pretreated patients may be considered. Figure 1 Figure 1. Disclosures Kantarjian: Jazz: Research Funding; Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Aptitude Health: Honoraria; NOVA Research: Honoraria; Ascentage: Research Funding; Ipsen Pharmaceuticals: Honoraria; Astra Zeneca: Honoraria; Astellas Health: Honoraria; BMS: Research Funding; Daiichi-Sankyo: Research Funding; KAHR Medical Ltd: Honoraria; Immunogen: Research Funding; AbbVie: Honoraria, Research Funding; Precision Biosciences: Honoraria; Taiho Pharmaceutical Canada: Honoraria. DiNardo: Novartis: Honoraria; Forma: Honoraria, Research Funding; Foghorn: Honoraria, Research Funding; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria; Agios/Servier: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; ImmuneOnc: Honoraria, Research Funding; AbbVie: Consultancy, Research Funding; Notable Labs: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Celgene, a Bristol Myers Squibb company: Honoraria, Research Funding. Borthakur: GSK: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Protagonist: Consultancy; Takeda: Membership on an entity's Board of Directors or advisory committees; University of Texas MD Anderson Cancer Center: Current Employment; ArgenX: Membership on an entity's Board of Directors or advisory committees; Astex: Research Funding; Ryvu: Research Funding. Daver: ImmunoGen: Consultancy, Research Funding; Trovagene: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; FATE Therapeutics: Research Funding; Gilead Sciences, Inc.: Consultancy, Research Funding; Trillium: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Glycomimetics: Research Funding; Novimmune: Research Funding; Hanmi: Research Funding; Sevier: Consultancy, Research Funding; Novartis: Consultancy; Jazz Pharmaceuticals: Consultancy, Other: Data Monitoring Committee member; Dava Oncology (Arog): Consultancy; Celgene: Consultancy; Syndax: Consultancy; Shattuck Labs: Consultancy; Agios: Consultancy; Kite Pharmaceuticals: Consultancy; SOBI: Consultancy; STAR Therapeutics: Consultancy; Karyopharm: Research Funding; Newave: Research Funding. Pemmaraju: Dan's House of Hope: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Consultancy; ASH Communications Committee: Membership on an entity's Board of Directors or advisory committees; Sager Strong Foundation: Other; Daiichi Sankyo, Inc.: Other, Research Funding; HemOnc Times/Oncology Times: Membership on an entity's Board of Directors or advisory committees; DAVA Oncology: Consultancy; Aptitude Health: Consultancy; Springer Science + Business Media: Other; Roche Diagnostics: Consultancy; Novartis Pharmaceuticals: Consultancy, Other: Research Support, Research Funding; LFB Biotechnologies: Consultancy; ASCO Leukemia Advisory Panel: Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy; MustangBio: Consultancy, Other; Cellectis S.A. ADR: Other, Research Funding; Samus: Other, Research Funding; Plexxicon: Other, Research Funding; Affymetrix: Consultancy, Research Funding; Stemline Therapeutics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; CareDx, Inc.: Consultancy; Abbvie Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Protagonist Therapeutics, Inc.: Consultancy; Clearview Healthcare Partners: Consultancy; Blueprint Medicines: Consultancy; Bristol-Myers Squibb Co.: Consultancy; ImmunoGen, Inc: Consultancy; Pacylex Pharmaceuticals: Consultancy. Alvarado: Sun Pharma: Consultancy, Research Funding; Daiichi-Sankyo: Research Funding; Astex Pharmaceuticals: Research Funding; CytomX Therapeutics: Consultancy; BerGenBio: Research Funding; FibroGen: Research Funding; Jazz Pharmaceuticals: Research Funding; MEI Pharma: Research Funding. Burger: AstraZeneca: Consultancy; Beigene: Research Funding, Speakers Bureau; Pharmacyclics LLC: Consultancy, Other: Travel/Accommodations/Expenses, Research Funding, Speakers Bureau; Novartis: Other: Travel/Accommodations/Expenses, Speakers Bureau; Gilead: Consultancy, Other: Travel/Accommodations/Expenses, Research Funding, Speakers Bureau; TG Therapeutics: Other: Travel/Accommodations/Expenses, Research Funding, Speakers Bureau; Janssen: Consultancy, Other: Travel/Accommodations/Expenses, Speakers Bureau. Ravandi: Syros Pharmaceuticals: Consultancy, Honoraria, Research Funding; Jazz: Honoraria, Research Funding; Astex: Honoraria, Research Funding; Taiho: Honoraria, Research Funding; Agios: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; AstraZeneca: Honoraria; Novartis: Honoraria; Xencor: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Prelude: Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Research Funding. Kadia: AstraZeneca: Other; Ascentage: Other; Jazz: Consultancy; BMS: Other: Grant/research support; AbbVie: Consultancy, Other: Grant/research support; Aglos: Consultancy; Amgen: Other: Grant/research support; Cure: Speakers Bureau; Dalichi Sankyo: Consultancy; Genfleet: Other; Cellonkos: Other; Sanofi-Aventis: Consultancy; Pulmotech: Other; Novartis: Consultancy; Pfizer: Consultancy, Other; Liberum: Consultancy; Genentech: Consultancy, Other: Grant/research support; Astellas: Other.

Introduction: Ixazomib is an oral proteasome inhibitor (PI) that is currently approved to be administered once weekly in combination with lenalidomide (LEN) and dexamethasone in RRMM (Moreau et al N Eng J Med 2016; 374:1621-1634). As most patients are LEN refractory at the time of first relapse, pomalidomide-based regimens are commonly utilized due to their proven efficacy in this population. We hypothesized that twice weekly dosing of ixazomib may be more efficacious as this has been previously studied as monotherapy (Richardson et al, Blood 2014 Aug 14;124(7):1038-46) and in combination with LEN demonstrating promising activity and safety (Richardson et al, Br J Haematol. 2018 Jul;182(2):231-244). We present results of our phase I/II trial of twice weekly ixazomib in combination with pomalidomide and dexamethasone in RRMM, including the recommended phase II dose and first report of efficacy of this combination. Methods: This is a phase I/II multicenter, single-arm, open label study evaluating the combination of twice weekly ixazomib with pomalidomide and dexamethasone in RRMM. The primary objective for phase I portion is to determine safety and the maximum tolerated dose (MTD) of this combination using a standard 3+3 dose escalation design and primary objective of the phase II portion is overall response rate (ORR) with secondary outcomes including progression-free survival (PFS) and clinical benefit rate (CBR) Ixazomib is studied at doses of 3mg or 4mg on days 1, 4, 8, 11, pomalidomide at a dose of 2mg, 3mg and 4mg on days 1-14 and dexamethasone is administered at a dose of 12mg on days 1, 2, 4, 5, 8, 9, 11, 12 (8mg for patients > 75 years old) on a 21 day cycle (Table 1). Patients were included if they received 2 prior lines of therapy, but 1 prior line was allowed if first line treatment included a PI and an immunomodulatory agent and disease relapse occurred within 60 days of last therapy. Patients who were ixazomib exposed or pomalidomide refractory were excluded. Results: At the time of data cutoff, 22 patients have been enrolled across all cohorts. There were two dose-limiting toxicities (DLT) noted during the dose escalation phase (upper respiratory infection and neutropenia, respectively) establishing the RP2D of 4mg ixazomib and 4mg pomalidomide. Median age at the time of enrollment was 68 years old with ISS stage at diagnosis of I (14%), II (32%), and III (23%). High-risk FISH abnormalities were seen in 43% of patients as follows: del 17p (9%), gain 1q (36%), t(4;14) (5%), t(14;16) (9%). Median prior lines of therapy was 2 (range 1-4) with 100% of patients having prior treatment with lenalidomide and 95% with prior bortezomib. Fifty-nine percent of patients had a prior autologous stem cell transplant. Ten patients have been enrolled at the RP2D at the time of data cut off. The most common treatment-related toxicities were mainly low grade (Grade 1-2) and included neutropenia (45%), lower extremity edema (41%), insomnia (36%), dyspnea (32%) and weight gain (32%). Grade 3 or greater toxicities were noted in 36% of patients and included neutropenia (18%), thrombocytopenia (5%), anemia (5%), atrial fibrillation (5%), dehydration (5%), diarrhea (5%), fall (5%), lung infection (5%), and pneumonitis (5%). Dose reductions occurred in 13 patients and predominantly involved dexamethasone due to weight gain, insomnia, atrial fibrillation and fatigue. There have been no discontinuations due to toxicity and no treatment related mortality at the time of data cutoff. The ORR in all cohorts was 45%, with 9% achieving sCR, 9% VGPR and 86% achieving stable disease or better. At the RP2D, the ORR was 50% with 30% of patients achieving VGPR or better. At the median follow up of 10 months, median PFS was 13 months (95% CI: 11-NR) and median overall survival was not reached. Conclusions: Twice weekly ixazomib in combination with pomalidomide and dexamethasone is a generally well-tolerated regimen with promising activity. The recommended phase II dose has been established at 4mg of ixazomib and 4mg of pomalidomide demonstrating efficacy in a high-risk cohort of RRMM patients. The all-oral nature of this regimen has allowed for robust accrual during the COVID 19 pandemic. Figure 1 Figure 1. Disclosures Nadeem: BMS: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees. Mo: Karyopharm: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Epizyme: Consultancy; Eli Lilly: Consultancy; BMS: Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVIE: Consultancy. Bianchi: Jacob D. Fuchsberg Law Firm: Consultancy; MJH: Honoraria; Karyopharm: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. Sanchorawala: Celgene: Research Funding; Pfizer: Honoraria; Sorrento: Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees; Caelum: Membership on an entity's Board of Directors or advisory committees, Research Funding; Regeneron: Membership on an entity's Board of Directors or advisory committees; Proclara: Membership on an entity's Board of Directors or advisory committees; Oncopeptide: Research Funding; Karyopharm: Research Funding. Sperling: Adaptive: Consultancy. Munshi: Janssen: Consultancy; Takeda: Consultancy; Bristol-Myers Squibb: Consultancy; Celgene: Consultancy; Amgen: Consultancy; Karyopharm: Consultancy; Oncopep: Consultancy, Current equity holder in publicly-traded company, Other: scientific founder, Patents & Royalties; Legend: Consultancy; Abbvie: Consultancy; Adaptive Biotechnology: Consultancy; Novartis: Consultancy; Pfizer: Consultancy. Ghobrial: AbbVie, Adaptive, Aptitude Health, BMS, Cellectar, Curio Science, Genetch, Janssen, Janssen Central American and Caribbean, Karyopharm, Medscape, Oncopeptides, Sanofi, Takeda, The Binding Site, GNS, GSK: Consultancy. Anderson: Sanofi-Aventis: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Millenium-Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Scientific Founder of Oncopep and C4 Therapeutics: Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company; Mana Therapeutics: Membership on an entity's Board of Directors or advisory committees. Richardson: AbbVie: Consultancy; Karyopharm: Consultancy, Research Funding; Janssen: Consultancy; Protocol Intelligence: Consultancy; Takeda: Consultancy, Research Funding; GlaxoSmithKline: Consultancy; Regeneron: Consultancy; Secura Bio: Consultancy; Sanofi: Consultancy; AstraZeneca: Consultancy; Celgene/BMS: Consultancy, Research Funding; Oncopeptides: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding.

Background: Based on the results of a phase I/II study in Japan (Trial registration: JapicCTI-173646), tirabrutinib (TIR), a second-generation inhibitor of Bruton's tyrosine kinase, was approved in March 2020 for the treatment of relapsed or refractory primary central nervous system lymphoma (r/r PCNSL). We have previously reported overall response rate of 63.6% and manageable safety profile results of this study (Narita et al. Neuro Oncol. 2021;23(1):122-133). Further, one-year follow-up data after the last patient had enrolled showed that the effects of TIR persisted in r/r PCNSL patients (Mishima et al. Poster presented at the Society for Neuro-Oncology virtual conference; November 19-21, 2020). Here, based on this one-year follow-up data, we describe the Quality of Life (QoL) and Karnofsky Performance Status (KPS) in r/r PCNSL patients treated with TIR. Methods: Patients with r/r PCNSL, age ≥20 years, and KPS ≥70 were treated with TIR once daily (QD) at a dose of 320 mg, 480 mg, or 480 mg upon fasting (480 mg fasted QD). TIR was administered in 28-day cycles, and treatment was continued until disease progression or clinically unacceptable toxicity was observed. QoL was assessed using questionnaires issued by the European Organization for Research and Treatment of Cancer (EORTC), namely QLQ-C30 (EORTC QLQ-C30), EORTC QLQ-BN20, and EuroQol 5 dimensions 3-level (EQ-5D-3L). The QoL survey was conducted during the screening period, on Day 28 of Cycle 1, after every 2 cycles (i.e., after Day 1 of Cycle 3), after every 4 cycles (i.e., after Day 1 of Cycle 25), and at the end of treatment. KPS was measured during the screening period, on days 1, 8, 15, and 28 of Cycle 1, on day 1 of every cycle after Cycle 3, and at the end of treatment. Results: Forty-four patients were prospectively enrolled, and 20, 7, and 17 patients were treated with TIR at 320 mg QD, 480 mg QD, and 480 mg fasted QD, respectively. Median patient age was 60 years (range 29-86). Median follow-up period was 14.9 months (range, 1.4-27.7) for the entire cohort but was 19.1 months, 23.5 months, and 12.0 months for the 320 mg QD, 480 mg QD, and 480 mg fasted QD groups, respectively. At the time of data cutoff (February 25, 2020), 11 patients (25%) remained on treatment. Mean (SD) score for the global health status/QoL section of the EORTC QLQ-C30 was 50.9 (23.7) at baseline and remained relatively constant during treatment (Figure 1). This trend was also observed for emotional function, cognitive function, and fatigue sections of the EORTC QLQ-C30, for motor dysfunction, communication deficit, weakness of legs, and bladder control sections of the EORTC QLQ-BN20, and in items pertaining to self-care, usual activities, and anxiety/depression in the EQ-5D-3L. Median KPS was 80.0 (range, 70-100) at baseline, which remained unchanged during TIR treatment (Figure 2). Conclusion: QoL and KPS scores in r/r PCNSL patients were maintained during TIR administration, a new treatment option for r/r PCNSL, which does not lead to the deterioration of QoL and KPS. Figure 1 Figure 1. Disclosures Terui: Ono Pharmaceutical: Speakers Bureau; MSD: Speakers Bureau; Janssen: Speakers Bureau; Esai: Speakers Bureau; Chugai Pharmaceutical: Speakers Bureau; Celgene: Speakers Bureau; AbbVie: Speakers Bureau; Takeda Pharmaceutical: Speakers Bureau. Narita: Ono Pharmaceutical co.: Honoraria, Research Funding; Dainippon-Sumitomo: Membership on an entity's Board of Directors or advisory committees, Research Funding; Eisai: Honoraria, Research Funding; Stella-pharma: Research Funding; Daiichi-Sankyo: Honoraria, Research Funding; Bayer: Research Funding; Ohara: Research Funding; Chugai Pharmaceutical co.: Honoraria; Novocure: Honoraria. Nagane: AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Chugai: Honoraria, Research Funding; Daiichi-Sankyo: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Eisai: Honoraria, Research Funding; Pfizer: Research Funding; MSD: Research Funding; Astellas: Research Funding; Nippon-Kayaku: Honoraria, Research Funding; Bayer: Honoraria, Research Funding; Shionogi: Research Funding; Otsuka: Research Funding; Ono Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novocure: Honoraria; Sumitomo Dainippon Pharma: Honoraria; RIEMSER: Membership on an entity's Board of Directors or advisory committees. Mishima: Ono Pharmaceutical Co: Research Funding; Astellas: Research Funding; HOYA Technosurgical Co.: Research Funding; Daiichi-Sankyo: Research Funding; AbbVie: Research Funding; Medical U and A: Research Funding; Teijin Pharma: Research Funding; Eisai: Research Funding; MSD: Research Funding; Chugai: Research Funding. Arakawa: Sanofi: Research Funding; Carl Zeiss: Honoraria, Research Funding; Brainlab: Honoraria, Research Funding; Nihon Medi-Physics: Research Funding; Ono Pharmaceutical: Honoraria, Research Funding; Philips: Research Funding; Siemens: Research Funding; Tanabe Mitsubishi: Research Funding; Chugai: Honoraria, Research Funding; Eisai: Honoraria, Research Funding; Merck: Honoraria, Research Funding; Meiji Seika: Honoraria, Research Funding; Daiichi Sankyo: Honoraria, Research Funding; CSL Behring: Honoraria, Research Funding; Takeda: Research Funding; Pfizer: Research Funding; Stryker: Research Funding; Astellas Pharma: Research Funding; Taiho Pharma: Research Funding; Nippon Kayaku: Honoraria; Novocure: Honoraria; UCB Japan: Honoraria; Integra Japan: Honoraria; Otsuka: Honoraria; Abbvie: Honoraria. Yonezawa: Eisai: Speakers Bureau; Ono Pharmaceutical co.: Speakers Bureau; Chugai Pharmaceutical co.: Speakers Bureau. Fukuhara: Celgene: Honoraria, Research Funding; Chugai Pharmaceutical: Honoraria, Research Funding; Eisai: Honoraria; HUYA Bioscience International: Honoraria; Incyte: Research Funding; Janssen: Honoraria; Kyowa Kirin: Honoraria; Nippon Shinyaku: Honoraria; Novartis: Honoraria; Ono Pharmaceutical: Honoraria, Research Funding; Takeda Pharmaceutical: Honoraria; Zenyaku Kogyo: Honoraria; Bayer: Research Funding; AbbVie: Honoraria. Sugiyama: Daichi Sankyo Inc.: Consultancy; Ono Pharmaceutical Inc: Honoraria. Aoi: Ono Pharma USA, Inc.: Current Employment. Nishikawa: Novocure: Consultancy; Chugai: Honoraria, Research Funding; MSD: Research Funding; Daiichi-Sankyo: Honoraria, Research Funding; Eisai: Honoraria, Research Funding; Ono: Honoraria; Nihon-Kayaku: Honoraria. OffLabel Disclosure: Tirabrutinib. Clinical trial for PCNSL.

Background: Adoptive cell immunotherapies for opportunistic virus in immunocompromised patients using haploidentical memory T cells have shown to be safe and effective. Since severe cases of COVID-19 present a dysregulated immune system with T cell lymphopenia and a hyper-inflammatory state we have proposed that a similar strategy could be proven to be efficient for COVID-19 patients. This is a study protocol of an open-label, multicenter, double-arm, randomized, dose-finding phase I/II clinical trial to evaluate the feasibility, safety, tolerability, and efficacy of the administration of a single dose of allogenic SARS-CoV-2 specific memory CD45RA - T cells and Natural Killer (NK) cells in COVID-19 patients with lymphopenia and pneumonia. The aim of the study is to find efficient treatments for patients with moderate/severe COVID-19. Identification of Specific memory T cells and NK cells: i)Memory T Cells: we first determined the existence of SARS-CoV-2 specific T cells within the CD45RA - T memory cells of the blood of convalescent donors. Memory T cells can respond quickly to the infection and provide long-term immune protection to reduce the severity of the COVID-19 symptoms without inducing classically T cell alloreactivity. Also, CD45RA - memory T cells confer protection for other pathogens the donors encountered in their life. ii)NK cells: we determined the phenotype of NK cells after COVID-19 and the main characteristic of SARS-CoV-2 specific NK population in the blood of convalescent donors, as it has been shown for cytomegalovirus infections. Also, NK cells confer protection for other pathogens the donors encountered in their life. Pilot Phase I- Safety, feasibility, and dose escalation: Between September and November 2020 a phase 1, dose-escalation, single-center clinical trial was conducted to evaluate the safety and feasibility of the infusion of CD45RA - memory T cells containing SARS-CoV-2 specific T cells as adoptive cell therapy against moderate/severe cases of COVID-19. Nine participants with pneumonia and/or lymphopenia and with at least one human leukocyte antigen (HLA) match with the donor were infused. The first three subjects received the lowest dose (1x10 5 cells/kg), the next three received the intermediate dose (5x10 5 cells/kg) and the last three received the highest dose (1x10 6 cells/kg) of CD45RA - memory T cells. Clinicaltrials.gov registration: NCT04578210. Findings: All participants' clinical status measured by National Early Warning Score (NEWS) and 7-category point ordinal scales showed improvement six days after infusion. No serious adverse events were reported. Inflammatory parameters were stabilized post-infusion and the participants showed lymphocyte recovery two weeks after the procedure. Donor microchimerism was observed at least for three weeks after infusion in all patients. Interpretation: This study provides preliminary evidence supporting the idea that treatment of COVID-19 patients with moderate/severe symptoms using convalescent SARS-CoV-2 specific CD45RA - memory T cells is feasible and safe. We did not find dose-liming toxicity. The Recommended Phase 2 dose was 1x10 6 CD45RA - T cells. Phase II- Efficacy: Between January 2021 and July 2021 patients have been enrolled based on the matched with the HLA genotype of the convalescent donors and following the protocol inclusion/exclusion criteria. The primary outcome is the incidence of patient recovery at day 14, defined as normalization of fever and oxygen saturation or lymphopenia recovery. Secondary outcomes are the time to normal level of lymphocytes, the proportion of patients showing clinical improvement at day 7, time to first negative SARS-CoV-2 PCR, the incidence of treatment-related adverse events, duration of hospitalization, time to discharge, time to improvement by one category a 7-point ordinal scale or NEWS score, the proportion of patients requiring intensive care unit, and all-cause mortality. In addition, lymphocyte recovery by multiparametric flow cytometry and donor chimerism by real-time PCR in the experimental arm was monitored weekly during the first month. This study provides preliminary evidence supporting the idea that treatment of COVID-19 patients with moderate/severe symptoms using convalescent CD45RA - memory T cells is safe and feasible. The phase II clinical trial is ongoing to demonstrate efficacy. Figure 1 Figure 1. Disclosures Soria: Celgene: Other: Fees; Gilead: Other: Fees; AbbVie: Other: Fees.

Fanconi anemia (FA) is an inherited disorder associated with loss of function mutations in gene members of the FA-BRCA pathway involved in interstrand cross-link DNA damage repair during cell division. Progressive bone marrow failure (BMF) is a primary cause of morbidity and mortality in patients with FA. Allogeneic hematopoietic stem and progenitor cell (HSPC) transplantation is the only curative treatment for FA-associated BMF. However, donor availability, graft failure, and FA-specific transplant toxicities remain significant hurdles. Attempts at genetic correction of FA are underway but collection of sufficient numbers of autologous HSPCs is challenging in subjects with advanced BMF. Androgens have been successfully used but side effects often prevent prolonged therapy. The orally bioavailable small molecule mimetic of thrombopoietin, eltrombopag (EPAG), was recently shown to stimulate multipotent long-term repopulating HSPCs in patients with acquired BMF, resulting in persistent trilineage hematopoiesis. EPAG promotes DNA repair (Guenther, Exp Hematol 2019) and maintains HSPCs under inflammatory conditions (Alvarado, Blood 2019), indicating potential relevance in FA. In this study, we investigated whether EPAG may offer a novel therapeutic modality for FA-associated BMF. We have enrolled 10 patients (FANCA, n=9 and FANCC, n=1) to date in a prospective phase I/II study of EPAG in Fanconi anemia (NCT03204188). All subjects received EPAG at an oral daily dose adjusted for age and ethnicity. The primary efficacy endpoint was the proportion of subjects with at least 2-fold increase in marrow cellularity or CD34+ HSPC frequency (marrow response), or clinically significant improvement in peripheral blood (PB) counts at 6 months (blood response). The primary safety endpoint was the global toxicity profile assessed at 6 months using CTCAE criteria. Responders were invited to continue on the extension phase of the study for an additional 3 years. Four of 10 patients have reached the 6-month assessment endpoint, and a pre-specified 3-month interim analysis is available on two additional subjects. A marrow response was observed in all 4 subjects at 6 months. Mean marrow cellularity increased by a factor of 4 (Fig. A/B), and CD34+ HSPC frequency improved 2.5-fold at 6 months relative to pre-treatment values (Fig. C/D). Marrow response criteria were also met in the other two subjects at the 3-month interim assessment. Primary PB response was observed in 2 of 4 patients in one (hemoglobin) or two lineages (hemoglobin and platelets) at 6 months of treatment. Responders continue to receive EPAG at 10 or 25 months with sustained improvements in blood counts and transfusion independence. The subject treated for 25 months recently met response criteria in a third lineage (neutrophils) (Fig. E). Both patients who had a marrow but no PB response are clinically well; one subject (FANCA) underwent an unrelated allogeneic HSPC transplantation one year ago, and the other subject (FANCC) recently entered the extension phase of this study. Unilineage PB response criteria were also met in one of two subjects at the 3-month interim assessment. No drug-related serious adverse events have occurred during EPAG treatment. All patients tolerated the maximum dose of EPAG and no interruption or dose reduction was required for adverse events attributable to EPAG. Patients without transfusional iron overload at study entry developed progressive depletion of iron stores attributable to the known potent iron chelating and mobilizing properties of EPAG. At a median of 3 months after initiating EPAG (range, 1 to 6 months), affected patients initiated daily oral iron supplementation with gradual amelioration of iron store levels. To date, there has been no occurrence of marrow fibrosis, solid malignancies or clonal evolution, defined as abnormalities on standard metaphase analysis of bone marrow or overt clinical transformation to MDS/AML. In sum, treatment with EPAG was associated with increased marrow HSPCs in all subjects and PB responses in a subset of patients with Fanconi anemia. The overall safety profile was favorable. Further follow-up and expansion of the ongoing patient cohort will confirm EPAG's potential as a safe and efficient long-term therapeutic modality for FA-associated BMF. Alternatively, EPAG could also be used safely to boost marrow CD34+ cell numbers prior to autologous gene therapy applications. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Introduction: Polycomb repressive complex 2 (PRC2) regulates transcription via trimethylation of histone H3 at lysine 27 (H3K27me3). Enhancer of zeste homolog 2 (EZH2) in conjunction with embryonic ectoderm development (EED) is a catalytic subunit of PRC2 and functions as a histone methyltransferase for H3K27. H3K27me3 appears to be a unifying component in many malignancies, inducing transcriptional repression. EED is a core component of PRC2 that modifies the epigenetic status of target genes, including cell cycle control genes. Dysregulation of this pathway leads to tumorigenesis in several diseases. MAK683 is a specific oral inhibitor that impairs EED binding to H3K27me3. This is a Phase I/II study of MAK683 in adult patients with advanced malignancies for whom no effective standard treatment is available. Here, we present data from a subset of patients with diffuse large B-cell lymphoma (DLBCL). Methods: Patients with DLBCL received escalating doses of MAK683 in fasted conditions. Patients were administered MAK683 10, 20, 40, 80, 120, 240, 300, 500, and 800 mg once daily (QD) or 60, 80, 120, 150, and 300 mg twice daily (BID) orally in 28-day cycles until unacceptable or dose-limiting toxicities (DLTs) had developed, disease progression, or death. The primary objective was to characterize safety and tolerability and determine the maximum tolerated dose and/or recommended Phase II dose (RP2D). Results: As of March 5, 2021, 31 patients with an Eastern Cooperative Oncology Group Performance Status of 0-2 were treated. Median age was 70 years (range: 33-84) and patients were heavily pre-treated, with a median of 4 (range: 1-16) prior lines of therapy. Overall, 30 patients (97%) discontinued treatment due to progressive disease (26 patients, 84%), adverse events (3 patients, 10%), and physician's decision (1 patient, 3%). In total, 21 (68%) patients experienced ≥1 treatment-related adverse event (TRAE) of any grade, and the most common (≥20%) TRAEs were thrombocytopenia (29%) and anemia (23%). Grade 3/4 TRAEs were reported in 14 (45%) patients, with ≥15% of patients reporting thrombocytopenia (19%), neutropenia, and decreased neutrophil count (16% each). DLTs were reported in 7 patients, all of which were hematological and therefore may be related to the underlying disease in this subset of patients. Patients in both the QD dosing group (120 mg, 240 mg, and 800 mg; n=1 each) and BID dosing group (60 mg, n=1; 80 mg, n=2; 150 mg, n=1) reported DLTs. There were no treatment-related deaths in this study. Overall response rate was 16% (95% CI: 5─34) and the disease control rate was 29% (95% CI: 14─48). Two patients (6%) achieved a complete response (CR) and 3 patients (10%) achieved a partial response. Four patients (13%) reported stable disease. Pharmacokinetic data showed rapid absorption of MAK683 across all dosing regimens tested and drug exposure increased with dose. Conclusions: MAK683 was generally well tolerated and there were preliminary signs of activity in patients with treatment-resistant DLBCL. The use of MAK683 as a novel strategy for the inhibition of EED may have potential in relapsed/refractory DLBCL. Disclosures Ribrag: PharmaMar: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Astex Pharmaceuticals: Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees; MSD Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Epizyme: Honoraria, Research Funding; Argen-X: Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Nanostring: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Infinity Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; GSK: Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees. Michot: GSK: Honoraria; MSD: Consultancy, Honoraria; Celgene: Honoraria; Innate Pharma: Research Funding; Incyte: Research Funding; H3 biomedecine: Research Funding; GSK: Consultancy, Honoraria, Research Funding; Genentech: Research Funding; Gamamabs: Research Funding; Forma: Research Funding; Exelixis: Research Funding; Eos: Research Funding; Eisai: Research Funding; Debiopharm: Research Funding; Daiichi Sankyo,: Research Funding; Clovis: Research Funding; Chugai: Research Funding; Boeringer Ingelheim: Research Funding; Celgene: Research Funding; Blueprint: Research Funding; Beigene: Research Funding; Bayer: Research Funding; Argen-x: Research Funding; Amgen: Research Funding; Agios: Research Funding; Aduro: Research Funding; Abbvie: Research Funding; ASTEX: Research Funding, Speakers Bureau; Astra Zeneca: Honoraria, Research Funding; Roche: Honoraria; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding. Igleias: Merck Serono, MSD, BMS, Lilly, Roche, Bayer, Sanofi: Consultancy. Tan: Novartis, Bayer, Boehringer Ingelheim, MSD, Astra Zeneca, Eli-Lilly, Loxo: Consultancy; Astra Zeneca, Pfizer, Novartis: Research Funding; Merck, Pfizer, Novartis, Takeda, Bayer, Boehringer Ingelheim, Roche: Honoraria. Ma: Novartis, Merck, Y-Biologies, Taiho, Daiichi: Honoraria, Speakers Bureau; Novartis, Inglheim: Research Funding. Wainberg: Plexxikon, BMS, EMD Serono: Research Funding; Roche, Novartis, BMS, Merck, Pfizer, Lilly, Bayer, Astra Zeneca, Daiichi, Astellas, Amgen: Consultancy. Fan: Novartis Institutes for Biomedical Research: Current Employment. Suenaga: Novartis Pharma K.K.: Current Employment. Cheng: Novartis: Current Employment. Lai: Novartis: Current equity holder in publicly-traded company; Novartis Institutes for Biomedical Research: Current Employment. Yokota: AstraZeneca, Chugai Pharma, MSD, Syneos Health, Lilly, Incyte, Novartis, GlaxoSmithKline, Ascent: Research Funding; Abbott Japan, Ono Pharmaceutical, Chugai Pharma, Bristol-Myers Squibb, Merck Biopharma, MSD, Rakuten Medical, Eisai: Honoraria; Merck Biopharma, MSD, Rakuten Medical: Membership on an entity's Board of Directors or advisory committees.

Background: In MDS, hypomethylating agents (HMA) remain the standard of care. ASTX727, an oral formulation of the fixed dose combination of the HMA decitabine and cytidine deaminase inhibitor cedazuridine, was recently approved for the treatment of MDS and CMML. Venetoclax (Ven), an orally bioavailable BCL-2 inhibitor in combination with azacitidine has shown clinical activity in treatment-naïve higher risk MDS. Based on this data, we designed a total oral therapy with Ven+ASTX727 combination to improve the clinical outcomes and quality of life in pts with higher risk MDS or CMML. Methods: This single arm Phase I/II study of orally administered ASTX727 in combination with Ven (NCT04655755) is enrolling pts aged ≥18 years with treatment-naïve higher risk MDS (intermediate-2 or high) per IPSS or CMML with excess blasts ≥5%. Prior bcl2 inhibitor therapy is not allowed. To mitigate tumor lysis syndrome, pretreatment white blood cell count should be less than 10 × 10 9/L. Cytoreduction is allowed. The phase I 3+3 design of venetoclax with ASTX727 has an intended sample size of 12 pts. ASTX727 (cedazuridine/decitabine at 100 mg/35 mg) is administered orally daily on days 1-5 of each treatment cycle and Ven on days 1-14 of the first cycle and thereafter. Three dose levels of venetoclax in combination with ASTX727 will be tested (Table 1) The safety population includes all patients who received any dose of Ven+ ASTX727, and the efficacy population includes patients who have a valid baseline and post-baseline disease assessment and had received at least one dose of the study drug. The primary objective is to determine the safety and tolerability (phase 1) and overall response rate (ORR) (phase 2) of Ven+ASTX727 combination. Results: In phase I portion, seven pts have been enrolled to date (Table 2). The median age is 72 years (range, 54-84) with five pts aged ≥65 yrs. These pts had a median bone marrow blast count of 13% (range,6-15), and harbored a median number of 4 (range,1-7) mutations. Greater than 50% of the cohort harbored adverse risk mutations such as ASXL1(71%), RUNX1 (57%). Three pts were enrolled in dose level 0 and four pts in dose level +1. No DLTs were observed in the initial 6 pt safety lead-in. The 30-day and 60-day mortality rates were 0% each. No tumor lysis syndrome was observed. All seven pts achieved a response (100%) with three pts achieving CR (43%) and four pts achieving marrow CR (57%). Among the responders, two pts achieved MRD negativity (29%). All pts achieved a response within 1 cycle. One pt with TP53mut proceeded to hematopoietic stem cell transplant at the end of 2 cycles and the remaining six pts continue on study. At a median follow up of 3.8 months, the median duration of response was not reached (range,1.8-5.1+ months), and the median overall survival was not reached (range,2.7-6.2+ months). Conclusion: Ven+ASTX727 combination appears safe and demonstrates preliminary efficacy in pts with higher risk MDS or CMML with excess blasts. Total oral therapy of Ven+ASTX727 combination appears to be a promising strategy for HR MDS or CMML pts who often require long term treatment. Figure 1 Figure 1. Disclosures Kantarjian: Daiichi-Sankyo: Research Funding; Jazz: Research Funding; Immunogen: Research Funding; Ascentage: Research Funding; Aptitude Health: Honoraria; Astellas Health: Honoraria; Ipsen Pharmaceuticals: Honoraria; Astra Zeneca: Honoraria; KAHR Medical Ltd: Honoraria; Pfizer: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; NOVA Research: Honoraria; Taiho Pharmaceutical Canada: Honoraria; Precision Biosciences: Honoraria; Amgen: Honoraria, Research Funding; BMS: Research Funding; AbbVie: Honoraria, Research Funding. Short: Novartis: Honoraria; AstraZeneca: Consultancy; Astellas: Research Funding; Jazz Pharmaceuticals: Consultancy; NGMBio: Consultancy; Takeda Oncology: Consultancy, Research Funding; Amgen: Consultancy, Honoraria. Alvarado: CytomX Therapeutics: Consultancy; FibroGen: Research Funding; Sun Pharma: Consultancy, Research Funding; MEI Pharma: Research Funding; Daiichi-Sankyo: Research Funding; Astex Pharmaceuticals: Research Funding; BerGenBio: Research Funding; Jazz Pharmaceuticals: Research Funding. Pemmaraju: ASH Communications Committee: Membership on an entity's Board of Directors or advisory committees; Samus: Other, Research Funding; Novartis Pharmaceuticals: Consultancy, Other: Research Support, Research Funding; MustangBio: Consultancy, Other; Plexxicon: Other, Research Funding; Daiichi Sankyo, Inc.: Other, Research Funding; Dan's House of Hope: Membership on an entity's Board of Directors or advisory committees; ASCO Leukemia Advisory Panel: Membership on an entity's Board of Directors or advisory committees; Stemline Therapeutics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; CareDx, Inc.: Consultancy; Springer Science + Business Media: Other; Celgene Corporation: Consultancy; Aptitude Health: Consultancy; Abbvie Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Cellectis S.A. ADR: Other, Research Funding; Affymetrix: Consultancy, Research Funding; HemOnc Times/Oncology Times: Membership on an entity's Board of Directors or advisory committees; Roche Diagnostics: Consultancy; DAVA Oncology: Consultancy; Protagonist Therapeutics, Inc.: Consultancy; Incyte: Consultancy; Sager Strong Foundation: Other; LFB Biotechnologies: Consultancy; Clearview Healthcare Partners: Consultancy; Blueprint Medicines: Consultancy; Bristol-Myers Squibb Co.: Consultancy; ImmunoGen, Inc: Consultancy; Pacylex Pharmaceuticals: Consultancy. Daver: ImmunoGen: Consultancy, Research Funding; Novimmune: Research Funding; Genentech: Consultancy, Research Funding; Trillium: Consultancy, Research Funding; Trovagene: Consultancy, Research Funding; Gilead Sciences, Inc.: Consultancy, Research Funding; Glycomimetics: Research Funding; FATE Therapeutics: Research Funding; Abbvie: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Sevier: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Hanmi: Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Consultancy; Jazz Pharmaceuticals: Consultancy, Other: Data Monitoring Committee member; Dava Oncology (Arog): Consultancy; Celgene: Consultancy; Syndax: Consultancy; Shattuck Labs: Consultancy; Agios: Consultancy; Kite Pharmaceuticals: Consultancy; SOBI: Consultancy; STAR Therapeutics: Consultancy; Karyopharm: Research Funding; Newave: Research Funding. Kadia: Sanofi-Aventis: Consultancy; AstraZeneca: Other; Ascentage: Other; Genfleet: Other; Amgen: Other: Grant/research support; BMS: Other: Grant/research support; Cure: Speakers Bureau; Jazz: Consultancy; Genentech: Consultancy, Other: Grant/research support; Dalichi Sankyo: Consultancy; Novartis: Consultancy; Liberum: Consultancy; Pfizer: Consultancy, Other; AbbVie: Consultancy, Other: Grant/research support; Aglos: Consultancy; Astellas: Other; Cellonkos: Other; Pulmotech: Other. Borthakur: Astex: Research Funding; Ryvu: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Protagonist: Consultancy; University of Texas MD Anderson Cancer Center: Current Employment; GSK: Consultancy; ArgenX: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Jabbour: Amgen, AbbVie, Spectrum, BMS, Takeda, Pfizer, Adaptive, Genentech: Research Funding.

Background: Pevonedistat is a first-in-class inhibitor of NEDD8-activating enzyme that catalyzes the rate-limiting step of protein neddylation, a critical step in the degradation of cellular proteins that occurs upstream of the proteasome. The combination of azacitidine plus pevonedistat has resulted in high response rates and durable remissions in both myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), particularly in secondary AML (s-AML). Preclinical studies suggest that pevonedistat synergizes with venetoclax through neutralization of Mcl-1, providing rationale for the triplet combination of azacitidine, venetoclax and pevonedistat. Methods: In this phase I/II study, adult patients (pts) with newly diagnosed s-AML, including pts with therapy-related AML (t-AML) or AML with MDS-related changes, who were unsuitable for intensive chemotherapy were eligible. Pts were required to have a performance status ≤2, total bilirubin ≤ upper limit of normal (ULN), ALT/AST ≤2.5 x ULN, and creatinine clearance ≥30 mL/min. In cycle 1, pts received azacitidine 75 mg/m 2 SC/IV on days 1-7, venetoclax on days 1-28, and pevonedistat 20 mg/m 2 IV on days 1, 3 and 5 on a 28-day schedule. Venetoclax dose ranged from 200mg to 400mg daily during the phase I dose escalation. For cycles 2 and beyond, venetoclax was given on days 1-21. Results: Between 3/2019 and 5/2021, 28 pts were treated (3 pts at venetoclax 200mg daily and 25 pts at 400mg daily). Baseline characteristics are shown in Table 1. The median age was 74 years (range, 61-80), and 12 pts (43%) were ≥75 years of age. The study population was enriched with pts with poor-risk features, including 19 pts (68%) with adverse-risk cytogenetics, 14 (50%) with prior hypomethylating (HMA) or chemotherapy exposure for preceding hematologic malignancy, and 8 (29%) with TP53 mutation. The overall response rate (CR+CRi+MLFS) was 71%, and the CR+CRi rate was 64%. Thirteen pts (46%) achieved CR as best response, 5 (18%) achieved CRi, and 2 (7%) achieved MLFS. Among the 18 pts who achieved CR/CRi, 8 (44%) achieved MRD negativity by multiparameter flow cytometry. Responses were observed across subgroups, including in 8/14 pts (57%) with prior HMA/chemotherapy exposure, 6/8 pts (75%) with TP53 mutation, 12/19 pts (63%) with poor-risk cytogenetics, and 8/9 pts (89%) without non-poor-risk cytogenetics. With a median follow-up of 13.4 months (range 0.4 to 26.3+ months), the median overall survival (OS) was 8.2 months, and the median relapse-free survival was 7.5 months (Figure 1). The median OS for pts with poor-risk and non-poor cytogenetics was 7.9 and 18.0 months, respectively; for pts with and without prior HMA/chemotherapy exposure was 6.2 and 8.9 months, respectively; and for pts with inv(3) AML, TP53-mutated AML, and non-inv(3)/non-TP53-mutated AML was 3.8, 8.9, and 18.0 months, respectively. Four pts (14% of the entire cohort, 20% of responding pts) proceed to hematopoietic stem cell transplantation (HSCT), 3 of whom are still alive and 1 with inv(3) who relapsed post-HSCT and died from progressive AML. The combination was overall well-tolerated with myelosuppression as expected with the combination of HMA plus venetoclax in AML. The median number of cycles received was 2 (range, 1-13 cycles). Non-hematologic grade ≥3 adverse events occurring in ≥2 pts included infection or neutropenic fever in 18 pts (61%), hypophosphatemia in 8 pts (29%), hyperglycemia, hyperbilirubinemia and ALT/AST elevation in 3 pts each (11%), and pneumonitis, acute kidney injury, hypokalemia and vomiting in 2 pts each (7%). One pt developed multiorgan failure on cycle 1, day 1 of therapy, with transaminase elevation, hyperbilirubinemia, renal failure and hyperferritinemia; this pt recovered with holding therapy and supportive care. Hypophosphatemia, which has previously been reported with pevonedistat, was easily managed with oral or intravenous phosphorus supplementation. The 4-week and 8-week mortality rates were 7% and 14%, respectively. Conclusions: The combination of azacitidine, venetoclax and pevonedistat was safe and effective in a very poor-risk population of pts with s-AML, half of whom had prior HMA or chemotherapy exposure for antecedent hematologic malignancy. A randomized study evaluating azacitidine and venetoclax ± pevonedistat (NCT04266795) is ongoing and will help to clarify the potential role of pevonedistat in the frontline treatment of AML. Figure 1 Figure 1. Disclosures Short: AstraZeneca: Consultancy; Jazz Pharmaceuticals: Consultancy; NGMBio: Consultancy; Astellas: Research Funding; Novartis: Honoraria; Takeda Oncology: Consultancy, Research Funding; Amgen: Consultancy, Honoraria. Alvarado: Daiichi-Sankyo: Research Funding; Jazz Pharmaceuticals: Research Funding; FibroGen: Research Funding; BerGenBio: Research Funding; MEI Pharma: Research Funding; Sun Pharma: Consultancy, Research Funding; CytomX Therapeutics: Consultancy; Astex Pharmaceuticals: Research Funding. Konopleva: KisoJi: Research Funding; Ascentage: Other: grant support, Research Funding; AstraZeneca: Other: grant support, Research Funding; Agios: Other: grant support, Research Funding; Ablynx: Other: grant support, Research Funding; Cellectis: Other: grant support; Forty Seven: Other: grant support, Research Funding; AbbVie: Consultancy, Honoraria, Other: Grant Support, Research Funding; Rafael Pharmaceuticals: Other: grant support, Research Funding; Eli Lilly: Patents & Royalties: intellectual property rights, Research Funding; Calithera: Other: grant support, Research Funding; Sanofi: Other: grant support, Research Funding; Stemline Therapeutics: Research Funding; F. Hoffmann-La Roche: Consultancy, Honoraria, Other: grant support; Reata Pharmaceuticals: Current holder of stock options in a privately-held company, Patents & Royalties: intellectual property rights; Genentech: Consultancy, Honoraria, Other: grant support, Research Funding; Novartis: Other: research funding pending, Patents & Royalties: intellectual property rights. Jabbour: Amgen, AbbVie, Spectrum, BMS, Takeda, Pfizer, Adaptive, Genentech: Research Funding. Yilmaz: Pfizer: Research Funding; Daiichi-Sankyo: Research Funding. Jain: Genentech: Honoraria, Research Funding; Cellectis: Honoraria, Research Funding; Precision Biosciences: Honoraria, Research Funding; ADC Therapeutics: Honoraria, Research Funding; Pfizer: Research Funding; Adaptive Biotechnologies: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Aprea Therapeutics: Research Funding; Janssen: Honoraria; Incyte: Research Funding; Servier: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; Fate Therapeutics: Research Funding; Beigene: Honoraria; TG Therapeutics: Honoraria; Pharmacyclics: Research Funding; AbbVie: Honoraria, Research Funding. Borthakur: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Ryvu: Research Funding; ArgenX: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Astex: Research Funding; University of Texas MD Anderson Cancer Center: Current Employment; GSK: Consultancy; Protagonist: Consultancy. DiNardo: ImmuneOnc: Honoraria, Research Funding; Notable Labs: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Foghorn: Honoraria, Research Funding; Forma: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria; Novartis: Honoraria; Agios/Servier: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Research Funding; Celgene, a Bristol Myers Squibb company: Honoraria, Research Funding. Daver: Astellas: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Sevier: Consultancy, Research Funding; Glycomimetics: Research Funding; Gilead Sciences, Inc.: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; FATE Therapeutics: Research Funding; Amgen: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Trovagene: Consultancy, Research Funding; Hanmi: Research Funding; Novimmune: Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Trillium: Consultancy, Research Funding; ImmunoGen: Consultancy, Research Funding; Novartis: Consultancy; Jazz Pharmaceuticals: Consultancy, Other: Data Monitoring Committee member; Dava Oncology (Arog): Consultancy; Celgene: Consultancy; Syndax: Consultancy; Shattuck Labs: Consultancy; Agios: Consultancy; Kite Pharmaceuticals: Consultancy; SOBI: Consultancy; STAR Therapeutics: Consultancy; Karyopharm: Research Funding; Newave: Research Funding. Issa: Syndax Pharmaceuticals: Research Funding; Novartis: Consultancy, Research Funding; Kura Oncology: Consultancy, Research Funding. Pemmaraju: MustangBio: Consultancy, Other; ASH Communications Committee: Membership on an entity's Board of Directors or advisory committees; Aptitude Health: Consultancy; Samus: Other, Research Funding; Plexxicon: Other, Research Funding; Sager Strong Foundation: Other; CareDx, Inc.: Consultancy; Cellectis S.A. ADR: Other, Research Funding; Daiichi Sankyo, Inc.: Other, Research Funding; Dan's House of Hope: Membership on an entity's Board of Directors or advisory committees; HemOnc Times/Oncology Times: Membership on an entity's Board of Directors or advisory committees; ASCO Leukemia Advisory Panel: Membership on an entity's Board of Directors or advisory committees; Abbvie Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Springer Science + Business Media: Other; Pacylex Pharmaceuticals: Consultancy; Celgene Corporation: Consultancy; Roche Diagnostics: Consultancy; DAVA Oncology: Consultancy; Stemline Therapeutics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; LFB Biotechnologies: Consultancy; Novartis Pharmaceuticals: Consultancy, Other: Research Support, Research Funding; Incyte: Consultancy; Affymetrix: Consultancy, Research Funding; Protagonist Therapeutics, Inc.: Consultancy; Clearview Healthcare Partners: Consultancy; Blueprint Medicines: Consultancy; Bristol-Myers Squibb Co.: Consultancy; ImmunoGen, Inc: Consultancy. Sasaki: Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Research Funding. Ravandi: AstraZeneca: Honoraria; Jazz: Honoraria, Research Funding; Taiho: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Agios: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Honoraria, Research Funding; Astex: Honoraria, Research Funding; Syros Pharmaceuticals: Consultancy, Honoraria, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Xencor: Honoraria, Research Funding; Novartis: Honoraria; Prelude: Research Funding. Kadia: Genfleet: Other; Cure: Speakers Bureau; Genentech: Consultancy, Other: Grant/research support; Amgen: Other: Grant/research support; Dalichi Sankyo: Consultancy; Jazz: Consultancy; Novartis: Consultancy; Liberum: Consultancy; Aglos: Consultancy; Pfizer: Consultancy, Other; AbbVie: Consultancy, Other: Grant/research support; Pulmotech: Other; BMS: Other: Grant/research support; Astellas: Other; Sanofi-Aventis: Consultancy; AstraZeneca: Other; Cellonkos: Other; Ascentage: Other. Andreeff: Breast Cancer Research Foundation: Research Funding; Aptose: Consultancy; Daiichi-Sankyo: Consultancy, Research Funding; Karyopharm: Research Funding; Novartis, Cancer UK; Leukemia & Lymphoma Society (LLS), German Research Council; NCI-RDCRN (Rare Disease Clin Network), CLL Foundation; Novartis: Membership on an entity's Board of Directors or advisory committees; Glycomimetics: Consultancy; Senti-Bio: Consultancy; Oxford Biomedica UK: Research Funding; Syndax: Consultancy; AstraZeneca: Research Funding; ONO Pharmaceuticals: Research Funding; Amgen: Research Funding; Reata, Aptose, Eutropics, SentiBio; Chimerix, Oncolyze: Current holder of individual stocks in a privately-held company; Medicxi: Consultancy. Bose: Pfizer: Research Funding; Constellation Pharmaceuticals: Research Funding; Novartis: Honoraria; Sierra Oncology: Honoraria; Kartos Therapeutics: Honoraria, Research Funding; Blueprint Medicines: Honoraria, Research Funding; CTI BioPharma: Honoraria, Research Funding; Celgene Corporation: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Incyte Corporation: Honoraria, Research Funding; Astellas: Research Funding; NS Pharma: Research Funding; Promedior: Research Funding. Kantarjian: Ipsen Pharmaceuticals: Honoraria; Amgen: Honoraria, Research Funding; Precision Biosciences: Honoraria; Astellas Health: Honoraria; Astra Zeneca: Honoraria; Immunogen: Research Funding; Daiichi-Sankyo: Research Funding; KAHR Medical Ltd: Honoraria; Aptitude Health: Honoraria; Pfizer: Honoraria, Research Funding; Ascentage: Research Funding; NOVA Research: Honoraria; BMS: Research Funding; Jazz: Research Funding; Novartis: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Taiho Pharmaceutical Canada: Honoraria. Cortes: Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Bio-Path Holdings, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sun Pharma: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Bristol Myers Squibb, Daiichi Sankyo, Jazz Pharmaceuticals, Astellas, Novartis, Pfizer, Takeda, BioPath Holdings, Incyte: Consultancy, Research Funding.

Background: MDS is a clonal hematological disorder characterized by bone marrow dysplasia, ineffective hematopoiesis, and an increased risk of transformation to acute myeloid leukemia (AML). For the majority of high-risk MDS patients who are not eligible for curative allogeneic hematopoietic stem cell transplantation (aHSCT), hypomethylating agents (HMAs) such as 5-azacytidine (AZA) represent the standard of care. However, overall response rates (ORRs) with AZA monotherapy remain relatively low (28-48%) and the length of response is limited (median 8-10m). In patients who fail or relapse after HMA therapy, prognosis is dismal and therapeutic options are limited. Pre-clinical data suggest BCL-2 inhibitors such as Venetoclax (VEN) are synergistic with HMAs in MDS. We designed this phase I/II study (NCT04160052) to evaluate the safety, tolerability, and response rate of the AZA-VEN combination for the treatment of high-risk MDS and chronic myelomonocytic leukemia (CMML). Methods: Patients ≥ 18 years of age were eligible for enrollment if they were diagnosed with HMA-naïve high-risk MDS (IPSS Int-2/High), relapsed/refractory MDS after at least 4 cycles of HMA therapy, or CMML. Bone marrow (BM) blast count > 5% was required. Patients with prior BCL-2 inhibitor exposure and low risk MDS (IPSS Low/Int-1) were excluded. AZA 75 mg/m 2 IV/SC on days 1-5 and escalating doses (3+3 algorithm) of VEN PO on days 1-7 or 1-14 were administered every 28 days. VEN dosage was adjusted for concomitant CYP3A inhibitor use. The primary objective is safety and tolerability (phase I) and ORR (phase II). The incidence and severity of adverse events (AEs) were evaluated using CTCAE v 5.0. ORR was defined as the proportion of patients who achieved complete remission (CR), partial remission (PR), marrow CR (mCR), or hematological improvement (HI) lasting at least 4 weeks (Modified IWG Response Criteria for MDS, Cheson 2006). Overall survival (OS) and progression-free survival (PFS) were assessed as secondary objectives. Results: As of July 31 st 2021, 17 patients (median age 68, range 58-84) have been enrolled in the phase I portion of the study (8 HMA-naïve MDS, 4 MDS after HMA failure, and 5 CMML). The median BM blast count was 11% (6-19%). 13 patients (76%) were Int-2 and 4 patients (24%) were High risk by IPSS. Good, intermediate, and poor risk cytogenetics were observed in 6 (35%), 4 (24%), and 7 (41%) patients, respectively. 6 patients (35%) had complex karyotypes and 5 (29%) had TP53 mutations. Of the 7 previously treated patients, the median number of prior therapies was 1 (1-5). The median number of cycles of AZA-VEN completed on study at the time of data cutoff was 3 (0-10) and the median follow-up was 11.6m. VEN dose ranged from 20 to 400 mg daily. 5 (29%) patients went off study for aHSCT but continued to be followed for the survival analysis. The most common grade 3/4 AEs were thrombocytopenia (35%), lung infections (29%), and neutropenia (24%). 2 grade 5 AEs (sepsis) occurred on study, one in a patient whose best response was SD after 5 cycles and one in a patient who had completed only 2 days of cycle 1. 30-day mortality was 6%. 15 patients were evaluable for response because they had completed at least 1 cycle of the study drugs. The ORR was 93% (1 CR, 9 mCR, 4 mCR with HI). In responders, the median number of cycles to response was 1 (range 1-2) and median duration of response 6.3m. No patient responded beyond cycle 2. Median PFS and OS for the evaluable cohort were 8.4m and 13m, respectively. Transformation to AML occurred in 3 patients (20%). Of the 4 survivors beyond 10m, 3 (75%) have undergone consolidative aHSCT. Conclusions: AZA-VEN was a tolerable and effective treatment strategy in this high-risk group of patients. Notably, a very high ORR was observed in this phase I study. Responses were rapid compared to historical data with AZA alone. AZA-VEN was an effective bridge to aHSCT. Recruitment is ongoing to determine the MTD/RP2D. Figure 1 Figure 1. Disclosures Jabbour: Amgen, AbbVie, Spectrum, BMS, Takeda, Pfizer, Adaptive, Genentech: Research Funding. Kantarjian: Novartis: Honoraria, Research Funding; Astra Zeneca: Honoraria; Amgen: Honoraria, Research Funding; Ipsen Pharmaceuticals: Honoraria; BMS: Research Funding; Daiichi-Sankyo: Research Funding; Jazz: Research Funding; Pfizer: Honoraria, Research Funding; Aptitude Health: Honoraria; Ascentage: Research Funding; AbbVie: Honoraria, Research Funding; Immunogen: Research Funding; NOVA Research: Honoraria; KAHR Medical Ltd: Honoraria; Astellas Health: Honoraria; Precision Biosciences: Honoraria; Taiho Pharmaceutical Canada: Honoraria. DiNardo: Agios/Servier: Consultancy, Honoraria, Research Funding; Novartis: Honoraria; Takeda: Honoraria; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Research Funding; ImmuneOnc: Honoraria, Research Funding; Forma: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Notable Labs: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Foghorn: Honoraria, Research Funding; Celgene, a Bristol Myers Squibb company: Honoraria, Research Funding. Daver: Astellas: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Hanmi: Research Funding; Trillium: Consultancy, Research Funding; FATE Therapeutics: Research Funding; Sevier: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Consultancy; Glycomimetics: Research Funding; Novimmune: Research Funding; Genentech: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Gilead Sciences, Inc.: Consultancy, Research Funding; ImmunoGen: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Trovagene: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Other: Data Monitoring Committee member; Dava Oncology (Arog): Consultancy; Celgene: Consultancy; Syndax: Consultancy; Shattuck Labs: Consultancy; Agios: Consultancy; Kite Pharmaceuticals: Consultancy; SOBI: Consultancy; STAR Therapeutics: Consultancy; Karyopharm: Research Funding; Newave: Research Funding. Kadia: Sanofi-Aventis: Consultancy; Cellonkos: Other; Ascentage: Other; Novartis: Consultancy; Liberum: Consultancy; Genfleet: Other; Astellas: Other; AstraZeneca: Other; Jazz: Consultancy; Pulmotech: Other; Pfizer: Consultancy, Other; Aglos: Consultancy; Genentech: Consultancy, Other: Grant/research support; Dalichi Sankyo: Consultancy; Cure: Speakers Bureau; BMS: Other: Grant/research support; Amgen: Other: Grant/research support; AbbVie: Consultancy, Other: Grant/research support. Takahashi: Celgene/BMS: Consultancy; Symbio Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; GSK: Consultancy. Short: Takeda Oncology: Consultancy, Research Funding; Astellas: Research Funding; Novartis: Honoraria; NGMBio: Consultancy; Jazz Pharmaceuticals: Consultancy; AstraZeneca: Consultancy; Amgen: Consultancy, Honoraria. Alvarado: Sun Pharma: Consultancy, Research Funding; Jazz Pharmaceuticals: Research Funding; BerGenBio: Research Funding; CytomX Therapeutics: Consultancy; Astex Pharmaceuticals: Research Funding; MEI Pharma: Research Funding; Daiichi-Sankyo: Research Funding; FibroGen: Research Funding. Thompson: Genentech: Other: Institution: Advisory/Consultancy, Honoraria, Research Grant/Funding; Amgen: Other: Institution: Honoraria, Research Grant/Funding; Janssen: Consultancy, Honoraria; Pharmacyclics: Other: Institution: Advisory/Consultancy, Honoraria, Research Grant/Funding; Adaptive Biotechnologies: Other: Institution: Advisory/Consultancy, Honoraria, Research Grant/Funding, Expert Testimony; AbbVie: Other: Institution: Advisory/Consultancy, Honoraria, Research Grant/Funding; Gilead: Other: Institution: Advisory/Consultancy, Honoraria. Yilmaz: Daiichi-Sankyo: Research Funding; Pfizer: Research Funding. Ravandi: Astex: Honoraria, Research Funding; Prelude: Research Funding; Taiho: Honoraria, Research Funding; Agios: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; Novartis: Honoraria; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Research Funding; Syros Pharmaceuticals: Consultancy, Honoraria, Research Funding; Xencor: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding. Pemmaraju: Plexxicon: Other, Research Funding; ASCO Leukemia Advisory Panel: Membership on an entity's Board of Directors or advisory committees; ASH Communications Committee: Membership on an entity's Board of Directors or advisory committees; Sager Strong Foundation: Other; Roche Diagnostics: Consultancy; MustangBio: Consultancy, Other; Aptitude Health: Consultancy; Dan's House of Hope: Membership on an entity's Board of Directors or advisory committees; Samus: Other, Research Funding; DAVA Oncology: Consultancy; CareDx, Inc.: Consultancy; Springer Science + Business Media: Other; Cellectis S.A. ADR: Other, Research Funding; Daiichi Sankyo, Inc.: Other, Research Funding; HemOnc Times/Oncology Times: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Consultancy; Abbvie Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Stemline Therapeutics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; LFB Biotechnologies: Consultancy; Novartis Pharmaceuticals: Consultancy, Other: Research Support, Research Funding; Incyte: Consultancy; Affymetrix: Consultancy, Research Funding; Protagonist Therapeutics, Inc.: Consultancy; Clearview Healthcare Partners: Consultancy; Blueprint Medicines: Consultancy; Bristol-Myers Squibb Co.: Consultancy; ImmunoGen, Inc: Consultancy; Pacylex Pharmaceuticals: Consultancy. OffLabel Disclosure: Venetoclax is not currently approved for MDS but has promising pre-clinical activity data.

Background: The prognosis of relapsed/refractory (R/R) myeloid malignancies remains poor, and the development of novel treatment strategies is crucial. Although chimeric antigen receptor (CAR)-modified T cell therapy for B cell malignancies has shown excellent clinical efficacy, the use of CAR-T cells for myeloid malignancies has been more challenging, partly due to the heterogeneous expression of candidate target antigens in leukemia cells and shared expression of those antigens in normal myeloid cells or progenitor cells. We previously developed the piggyBac-modified chimeric antigen receptor (CAR)-T cells targeting CD116, also known as GM-CSF receptor alpha chain (GMR) (Nakazawa Y, et al. J Hematol Oncol. 2016 and Hasegawa A, et al. Clin Transl Immunology. 2021). GMR CAR-T cells showed substantial antitumor effects against both acute myeloid leukemia and juvenile myelomonocytic leukemia. Moreover, modulation of the spacer and antigen recognition site of the CAR vector further enhanced the anti-tumor effects of GMR CAR-T cells. GMR CAR-T cells showed an acceptable safety profile with limited cytotoxicity on normal hematopoietic cells except monocytes. Based on these results, we have initiated a first-in-human clinical trial of GMR CAR-T cell therapy in March 2021 in Japan. Study Design and Methods: The study is a phase I/II, single-center, dose-escalation study with a traditional 3+3 dose-escalation design (Table 1). Maximum of 18 patients will be recruited. Primary objectives of this study are to determine the safety and severe adverse events of piggyBac-modified GMR CAR-T cells for CD116 + relapsed/refractory myeloid malignancies by assessing the dose-limiting toxicity within 28 days from the single infusion of GMR CAR-T cells. The patients with CD116 + myeloid malignancies aged more than 1 year with myeloid malignancies who experienced an induction failure or a relapse after hematopoietic stem cell transplantation (HSCT) will be recruited. CD116 is defined as positive when a CD116 relative mean fluorescence (RFI) in leukemia cells ≥ 2. RFI was calculated by dividing the MFI of samples with that of the isotype control. Major exclusion criteria are as follows, acute promyelocytic leukemia, acute graft-versus-host disease (GVHD) (Grade ≥ 2), extensive chronic GVHD, and concurrent treatment with corticosteroid (≥ 6 mg/m2). Statistical analysis will be performed when the data will be fixed. Peripheral blood mononuclear cells will be harvested from the patient by leukapheresis and then will be transduced with GMR CAR vector by piggyBac transposon system. All manufacturing process of GMR CAR-T cells is performed in Cell Processing Center in Shinshu University Hospital under good manufacturing practice conditions. The patient will be treated with lymphodepleting chemotherapy consisting of fludarabine and cyclophosphamide, followed by CAR-T cell infusion. The dose of CAR-T cells will be 3 x 10 5 and 1 x 10 6 in cohorts 1 & 2 and cohort 3, respectively (Table 1). Kinetics of GMR CAR-T cells will be determined by quantifying the GMR CAR gene in the peripheral blood using real-time PCR after the CAR-T cell infusion. All the patients will be required to receive HSCT by day 56 following CAR-T cell infusion. The primary endpoint of the study is the safety, pharmacokinetics, and efficacy of GMR CAR-T therapy (Trial registration: jRCT2033210029). Conclusion: We herein described the protocol of first-in-human GMR CAR-T cells for relapsed/refractory myeloid malignancies. By employing the optimized CAR vector and production protocol, the safety and efficacy of GMR CAR-T cells will be evaluated in this study. Figure 1 Figure 1. Disclosures Saito: Toshiba corporation: Research Funding. Yagyu: AGC Inc.: Research Funding. Nakazawa: AGC Inc.: Research Funding; Toshiba Corporation: Research Funding.

Introduction: Key characteristics of immune thrombocytopenia (ITP) include immune-mediated platelet destruction/impaired production, with resultant thrombocytopenia and increased bleeding risk. Durable response to current therapies remains an unmet need, particularly in the relapsed/refractory setting. Rilzabrutinib is the first oral, reversible, covalent inhibitor of Bruton tyrosine kinase designed to target immune-mediated pathways in ITP without inhibiting normal platelet aggregation. Initial phase I/II results in ITP demonstrated rapid and durable efficacy with rilzabrutinib that was well-tolerated at all dose levels, including the optimal 400 mg bid dose. Interim results on rilzabrutinib effects in patients with relapsed/refractory ITP were previously reported. Here we present long-term data from a larger group of patients who initiated rilzabrutinib at 400 mg bid and are continuing in the long-term extension (LTE) period. Methods: This ongoing, global phase I/II study (NCT03395210) enrolled adult patients from 8 countries with relapsed or refractory ITP who previously responded to ≥1 prior ITP therapy. Eligible patients with 2 baseline platelet counts of Results: As of June 1, 2021 in 60 patients, 45 patients initiated rilzabrutinib 400 mg bid and to date, 16 patients with durable, stable response proceeded to LTE at 400 mg bid. At enrollment for patients initiating rilzabrutinib 400 mg bid, median age was 49 y (range, 19-74), median duration of ITP was 6.1 y (range, 0.4-52.5), and median platelet count was 15×10 9/L (range, 2-33×10 9/L). Patients were heavily pretreated with a median of 6 prior treatment events (range, 1-53), including 24% with prior splenectomy. Overall, 18/45 patients (40%) achieved the primary endpoint. In primary responders, platelet counts of ≥30×10 9/L, ≥30×10 9/L with ≥20×10 9/L above baseline, and ≥50×10 9/L were maintained for a median of 95%, 86%, and 72% of weeks, respectively. Median time to first platelet counts of ≥30×10 9/L, ≥30×10 9/L with ≥20×10 9/L above baseline, and ≥50×10 9/L were 8.5 (7-134), 11.5 (7-134), and 12.5 (8-142) days, respectively. According to subgroup analyses, primary platelet responses were consistently >30% irrespective of baseline platelet counts, the use of concomitant therapy, duration of ITP, or number of prior therapies (Table). LTE patients received rilzabrutinib for an overall median duration of 462 days (range, 303-764). At LTE entry, patients had a median platelet count of 87×10 9/L (range, 16-321×10 9/L). In addition to all LTE patients achieving the primary endpoint during the main treatment period, these patients maintained platelet counts of ≥30×10 9/L, ≥30×10 9/L with ≥20×10 9/L above baseline, and ≥50×10 9/L, for a median of 100%, 96%, and 90%, of weeks, respectively, during the LTE period (Figure). Treatment-related treatment-emergent adverse events (TEAEs; all grade 1/2) were reported in 27/45 patients (60%); the most common were 36% diarrhea and 31% nausea, and all others were Conclusion: Oral rilzabrutinib 400 mg bid was well-tolerated and had durable, clinically significant platelet responses across subgroups and with extended treatment in patients with heavily pretreated ITP. Continued study in the ongoing, randomized phase III LUNA3 trial (NCT04562766) will further assess the magnitude and durability of rilzabrutinib's clinical benefit in ITP. Figure 1 Figure 1. Disclosures Kuter: Actelion (Syntimmune), Agios, Alnylam, Amgen, Argenx, Bristol Myers Squibb (BMS), Immunovant, Kezar, Principia, Protalex, Rigel, Takeda (Bioverativ), UCB: Research Funding; Up-to-Date: Patents & Royalties: Up-To-Date; Rubius: Current equity holder in publicly-traded company; Actelion (Syntimmune), Agios, Alnylam, Amgen, Argenx, BioCryst, Bristol Myers Squibb (BMS), Caremark, CRICO, Daiichi Sankyo, Dova, Genzyme, Immunovant, Incyte, Kyowa-Kirin, Merck Sharp Dohme, Momenta, Novartis, Pfizer, Principia, Protalex, Protalix, Rigel: Consultancy, Other: grant support and consulting fees; Platelet Disorder Support Association: Membership on an entity's Board of Directors or advisory committees. Mayer: Principia: Research Funding. Jansen: 3SBIO, Novartis: Other: Travel, accomodations, expenses; Advisory Board Novartis: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Other: Travel, Accommodations, Expenses. McDonald: Bayer, Sobi, Novartis, Amgen, argenx: Honoraria; Grifols: Research Funding. Baker: Roche, Janssen-Celeg: Membership on an entity's Board of Directors or advisory committees; Bayer, Takeda, Pfizer, Daiichi Sankyo, CSL Behring, Roche, Amgen, Celgene, Rigel Pharmaceuticals, Abbvie, Sanofi, MorphoSys AG, Acerta Pharma, Jansen-Cileg, Bristol-Myers Squibb, Boehringer Ingelheim, Portola, Technoclone, Alexion: Research Funding. Bird: Novartis, Amgen: Speakers Bureau. Garg: Amgen Janssen Novartis Sanofi Takeda: Honoraria; Takeda Janssen Novartis Sanofi: Other: Travel Accommodations, Expenses; University Hospital Leicester: Current Employment. Gernsheimer: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: personal fees ; Amgen: Honoraria; Cellphire: Consultancy; Dova: Consultancy, Honoraria; Principia: Membership on an entity's Board of Directors or advisory committees, Research Funding; Rigel: Membership on an entity's Board of Directors or advisory committees, Research Funding; NHLBI: Research Funding. Ghanima: Amgen, Novartis, Pfizer, Principia Biopharma Inc- a Sanofi Company, Sanofi, SOBI, Griffols, UCB, Argenx: Consultancy; Amgen, Novartis, Pfizer, Bristol Myers Squibb, SOBI, Griffols, Sanofi: Honoraria; Bayer, BMS/Pfizer: Research Funding. Bandman: Sanofi: Ended employment in the past 24 months. Arora: Principia Biopharma Inc, a Sanofi Company: Ended employment in the past 24 months. Burns: Sanofi: Ended employment in the past 24 months. Yao: Sanofi: Current Employment. Daak: Sanofi: Current Employment. Sourdille: Sanofi: Current Employment. Thomas: Chinook and Equillium Biopharma: Current holder of individual stocks in a privately-held company; Chinook: Membership on an entity's Board of Directors or advisory committees; Equillium Biopharma: Current Employment; Principia, a Sanofi Company: Ended employment in the past 24 months; Equillium Biopharma: Current equity holder in publicly-traded company. Neale: Principia Biopharma/Sanofi: Ended employment in the past 24 months; Principia Biopharma: Divested equity in a private or publicly-traded company in the past 24 months. Cooper: Sanofi and Principia: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel, accommodations expenses; Principia and Sanofi: Consultancy. OffLabel Disclosure: Rilzabrutinib is an investigational therapy being evaluated in a clinical study for the treatment of patients with immune thrombocytopenia.

BACKGROUND Lymphopenia is common after standard radiation therapy (RT) and temozolomide (TMZ) in high-grade gliomas (HGG) and correlates with shorter survival. Interleukin-7 (IL-7), a T-cell proliferation cytokine, is inappropriately low in HGG patients. Our previous preclinical studies demonstrated that NT-I7 (efineptakin alfa), a recombinant human IL-7, corrects lymphopenia and improves survival in murine glioma models. This study examines the safety and absolute lymphocyte counts (ALCs) following administration of NT-I7 patients with newly diagnosed HGG. METHODS Patients with HGG receiving RT/TMZ with ALC ≥600 were eligible. NT-I7 was administered intramuscularly within 1 week after completion of concurrent RT/TMZ and then every 12 weeks, for up to 4 total doses. Phase I examined 6 dose levels (60, 120, 240, 540, 720, and 960 mcg/kg) using the accelerated-titration design for the first 2 doses and 3 + 3 design thereafter to identify the maximum tolerated dose (MTD). Phase II is a double-blinded, placebo-controlled study with 10 HGG patients per arm comparing changes in ALC. Immune profiling will be performed with CyTOF and cytokine analysis. RESULTS Phase I is complete, with 19 patients (89% GBM, median age: 58 (range: 25-78), median baseline ALC: 1000 cells/mm3, median dexamethasone: 0 mg/day (range: 0-12)). The median number of NT-I7 doses administered was 2 (range: 2-4). The most common treatment-related adverse event was grade 1 or 2 injection site reactions (42%). Two patients had dose-limiting toxicities at 960 mcg/kg (grade 3 elevated alanine aminotransferase and grade 3 back pain), prompting selection of 720 mcg/kg for phase II. Dose-dependent increases in ALC were observed at 4 weeks ranging from 1.3x to 4.1x. Phase II enrollment is ongoing. CONCLUSIONS NT-I7 is well tolerated when administered after chemoradiotherapy for HGG patients with MTD of 720 mcg/kg and demonstrates dose-dependent increase of ALC. Phase II and immune profiling are ongoing. Clinical Trial ID: NCT03687957.