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Purpose:This study examined safety, pharmacokinetics, and efficacy of veliparib, a PARP inhibitor, combined with carboplatin and etoposide in patients with extensive-stage (ED) small cell lung cancer (SCLC) and other solid tumors.Patients and Methods:The 3 + 3 design was used for dose escalation of oral veliparib in combination with carboplatin (AUC 5 on day 1) and etoposide (100 mg/m2 on days 1–3) in 21-day cycles. Veliparib dose was explored from 80 to 240 mg b.i.d. on 7-day, 14-day, or continuous schedules. Patients without disease progression continued on maintenance monotherapy (veliparib 400 mg b.i.d.) until disease progression or unacceptable toxicity.Results:Thirty-nine patients were enrolled to determine the recommended phase II dose of 240 mg veliparib for 14 days combined with carboplatin and etoposide based on long-term tolerability. Dose-limiting toxicity occurred in 1 patient (grade 2 toxic motor polyneuropathy) at veliparib 240 mg b.i.d. for 7 days. Most common adverse events related to veliparib were nausea (39%), fatigue (39%), and hematologic toxicities. Continuous dosing of veliparib 240 mg b.i.d. with carboplatin and etoposide resulted in excessive chemotherapy dose delays due to hematologic toxicity (grade 3/4 neutropenia/thrombocytopenia). Etoposide pharmacokinetics was not affected by veliparib. Confirmed responses occurred in 17 of 39 (44%) and 16 of 25 (64%) of all enrolled and ED SCLC patients, respectively. At the RP2D, confirmed responses occurred in 6 of 13 (46%) and 5 of 6 (83%) of all enrolled and ED SCLC patients, respectively.Conclusions:Veliparib (240 mg b.i.d. 14 days) plus carboplatin/etoposide can be safely combined. Phase II of this study is ongoing in first-line patients with ED SCLC.

Correlative biomarker analysis: 4A, Shift in balance of tumoral myeloid cells correlates with response. 4B, Baseline circulating AMC and ANC correlate with PFS 4C, High baseline circulating AMC:ALC is associated with disease progression and resistance to immunotherapy 4D, Baseline circulating PMN-MDSC in IOF and ION

Table S1. Tolerability of veliparib, carboplatin, and etoposide over entire combination cycles treatment period Table S2. Mean {plus minus} SD (% CV) pharmacokinetic parameters of veliparib following oral administration of veliparib in combination with carboplatin and etoposide on Cycle 1 Day 1 Figure S1. Mean (+SD) dose normalized etoposide plasma concentration-time profile with and without veliparib co-administration Table S3. Pharmacokinetic parameters of etoposide {plus minus} veliparib Table S4. Objective response rate in biomarker cohort by tumor type and veliparib dose level Figure S2. Tumor response and time on study for all dosed patients (n=39) Figure S3. Progression-free survival by disease type Figure S4. Confirmed objective response by gene type in small cell lung cancer samples (n=17)

Supplementary Figure 1. Overview of XPO1's role in nuclear:cytoplasmic transport. Supplementary Figure 2. KPT-185 is much less toxic to patient-derived benign cells than patient-derived serous high grade OvCa cells. Supplementary Figure 3. FACS cell cycle analysis of indicated cell lines treated with KPT-185 at respective IC50 doses or control DMSO for 36 hours. Data shown as mean percentage in G1 phase. Supplementary Figure 4. Combinatorial effects of KPT-185 and cisplatin in OvCa cells. Supplementary Figure 5. Knockdown of p53 by p53 siRNA blocked the KPT-mediated apoptosis in CP70 cells. Supplementary Figure 6. P53 network following KPT-185 treatment in CP70 cells. Supplementary Figure7. Representative images and mutation status of original human tumor pathology specimens and paired PDX tumor sections.

Purpose: The high fatality-to-case ratio of ovarian cancer is directly related to platinum resistance. Exportin-1 (XPO1) is a nuclear exporter that mediates nuclear export of multiple tumor suppressors. We investigated possible clinicopathologic correlations of XPO1 expression levels and evaluated the efficacy of XPO1 inhibition as a therapeutic strategy in platinum-sensitive and -resistant ovarian cancer.Experimental Design: XPO1 expression levels were analyzed to define clinicopathologic correlates using both TCGA/GEO datasets and tissue microarrays (TMA). The effect of XPO1 inhibition, using the small-molecule inhibitors KPT-185 and KPT-330 (selinexor) alone or in combination with a platinum agent on cell viability, apoptosis, and the transcriptome was tested in immortalized and patient-derived ovarian cancer cell lines (PDCL) and platinum-resistant mice (PDX). Seven patients with late-stage, recurrent, and heavily pretreated ovarian cancer were treated with an oral XPO1 inhibitor.Results: XPO1 RNA overexpression and protein nuclear localization were correlated with decreased survival and platinum resistance in ovarian cancer. Targeted XPO1 inhibition decreased cell viability and synergistically restored platinum sensitivity in both immortalized ovarian cancer cells and PDCL. The XPO1 inhibitor–mediated apoptosis occurred through both p53-dependent and p53-independent signaling pathways. Selinexor treatment, alone and in combination with platinum, markedly decreased tumor growth and prolonged survival in platinum-resistant PDX and mice. In selinexor-treated patients, tumor growth was halted in 3 of 5 patients, including one with a partial response, and was safely tolerated by all.Conclusions: Taken together, these results provide evidence that XPO1 inhibition represents a new therapeutic strategy for overcoming platinum resistance in women with ovarian cancer. Clin Cancer Res; 23(6); 1552–63. ©2016 AACR.

Purpose:The CLASSICAL-Lung clinical trial tested the combination of pepinemab, an IgG4 humanized mAb targeting semaphorin 4D, with the PD-L1 inhibitor avelumab to assess the effects of coupling increased T-cell infiltration and reversal of immune suppression via pepinemab with sustained T-cell activation via checkpoint inhibition.Patients and Methods:This phase Ib/II, single-arm study was designed to evaluate the safety, tolerability, and efficacy of pepinemab in combination with avelumab in 62 patients with advanced non–small cell lung cancer (NSCLC), including immunotherapy-naïve (ION) patients and patients whose tumors progressed following anti-PD-1/L1 monotherapy (IOF). The main objectives were to evaluate safety/tolerability, establish a recommended phase 2 dose (RP2D), obtain a preliminary evaluation of antitumor activity, and investigate candidate biomarker activity.Results:The combination was well tolerated with no major safety signals identified. Pepinemab, 10 mg/kg with avelumab, 10 mg/kg, every 2 weeks, was selected as the RP2D. Among 21 evaluable ION patients, 5 patients experienced partial responses (PR), 4 patients evidenced clinical benefit ≥1 year, and the disease control rate (DCR) was 81%. Notably, overall response rate with the combination therapy was higher than previously reported for single-agent avelumab in the PD-L1-negative/low population. Among 29 evaluable IOF patients, the combination resulted in a DCR of 59%, including 2 PR and 7 patients with durable clinical benefit of ≥23 weeks. Biomarker analysis of biopsies demonstrated increased CD8 T-cell density correlating with RECIST response criteria.Conclusions:The combination of pepinemab with avelumab was well tolerated in NSCLC and showed signs of antitumor activity in immunotherapy-resistant and PD-L1-negative/low tumors.

Supplementary Figure Legend

Supplementary Table 1. cBIO data for XPO1 overexpression and association with survival. Supplementary Table 2. Clinical features of patient samples in TMA. Supplementary Table 3. Clinicopathologic features for patient-derived tumor cell lines.

Purpose: The CLASSICAL-Lung clinical trial tested the combination of pepinemab, an IgG4 humanized mAb targeting semaphorin 4D, with the PD-L1 inhibitor avelumab to assess the effects of coupling increased T-cell infiltration and reversal of immune suppression via pepinemab with sustained T-cell activation via checkpoint inhibition. Patients and Methods: This phase Ib/II, single-arm study was designed to evaluate the safety, tolerability, and efficacy of pepinemab in combination with avelumab in 62 patients with advanced non–small cell lung cancer (NSCLC), including immunotherapy-naïve (ION) patients and patients whose tumors progressed following anti-PD-1/L1 monotherapy (IOF). The main objectives were to evaluate safety/tolerability, establish a recommended phase 2 dose (RP2D), obtain a preliminary evaluation of antitumor activity, and investigate candidate biomarker activity. Results: The combination was well tolerated with no major safety signals identified. Pepinemab, 10 mg/kg with avelumab, 10 mg/kg, every 2 weeks, was selected as the RP2D. Among 21 evaluable ION patients, 5 patients experienced partial responses (PR), 4 patients evidenced clinical benefit ≥1 year, and the disease control rate (DCR) was 81%. Notably, overall response rate with the combination therapy was higher than previously reported for single-agent avelumab in the PD-L1-negative/low population. Among 29 evaluable IOF patients, the combination resulted in a DCR of 59%, including 2 PR and 7 patients with durable clinical benefit of ≥23 weeks. Biomarker analysis of biopsies demonstrated increased CD8 T-cell density correlating with RECIST response criteria. Conclusions: The combination of pepinemab with avelumab was well tolerated in NSCLC and showed signs of antitumor activity in immunotherapy-resistant and PD-L1-negative/low tumors.

Purpose: This study examined safety, pharmacokinetics, and efficacy of veliparib, a PARP inhibitor, combined with carboplatin and etoposide in patients with extensive-stage (ED) small cell lung cancer (SCLC) and other solid tumors. Patients and Methods: The 3 + 3 design was used for dose escalation of oral veliparib in combination with carboplatin (AUC 5 on day 1) and etoposide (100 mg/m2 on days 1–3) in 21-day cycles. Veliparib dose was explored from 80 to 240 mg b.i.d. on 7-day, 14-day, or continuous schedules. Patients without disease progression continued on maintenance monotherapy (veliparib 400 mg b.i.d.) until disease progression or unacceptable toxicity. Results: Thirty-nine patients were enrolled to determine the recommended phase II dose of 240 mg veliparib for 14 days combined with carboplatin and etoposide based on long-term tolerability. Dose-limiting toxicity occurred in 1 patient (grade 2 toxic motor polyneuropathy) at veliparib 240 mg b.i.d. for 7 days. Most common adverse events related to veliparib were nausea (39%), fatigue (39%), and hematologic toxicities. Continuous dosing of veliparib 240 mg b.i.d. with carboplatin and etoposide resulted in excessive chemotherapy dose delays due to hematologic toxicity (grade 3/4 neutropenia/thrombocytopenia). Etoposide pharmacokinetics was not affected by veliparib. Confirmed responses occurred in 17 of 39 (44%) and 16 of 25 (64%) of all enrolled and ED SCLC patients, respectively. At the RP2D, confirmed responses occurred in 6 of 13 (46%) and 5 of 6 (83%) of all enrolled and ED SCLC patients, respectively. Conclusions: Veliparib (240 mg b.i.d. 14 days) plus carboplatin/etoposide can be safely combined. Phase II of this study is ongoing in first-line patients with ED SCLC.

12085 Background: Anemia is prevalent in patients (pts) receiving myelosuppressive chemotherapy (> 60%) and exacerbated by repeated treatment cycles due to cytotoxic agent accumulation. Chemotherapy-induced anemia (CIA) management options are suboptimal. We evaluated the efficacy and safety of roxadustat in pts with anemia receiving myelosuppressive chemotherapy. Methods: This open-label, single-arm, proof-of-concept Phase 2 study included pts with mostly advanced, non-myeloid malignancies and CIA (hemoglobin [Hb] ≤10 g/dL) who had not received red blood cell (RBC) transfusion or erythropoietin-stimulating agents within 4 weeks of enrollment. Patients were treated with oral roxadustat for ≤16 weeks. The primary efficacy endpoint was maximum mean change in Hb within 16 weeks of baseline without RBC transfusion in pts who had received ≥1 dose of roxadustat and who had a baseline and ≥1 post-dose Hb assessment. Hb response and safety data were preliminarily assessed in pts receiving a starting dose of 2.0 mg/kg thrice weekly (TIW) for 4 weeks: doses of 100, 150, and 200 mg were given to pts weighing < 70, 70–100, and > 100 kg, respectively. Following a review of data from these pts, dose was increased to 2.5 mg/kg—150, 200, and 250 mg TIW to pts weighing < 70, 70–100, and > 100 kg, respectively—and adjusted every 4 weeks from Week 5 based on Hb response. Results: Patients were assigned to 2.0 mg/kg (n = 31) and 2.5 mg/kg (n = 61) starting doses, and 89 were assessed for efficacy. The maximum mean Hb change from baseline without RBC transfusion was 2.47±1.51 g/dL and 2.52±1.54 g/dL in the 2.0 mg/kg and 2.5 mg/kg cohorts, respectively. Hb increased by ≥1.5 g/dL in 73% of pts and ≥2.0 g/dL in 61% of pts. Median time to ≥2.0 g/dL Hb increase was 71.0 days. Both cohorts had higher proportions of pts with a Hb increase of ≥1, ≥1.5, or ≥2 g/dL at Week 16 compared with baseline. Median time to ≥1 and ≥2 g/dL Hb increase was shorter in pts who started on 2.5 mg/kg compared with 2.0 mg/kg doses (≥1 g/dL: 30 vs 44; ≥2 g/dL 57 vs 105, respectively). Fewer pts required an RBC transfusion (Week 5 to end of treatment) when starting on 2.5 mg/kg compared with 2.0 mg/kg doses (10.2% vs 20.0%). Subgroup analyses based on major tumor and baseline chemotherapy types demonstrated efficacy of roxadustat at both starting doses. The overall safety profile observed was consistent with the patient population under study. Overall, 92% of pts experienced an adverse event (AE). Most AEs were consistent with the underlying malignancies and chemotherapy regimens used. The incidence of deep vein thrombosis was 15.2% (n = 14) and pulmonary embolism was 9.8% (n = 9). There were 17 deaths (18.5%) during the study; none were attributed to roxadustat, and most were associated with disease progression. Conclusions: Roxadustat increased Hb in CIA regardless of tumor type and chemotherapy regimen. These data support additional clinical study. Clinical trial information: NCT04076943.

TPS2695 Background: Advances in immunotherapy have led to significantly improved survival and quality of life in some cancer patients, but many with less immunogenic tumor types derive suboptimal clinical benefit. Recombinant human interleukin-2 (IL-2, aldesleukin) can induce a response rate of ̃15% in metastatic renal cell carcinoma and metastatic melanoma, yet toxicities (vascular leak syndrome, cytokine storm) have limited its use. TransCon IL-2 β/γ, a novel prodrug with sustained release of a receptor-selective IL-2 (IL-2 β/γ), was designed to optimally address drawbacks of aldesleukin: potent activation of undesired IL-2Rα+ cell types and high Cmax with rapid clearance. TransCon IL-2 β/γ comprises 3 main components: IL-2 β/γ, a methoxy polyethylene glycol (mPEG) carrier molecule, and a linker connecting the two. Under physiological conditions, TransCon IL-2 β/γ releases active IL-2 β/γ from the mPEG carrier through cleavage of the TransCon Linker. This results in a lower Cmax and much longer effective t½ of free IL-2 β/γ compared to aldesleukin. PD-1 expression at the cell surface of activated cytotoxic T cells and natural killer cells provides a clear rationale to study TransCon IL-2 β/γ alone or in combination with pembrolizumab. Methods: IL Believe is a multicenter, first-in-human, Phase 1/2 study in 3 parts in adult patients with locally advanced or metastatic solid tumors. All patients need ≥1 measurable lesion per RECIST 1.1 and an ECOG score of ≤ 2. The primary objectives are to evaluate safety and tolerability, and to define the maximum tolerated dose and recommended Phase 2 dose (RP2D) of TransCon IL-2 β/γ alone or in combination with pembrolizumab. Parts 1 and 2 Dose Escalation (Phase 1) use a standard 3+3 design with increasing doses of intravenous (IV) TransCon IL-2 b/g alone (Part 1) or with 200 mg IV pembrolizumab in solid tumors where pembrolizumab monotherapy may have clinical activity (Part 2). Each part will enroll ̃15 patients. Part 3, Combination Dose Expansion (Phase 2) will evaluate preliminary clinical efficacy of TransCon IL-2 β/γ at the RP2D determined in Part 2, combined with chemotherapy. Platinum Resistant Ovarian Cancer is currently planned for dose expansion with other indication specific cohorts to be included in a subsequent amendment. Each cohort will be analyzed using a Simon 2-stage design and will enroll ̃56 patients. Other key objectives include the evaluation of pharmacokinetics, pharmacodynamic biomarkers, and antitumor activity according to RECIST 1.1. Recruitment started in January 2022 and is ongoing (NCT05081609). Clinical trial information: NCT05081609.

Background CDX-1140 is an agonist anti-CD40 mAb selected to optimize systemic exposure and hence tumor microenvironment (TME) ingress. CDX-1140 activity may be enhanced by combining with CDX-301 (recombinant Flt3L), a dendritic cell growth factor, or with pembrolizumab, an anti-PD-1 mAb. Methods Patients with advanced solid or hematologic (Part 1 only) tumors are enrolled. Part 1 dose-escalation results have been presented (SITC 2019). In Part 2, CDX-1140 dose-escalation (0.09–1.5 mg/kg q4w) is in combination with CDX-301 (75 mcg/kg sc QD x 5 for 2 cycles). In Part 3, CDX-1140 dose-escalation (0.72–1.5 mg/kg q3w) is in combination with pembrolizumab 200 mg q3w. Part 1 and 2 expansion cohorts are dosed at the CDX-1140 MTD, 1.5 mg/kg q4w. Part 3 expansion cohorts are planned. Peripheral blood and tumor biomarkers analysis are ongoing. Results 92 patients have been treated (Part 1 n=57, Part 2 n=31, Part 3 n=4). Part 1 expansion cohorts in SCCHN (n=7) and RCC (n=5) are fully enrolled. Part 2 dose-escalation completed to the highest CDX-1140 dose and a SCCHN expansion cohort is ongoing. Part 3 dose-escalation recently initiated. Safety data is available for 23 and 10 patients at the MTD in Part 1 and 2, respectively. In general, the safety profiles were similar, with arthralgia (52% vs. 50%), pyrexia (44% vs 50%), fatigue (30% vs. 50%), chills (39% vs. 40%), vomiting (30% vs. 20%), nausea (26% vs 40%), myalgia (22% vs. 30%), increased ALT (22% vs. 20%), and increased AST (22% vs. 30%) being the most common drug related AEs at the MTD in Part 1 and 2, respectively. Most AEs were low grade. Across all cohorts, cytokine release syndrome (CRS) (G2 n=4, G3 n=2) occurred in 6 (Part 1 n=2; Part 2 n=4) and pneumonitis (G3) occurred in 5 (Part 1 n=4; Part 2 n=1) patients. Immune activation in the TME consistent with CD40 agonism and increases serum inflammatory cytokines were observed. Evidence of anti-tumor activity/clinical benefit include SD (n=13), tumor cavitation (n=2) and a uPR in solid tumors. A patient with follicular lymphoma has an ongoing durable complete metabolic response. Conclusions The CDX-1140 MTD dose of 1.5 mg/kg, a dose level expected to provide good systemic exposure and TME penetration, is generally well tolerated alone and with CDX-301. Transaminitis and CRS have generally been low grade and infrequent. A cohort combining CDX-1140 with chemotherapy will be initiated in patients with previously untreated metastatic pancreatic adenocarcinoma. Trial Registration NCT03329950 Ethics Approval The study was approved by the following: Providence St. Joseph Health IRB, approval number MOD2020001128; WIRB, approval number 1188814 (Hauke, Gabrail, Bordoni & Gordon); University of Pennsylvania IRB, approval number UPCC 18917; Mount Sinai School of Medicine IRB, approval number 18-00202; Memorial Sloan Kettering Cancer Center IRB, approval number 18-225A; Houston Methodist IRB, approval number MOD00000836

TPS375 Background: In normal conditions, Claudin (CLDN)18.2 is a tight junction protein with expression strictly confined to differentiated epithelial cells in gastric mucosa. CLDN18.2 has been found to be upregulated, and involved in tumor development and progression in a variety of tumor types such as gastric, pancreatic, and bile duct cancer (BTC). The biological characteristics of CLDN18.2 suggest it is an ideal therapeutic target for cancer drug development. IMAB362 is the first anti-CLDN18.2 monoclonal antibody (mAb) of high potency to have been tested in humans and it revealed clinical efficacy in gastric cancer in a phase II study. TST001, a humanized IgG1 mAb, binds to a distinct epitope of CLDN18.2 with higher affinity and mediates CLDN18.2 expressing cancer cell death through antibody-dependent cellular cytotoxicity (ADCC) in comparison with IMAB362; Furthermore, TST001 is produced using an optimized glycoengineering process to increase affinity to FcR. The enhanced binding to CLDN18.2 on tumor cells and FcR on NK cells results in more efficient engagement of the tumor cells with NK cells and antibody mediated cellular cytotoxicity. In preclinical xenograft studies, TST001 displayed potent anti-tumor activities in the tumor models with medium to high level of CLDN18.2 expression and synergy anti-cancer effect with checkpoint inhibitor. A mAb specific for CLDN18.2 was also developed as an IHC based biomarker for patient enrollment in the clinical trials. Methods: This is an open-label, multi-center, phase I clinical trial to evaluate the safety, maximum tolerated dose (MTD), pharmacokinetics (PK) profile and preliminary anti-cancer effect of TST001 in patients with locally advanced or metastatic solid tumors. (NCT04396821) The study consists of two parts: Part A is a 3+3 dose escalation design with sequential dose cohorts of 1, 3, 6, 10mg/kg in Q2W and Q3W schedules. Based on the emerging safety data, higher doses may be proposed for testing. About 27-54 patients will be enrolled. Dose expansion (Part B) will utilize doses of TST001 based on the emerging data from Part A. In Part B, up to 20 patients with CLDN18.2 overexpression per tumor specific cohort will be enrolled to 3 cohorts: A: TST001 single agent in gastric/gastroesophageal junction (G/GEJ) cancer; B: TST001 + nivolumab in G/GEJ cancer; C: TST001 single agent in pancreatic cancer or BTC. All patients in Part B will be selected by CLDN18.2 expression by central lab testing. The safety, anti-tumor activity, and PK will be further assessed in Part B. Enrolment began in July 2020 in the USA and is ongoing in multiple sites. As of 20 September, 2021, 23 subjects were dosed in Part A and the dose of 10mg/kg is being tested. Another phase I study of TST001 single agent and in combination with chemotherapy in patients with metastatic solid tumor is also ongoing in China (NCT04495296).

Background/Introduction: Lower-risk (IPSS low risk and Int-1) myelodysplastic syndromes (MDS) are typically treated supportively to address cytopenias. DNA methyltransferase inhibitors (DNMTi) such as azacitidine and decitabine (DEC) are FDA-approved for higher risk MDS patients (pts), and while the DEC USPI includes IPSS Int-1 pts, it is not widely used in this population. Approved intravenous (IV) or subcutaneous (SC) regimens require 5-7 days of treatment every month burdening older cancer pts due to daily travel and treatment time and may increase potential risk from pandemic SARS-CoV-2 infection. Because DNMTis are rapidly degraded by cytidine deaminase (CDA) in the gut and liver, oral availability has only been recently possible. A randomized study with CC-486, an oral formulation of azacitidine, in the Int-1 population showed a median overall survival (mOS) of approximately 17 months for both placebo and treated patients (Garcia-Manero, 2021). Oral DEC 35 mg/cedazuridine 100 mg (ASTX727) or DEC-C, is an oral fixed dose combination (FDC) of DEC and the CDA inhibitor cedazuridine (CED) resulting in equivalent exposure (99%; 90% CI 93% to 106%) to standard IV DEC 20 mg/m 2 for 5 days in an intra-patient randomized cross-over study (Garcia-Manero et al, ASH 2019). Here, we present data on patients with lower risk MDS from that study. Methods: We used a randomized cross over design with pts randomized 1:1 in the first 2 cycles to either Sequence A: (DEC 35 mg/ CED 100 mg in Cycle 1 and IV DEC at 20 mg/m 2 in Cycle 2), or Sequence B (IV DEC in Cycle 1 and oral DEC/CED in Cycle 2). Cycles were repeated every 28 days unless delays were needed, and all patients received oral DEC-C in Cycles 3+ until disease progression or unacceptable toxicity. We conducted an intra-patient comparison of DEC PK (DEC AUC equivalence over 5 days of dosing). Pts were eligible as per the FDA-approved label of IV DEC (MDS pts by FAB classification including CMML, or MDS IPSS Intermediate-1, 2 or high-risk pts). Clinical endpoints were best response as assessed by an independent expert panel according to IWG 2006 response criteria, transfusion independence (TI), overall survival (OS), and safety. Results: Of the 133 pts treated in ASCERTAIN, 69 had a diagnosis of lower-risk MDS (93% Int-1, 7% LR). Median age was 70.0 years (range 45-87), 65% were male, median weight was 84 kg (range 50-127), median baseline hematologic parameters were: hemoglobin 89 g/L (range 69.8-146.5), WBCs 1.50 X 10 9/L (range 0.11-7.1), platelets (plt) 86 x 10 9/L (range 5-703), bone marrow blasts 4% (range 0-18), cytogenetics: 7 (10.1%) poor-risk, 21 (30.4%) intermediate risk, 37 (53.6%) better-risk, 4 (5.7%) missing or not evaluable. 27(39%) of the pts were RBC transfusion dependent (TD) and 6 (9%) plt TD. 17 (25%) had received prior MDS treatment, 3% prior DNMTi. Pts received a median of 9 cycles of therapy (range 1-28). Treatment-emergent adverse events of CTCAE Gr 3 or higher in >10% of pts, independent of relationship to ASTX727, included cytopenias (neutropenia [59%], thrombocytopenia [58%], anemia [48%], leukopenia [26%]), febrile neutropenia (32%), and pneumonia (19%). Sixteen pts (23%) achieved Complete Response (CR), 18 (26%) had marrow CR (mCR), including 9 (13%) with hematologic improvement (HI). Overall Response rate (ORR; CR + PR+ mCR + HI) was 57%. Of those RBC or plt TD at baseline, 13 (48%) became RBC TI and 4 (67%) became plt TI. With approximately 32 months of median follow up, neither median leukemia-free survival (mLFS) nor mOS had been reached (Figure 1). Twelve pts (17%) went on to allogeneic stem cell transplant. Conclusions: Oral decitabine/cedazuridine given as a FDC in MDS pts produced equivalent PK exposure to 20 mg/m 2 IV DEC; in lower risk MDS pts with treatment indicated, the agent was generally well-tolerated with prolonged treatment and could result in mLFS and mOS which exceeds 32 months. This FDC and other dosing regimens of oral DEC-C should be further studied in this patient population. References: Garcia-Manero, et al, ASH 2019 Savona, et al, Int. MDS Symp. 2021 Garcia-Manero, et al, Phase III, Randomized, Placebo-Controlled Trial of CC-486 (Oral Azacitidine) in Patients with Lower-Risk Myelodysplastic Syndromes. J.Clin.Onc. 2021 39:13, 1426-1436 Figure 1 Figure 1. Disclosures McCloskey: Pfizer: Consultancy; Jazz: Consultancy, Speakers Bureau; COTA: Other: Equity Ownership; Incyte: Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Novartis: Consultancy; BMS: Honoraria, Speakers Bureau; Amgen: Speakers Bureau. Griffiths: Alexion Pharmaceuticals: Consultancy, Research Funding; Abbvie: Consultancy, Honoraria; Taiho Oncology: Consultancy, Honoraria; Genentech: Research Funding; Novartis: Honoraria; Takeda Oncology: Consultancy, Honoraria; Astex Pharmaceuticals: Honoraria, Research Funding; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Apellis Pharmaceuticals: Research Funding; Boston Biomedical: Consultancy. Yee: Paladin: Membership on an entity's Board of Directors or advisory committees; TaiHo: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Research Funding; Geron: Research Funding; Janssen: Research Funding; Jazz: Research Funding; MedImmune: Research Funding; Onconova: Research Funding; Tolero: Research Funding; AbbVie: Honoraria; Bristol-Myers Squibb/Celgene: Membership on an entity's Board of Directors or advisory committees; Otsuka: Membership on an entity's Board of Directors or advisory committees; Shattuck Labs: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; F. Hoffmann La Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Forma Therapeutics: Research Funding; Astex: Membership on an entity's Board of Directors or advisory committees, Research Funding. Zeidan: Novartis: Consultancy, Other: Clinical Trial Committees, Travel support, Research Funding; Genentech: Consultancy; Ionis: Consultancy; Astellas: Consultancy; Epizyme: Consultancy; AbbVie: Consultancy, Other: Clinical Trial Committees, Research Funding; Jasper: Consultancy; Cardiff Oncology: Consultancy, Other: Travel support, Research Funding; BeyondSpring: Consultancy; Loxo Oncology: Consultancy, Other: Clinical Trial Committees; Janssen: Consultancy; Acceleron: Consultancy, Research Funding; AstraZeneca: Consultancy; Kura: Consultancy, Other: Clinical Trial Committees; Gilead: Consultancy, Other: Clinical Trial Committees; Agios: Consultancy; Daiichi Sankyo: Consultancy; Boehringer Ingelheim: Consultancy, Research Funding; Geron: Other: Clinical Trial Committees; BMS: Consultancy, Other: Clinical Trial Committees, Research Funding; BioCryst: Other: Clinical Trial Committees; Pfizer: Other: Travel support, Research Funding; Aprea: Consultancy, Research Funding; ADC Therapeutics: Research Funding; Jazz: Consultancy; Incyte: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Astex: Research Funding. Al-Kali: Astex: Other: Research support to institution; Novartis: Research Funding. Patel: Celgene-BMS: Membership on an entity's Board of Directors or advisory committees; PVI: Honoraria; Agios: Membership on an entity's Board of Directors or advisory committees. Sabloff: Pfizer: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; ROCHE: Membership on an entity's Board of Directors or advisory committees; TaiHo: Membership on an entity's Board of Directors or advisory committees; Jaxx: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees. Dao: Astex Pharmaceuticals, Inc.: Current Employment. Fazal: Taiho Pharmaceuticals: Consultancy, Honoraria, Speakers Bureau; Stemline Therapeutics: Consultancy, Honoraria, Speakers Bureau; Sanofi Genzyme: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Karyopharm Pharmaceuticals: Consultancy, Honoraria, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Honoraria, Speakers Bureau; Janssen Oncology: Consultancy, Honoraria, Speakers Bureau; Incyte: Consultancy, Honoraria, Speakers Bureau; Glaxo Smith Kline: Consultancy, Honoraria, Speakers Bureau; Gilead Sciences: Consultancy, Honoraria, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Speakers Bureau; AMGEN: Consultancy, Honoraria, Speakers Bureau; Agios: Consultancy, Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria, Speakers Bureau. Odenike: AbbVie, Celgene, Impact Biomedicines, Novartis, Taiho Oncology, Takeda: Consultancy; Celgene, Incyte, AstraZeneca, Astex, NS Pharma, AbbVie, Gilead, Janssen, Oncotherapy, Agios, CTI/Baxalta, Aprea: Research Funding. Kantarjian: AbbVie: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Ascentage: Research Funding; Pfizer: Honoraria, Research Funding; BMS: Research Funding; Daiichi-Sankyo: Research Funding; Amgen: Honoraria, Research Funding; Ipsen Pharmaceuticals: Honoraria; Jazz: Research Funding; Astellas Health: Honoraria; Immunogen: Research Funding; Astra Zeneca: Honoraria; Aptitude Health: Honoraria; KAHR Medical Ltd: Honoraria; NOVA Research: Honoraria; Precision Biosciences: Honoraria; Taiho Pharmaceutical Canada: Honoraria. DeZern: Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Taiho: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees. Roboz: Novartis: Consultancy; Mesoblast: Consultancy; Jasper Therapeutics: Consultancy; Jazz: Consultancy; MEI Pharma - IDMC Chair: Consultancy; Daiichi Sankyo: Consultancy; Otsuka: Consultancy; Bristol Myers Squibb: Consultancy; Blueprint Medicines: Consultancy; Bayer: Consultancy; AstraZeneca: Consultancy; Astellas: Consultancy; Astex: Consultancy; Amgen: Consultancy; Agios: Consultancy; Actinium: Consultancy; AbbVie: Consultancy; Janssen: Research Funding; Celgene: Consultancy; Glaxo SmithKline: Consultancy; Helsinn: Consultancy; Janssen: Consultancy; Pfizer: Consultancy; Roche/Genentech: Consultancy. Busque: Novartis: Consultancy. Leber: Astellas: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Otsuka: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TaiHo: Honoraria, Membership on an entity's Board of Directors or advisory committees; AMGEN: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Hao: Astex Pharmaceuticals, Inc.: Current Employment. Keer: Astex Pharmaceuticals, Inc.: Current Employment. Azab: Astex Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees. Savona: Geron: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; CTI: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS-Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; NOVARTIS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Ryvu: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sierra Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Taiho: Consultancy, Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; ALX Oncology: Research Funding; Astex: Research Funding; Incyte: Research Funding.

Background: BCL-2 inhibition with venetoclax has proved to be highly effective treatment for patients with CLL. However, when administered to patients with CLL who have a high tumor burden, venetoclax is associated with an elevated risk of tumor lysis syndrome (TLS). Because of this risk, venetoclax is initiated with a gradual, 5-week dose ramp-up, requiring close laboratory monitoring over an extended period. Lisaftoclax (APG-2575) is a novel, potent, selective BCL-2 inhibitor under clinical development for hematologic malignancies (HMs). Preliminary data in 18 patients with CLL treated in a first-in-human study suggested the feasibility of an abbreviated ramp-up of lisaftoclax that might also result in a lower incidence of neutropenia (Ailawadhi et al, J Clin Oncol 39, 2021; abstr 7502). Methods: This new study is a global, open-label, multicenter, two-part phase 1b dose escalation and dose expansion study to assess the safety and tolerability of lisaftoclax (Part 1) and lisaftoclax combined with rituximab or acalabrutinib (Part 2), including dose-limiting toxicity (DLT) and maximum tolerated dose (MTD). The trial is enrolling adults with (1) histologically confirmed CLL/SLL (by 2018 iwCLL criteria) that is relapsed or refractory to ≥ 1 prior therapy and requires treatment (also by 2018 iwCLL criteria); (2) adequate bone marrow function (in the absence of growth factors), including absolute neutrophils ≥ 1.0 × 10 9/L in patients without bone marrow involvement (not required in CLL/SLL patients with bone marrow involvement); and (3) adequate renal and hepatic function. Exclusion criteria: (1) recent history of allogeneic stem cell transplantation or CAR T-cell therapy (< 90 days); (2) prior treatment with a BCL-2 inhibitor (unless patient discontinued such therapy without disease progression); (3) treatment with vitamin K anticoagulants or previous discontinuation of treatment due to acalabrutinib toxicity (in acalabrutinib plus lisaftoclax cohort); (4) active Richter's syndrome; (5) infection (e.g. HIV, hepatitis); (6) CNS involvement; (7) prior cancer that has recurred within 2 years of screening and requires treatment (apart from adequately treated cervical or breast carcinoma in situ); (8) uncontrolled and other serious concomitant illnesses, including cardiovascular disease and diabetes; (9) failure to recover adequately after surgical procedures; and (10) active graft-vs-host disease or a requirement for immunosuppressive treatment. In a standard "3+3" dose escalation design (Part 1), lisaftoclax is being administered orally once daily in a 28-day cycle, with full doses of 200 to 1,200 mg (by 200-mg increments at 4 dose levels (400, 600, 800, and 1,000 mg) in parallel. The ramp-up is performed in the hospital with close monitoring for TLS and consists of the following doses and days of lisaftoclax treatment: 20 mg on Day 1, 50 mg on Day 2, 100 mg on Day 3, 200 mg on Day 4, 400 mg on Day 5, 600 mg on Day 6, 800 mg on Day 7, and 1,000 mg on Day 8. Patients who experience TLS on any of these days have their dose held until resolution of TLS before proceeding to the next dose. Part 2 includes a further standard 3+3 dose escalation of lisaftoclax combined with rituximab or acalabrutinib (in separate cohorts), with a further planned dose expansion at recommended phase 2 doses of these combination regimens. Primary outcome measures are (1) DLTs observed during cycle 1; and (2) MTD (measured over the same interval). DLT criteria are defined as grade 4 thrombocytopenia or neutropenia lasting > 7 days, grade 3 ≥ thrombocytopenia with bleeding, grade 4 febrile neutropenia, or grade 3 ≥ non-hematologic toxicities. As of July 19, 2021, 71 patients have been enrolled (of 144 planned). Clinicaltrial.gov identifier: NCT04215809. Disclosures Davids: Ascentage Pharma: Consultancy, Research Funding; Astra-Zeneca: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; MEI Pharma: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; Verastem: Consultancy, Research Funding; Surface Oncology: Research Funding; AbbVie: Consultancy; Adaptive Biotechnologies: Consultancy; BeiGene: Consultancy; Celgene: Consultancy; Eli Lilly and Company: Consultancy; Janssen: Consultancy; MEI Pharma: Consultancy; Merck: Consultancy; Research to Practice: Consultancy; Takeda: Consultancy. Siddiqi: Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Juno therapeutics: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BeiGene: Other: DSM Member, Speakers Bureau; PCYC: Speakers Bureau; Jannsen: Speakers Bureau; Dava Oncology: Honoraria; ResearchToPractice: Honoraria. Pagel: Gilead: Consultancy; AstraZeneca: Consultancy; BeiGene: Consultancy; Incyte/MorphoSys: Consultancy; Epizyme: Consultancy; Kite, a Gilead Company: Consultancy; Actinium Pharmaceuticals: Consultancy; MEI Pharma: Consultancy; Pharmacyclics/AbbVie: Consultancy. Pylypenko: Communal nonprofit enterprise "Cherkasy regional oncology dispensary of Cherkasy oblast council: Current Employment. Kriachok: Takeda, Roche, Abbivie, Janssen, MSD: Consultancy; Takeda, Roche, Abbvie, Janssen, MSD, Pfizer: Honoraria, Speakers Bureau. Usenko: Abbvie: Honoraria; Acerta: Honoraria; Ascentage: Honoraria; AstraZeneca: Honoraria; Celgene: Honoraria; Il Yang: Honoraria; Janssen: Honoraria; Karyopharm: Honoraria; Oncopeptides: Honoraria; Rigel: Honoraria; Takeda: Honoraria; UCB: Honoraria. Chen: Ascentage Pharma (Suzhou) Co., Ltd: Current Employment, Current equity holder in publicly-traded company. Huang: Ascentage Pharma (Suzhou) Co., Ltd.: Current Employment, Current equity holder in publicly-traded company. Li: Ascentage Pharma (Suzhou) Co., Ltd.: Current Employment, Current equity holder in publicly-traded company. Ahmad: Ascentage Pharma Group Inc.: Current Employment, Current equity holder in publicly-traded company. Mudenda: Ascentage Pharma Group Inc.: Current Employment, Current equity holder in publicly-traded company. Yang: Ascentage Pharma (Suzhou) Co., Ltd: Current Employment, Current equity holder in publicly-traded company, Other: Leadership and other ownership interests, Patents & Royalties, Research Funding. Zhai: Ascentage Pharma (Suzhou) Co., Ltd.: Current Employment, Current equity holder in publicly-traded company, Other: Leadership and other ownership interests, Patents & Royalties, Research Funding; Ascentage Pharma Group Inc.: Current Employment, Current equity holder in publicly-traded company, Other: Leadership and other ownership interests, Patents & Royalties, Research Funding.

Introduction: Hypomethylating agents (HMAs) or DNA methyltransferase inhibitors (DNMTi) such as decitabine or azacitidine are established standard of care for the treatment of MDS and CMML. The oral bioavailability of these agents has been limited due to rapid degradation by cytidine deaminase (CDA) in the gut and liver, hence requiring intravenous infusion or subcutaneous injections daily for 5-7 days every month (m). This parenteral administration requirement adds significant burden to older cancer patients due to daily time commitment and travel to treatment centers. It also increases exposure to and infection risk with SARS-CoV-2 during the COVID-19 pandemic. Oral decitabine 35 mg/cedazuridine 100 mg (ASTX727) is an oral fixed dose combination drug of decitabine and the CDA inhibitor cedazuridine that have shown 99% (90% CI 93% to 106%) equivalent exposure to standard dose IV decitabine 20 mg/m2 in a randomized cross-over study (Garcia-Manero et al, ASH 2019). Here, we present the clinical efficacy and safety results of oral decitabine/cedazuridine from 133 patient study in MDS and CMML (ASTX727-02 ASCERTAIN study). Methods: We used a randomized cross over design where patients were randomized in the first 2 cycles 1:1 to either Sequence A: decitabine 35 mg/ cedazuridine 100 mg in Cycle 1 followed by IV decitabine at 20 mg/m2 in Cycle 2, or Sequence B: IV decitabine in Cycle 1 followed by oral decitabine/cedazuridine in Cycle 2 to do an intra-patient comparison of decitabine PK (primary PK endpoint: decitabine AUC equivalence over 5 days of dosing). Cycles were repeated every 28 days. All patients received oral decitabine/cedazuridine in all subsequent cycles from Cycle 3 onwards until disease progression or unacceptable toxicity. Patients were eligible as per the FDA-approved label of IV decitabine (MDS patients by FAB classification including CMML, or MDS IPSS Intermediate-1, 2 or high-risk patients). Clinical endpoints were best response as assessed by an independent expert panel according to International Working Group (IWG) 2006 response criteria, transfusion independence for at least 8 or 16 consecutive weeks, overall survival, and safety. Adverse events (AEs) were graded by Common Terminology Criteria for Adverse Events (CTCAE) v 4.03. Results: 138 subjects were randomized, of whom 133 were treated on study. The median age was 71.0 years (range 44-88), 65% were male, 88% MDS and 12% CMML, 43% were either red blood cells (RBCs) or platelets transfusion-dependent at baseline, 25% had poor-risk cytogenetics, and 42% had baseline bone marrow blasts >5%. At the data cutoff for the response analysis, the median duration of follow up was 12.6 m (range 9.3 to 20.5 m) with median number of treatment cycles of 8 (range 1 to 18). Of the 133 treated patients the best response was complete response (CR) in 28 patients (21%; 95% CI 15-29%), marrow (m)CR with hematological improvement (HI) in 20 patients (15%), mCR without HI in 23 patients (17.3%), and HI in 10 patients (7.5%) for an overall objective response (CR+mCR+HI) in 81 patients (61%; 95% CI 52-69%). Median duration of CR was 7.5 m (range 1.6 to 17.5 m), and median time to CR was 4.3 m (range 2.1 to 15.2 m). Of the 133 treated patients 27 (20%) went on to receive allogeneic hematopoietic cell transplant. Of the 57 patients who were either RBCs or platelets transfusion-dependent at baseline, 30 (53%) became transfusion independent for both RBCs and platelets for at least 8 consecutive weeks, and 19 (33%) were both RBCs and platelets transfusion independent for at least 16 consecutive weeks. Median survival has not been reached. Most common Treatment-Emergent AEs of Grade ≥3 regardless of causality were neutropenia in 51.5%, thrombocytopenia in 50%, anemia in 40%, febrile neutropenia in 26%, leukopenia in 21%, pneumonia in 12%, and sepsis in 7% of patients treated with oral decitabine/cedazuridine (excluding the IV decitabine cycle). Summary/Conclusions: Efficacy and safety from oral decitabine 35 mg/ cedazuridine 100 mg daily for 5 days every 28 days are consistent with clinical data from standard IV decitabine 20 mg/m2 daily for 5 days. Oral decitabine/cedazuridine is the only oral HMA with systemic exposure equivalent to its injectable drug. Further investigation of oral decitabine/cedazuridine in all-oral combination studies is warranted and underway. Disclosures Savona: BMS: Consultancy; AbbVie: Consultancy; Gilead: Consultancy; Karyopharm: Consultancy, Current equity holder in publicly-traded company; Ryvu: Consultancy; Boehringer Ingelheim: Patents & Royalties; Takeda: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding. Griffiths:Celgene/BMS: Honoraria, Research Funding; Genentech Inc: Research Funding; Boston Biomedical: Honoraria; AbbVie Inc: Honoraria; Persimmune: Research Funding; Novartis: Honoraria, Research Funding; Alexion Pharmaceuticals: Honoraria, Research Funding; Astex Pharmceuticals: Research Funding. Zeidan:CCITLA: Other; Seattle Genetics: Consultancy, Honoraria; BeyondSpring: Consultancy, Honoraria; Taiho: Consultancy, Honoraria; Cardinal Health: Consultancy, Honoraria; Epizyme: Consultancy, Honoraria; Leukemia and Lymphoma Society: Other; Jazz: Consultancy, Honoraria; Trovagene: Consultancy, Honoraria, Research Funding; Ionis: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Research Funding; Astex: Research Funding; Daiichi Sankyo: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria, Research Funding; Otsuka: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; Acceleron: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Boehringer-Ingelheim: Consultancy, Honoraria, Research Funding; Celgene / BMS: Consultancy, Honoraria, Research Funding; Agios: Consultancy, Honoraria; ADC Therapeutics: Research Funding; Aprea: Research Funding; MedImmune/Astrazeneca: Research Funding; Cardiff Oncology: Consultancy, Honoraria, Other; Incyte: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria. Patel:DAVA Pharmaceuticals: Honoraria; France Foundation: Honoraria; Celgene: Consultancy, Speakers Bureau; Agios: Consultancy. Keating:Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Hoffman La Roche: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Merck: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy; Servier: Membership on an entity's Board of Directors or advisory committees; Shire: Membership on an entity's Board of Directors or advisory committees; Taiho: Membership on an entity's Board of Directors or advisory committees. Dao:Astex Pharmaceuticals, Inc.: Current Employment. Fazal:Jansen: Speakers Bureau; Gilead/Kite: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Jazz Pharma: Consultancy, Speakers Bureau; Karyopham: Speakers Bureau; Celgene: Speakers Bureau; Glaxosmith Kline: Consultancy, Speakers Bureau; Incyte Corporation: Consultancy, Honoraria, Speakers Bureau; Agios: Consultancy, Speakers Bureau; Stemline: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Odenike:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astex Pharmaceuticals, NS Pharma, Gilead Sciences, Janssen Oncology, Oncotherapy, Agios, CTI/Baxalta, Aprea: Other: Institutional research funding; Astra Zeneca: Research Funding; Incyte: Other: Institutional research funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Impact Biomedicines: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Kantarjian:Abbvie: Honoraria, Research Funding; BioAscend: Honoraria; Delta Fly: Honoraria; Ascentage: Research Funding; Janssen: Honoraria; Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Sanofi: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Immunogen: Research Funding; Aptitute Health: Honoraria; BMS: Research Funding; Daiichi-Sankyo: Honoraria, Research Funding; Jazz: Research Funding; Oxford Biomedical: Honoraria; Amgen: Honoraria, Research Funding; Adaptive biotechnologies: Honoraria. DeZern:MEI: Consultancy; Celgene: Consultancy, Honoraria; Astex: Research Funding; Abbvie: Consultancy. Roboz:Novartis: Consultancy; Janssen: Consultancy; Celgene: Consultancy; Astex: Consultancy; Amphivena: Consultancy; Agios: Consultancy; Pfizer: Consultancy; Abbvie: Consultancy; Array BioPharma: Consultancy; Bayer: Consultancy; Celltrion: Consultancy; Eisai: Consultancy; Jazz: Consultancy; Roche/Genentech: Consultancy; Sandoz: Consultancy; Actinium: Consultancy; Argenx: Consultancy; Astellas: Consultancy; Daiichi Sankyo: Consultancy; AstraZeneca: Consultancy; Orsenix: Consultancy; Otsuka: Consultancy; Takeda: Consultancy; Trovagene: Consultancy; Cellectis: Research Funding; Jasper Therapeutics: Consultancy; Epizyme: Consultancy; Helsinn: Consultancy; MEI Pharma: Consultancy. Busque:Pfizer: Honoraria; BMS: Honoraria; Novartis: Honoraria. Wells:Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Leber:Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Otsuka Pharmaceutical: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda/Palladin: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Treadwell: Honoraria, Membership on an entity's Board of Directors or advisory committees; Lundbeck: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS/Celgene: 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. Hao:Astex Pharmaceuticals, Inc.: Current Employment. Keer:Astex Pharmaceuticals, Inc.: Current Employment. Azab:Astex Pharmaceuticals, Inc.: Current Employment. Garcia-Manero:Acceleron Pharmaceuticals: Consultancy, Honoraria; AbbVie: Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; H3 Biomedicine: Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astex Pharmaceuticals: Consultancy, Honoraria, Research Funding; Amphivena Therapeutics: Research Funding; Helsinn Therapeutics: Consultancy, Honoraria, Research Funding; Onconova: Research Funding; Merck: Research Funding; Jazz Pharmaceuticals: Consultancy; Celgene: Consultancy, Honoraria, Research Funding; Novartis: Research Funding.

TPS2674 Background: Survivin, a member of the inhibitor of apoptosis protein family, is an attractive therapeutic target in cancer, due to its broad expression in solid tumors and hematologic malignancies but limited expression in normal tissues. Elevated survivin expression is associated with an increased invasive phenotype and worse clinical outcomes. ABBV-184 is a first-in-class T-cell receptor (TCR)/anti-cluster of differentiation 3 (CD3) bispecific molecule. It is composed of a soluble TCR that binds to a survivin-derived peptide bound to the class I MHC allele HLA-A2:01 expressed on tumor cells and to the CD3 receptor on T cells. Preclinical data have demonstrated that treatment with ABBV-184 results in T-cell activation, proliferation, and redirected cytotoxicity of HLA-A2:01–positive target cell lines. This first-in-human trial evaluates ABBV-184 monotherapy in patients with previously treated acute myeloid leukemia (AML) or non-small cell lung cancer (NSCLC). Methods: Patients (≥18 years, Eastern Cooperative Oncology Group performance status ≤2, HLA-A2:01 restricted genotype) with relapsed or refractory AML or NSCLC are currently enrolling in this phase 1 multicenter, open-label trial (NCT04272203), which includes parallel dose-escalation and dose-expansion phases for both diseases. Primary objectives are to determine the recommended phase 2 dose (RP2D) of ABBV-184 (dose escalation) and to assess its preliminary efficacy (dose expansion). Secondary objectives include safety, tolerability, pharmacokinetics (PK), and immunogenicity assessments (dose escalation and dose expansion) and duration of response (dose expansion). Patients will receive intravenous infusion of ABBV-184 once weekly. Dose escalation of ABBV-184 is guided by a Bayesian optimal interval design and the RP2D will be determined on the basis of clinical safety, PK, and pharmacodynamic data. For patients with AML, disease assessment is performed according to modified European LeukemiaNet-International Working Group criteria. For patients with NSCLC, response will be assessed using Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 and immune RECIST. Treatment can continue until disease progression or intolerable toxicity. Biomarker assessments will include longitudinal profiling of peripheral blood immune cells and cytokines, analysis of HLA-A2 and survivin levels on AML bone marrow blasts and NSCLC tumor biopsies, and retrospective correlations of biomarker data with antitumor activity. Enrollment initiated in Sep 2020, with 7 patients enrolled as of Jan 2021. Clinical trial information: NCT04272203.

3080 Background: ORIN1001 is a first-in-class small molecule with a novel, unique enzyme and mode of inhibition that selectively inhibits Inositol Requiring Enzyme 1α (IRE1) RNAse and blocks X-Box Binding Protein 1 (XBP1) activation in the endoplasmic reticulum (ER). IRE1α/XBP1 has been implicated in a host of pathologies, and molecules that modulate it are under intense investigation for the treatment of oncologic, metabolic, neurodegenerative and other diseases. ORIN1001 has demonstrated preclinical anti-tumor activity alone and in combination with standard of care across multiple animal models including breast, prostate, lung, liver, pancreatic, brain, colon, ovarian, esophageal, and hematologic cancers and is now undergoing first-in-human testing. Methods: A phase 1, open label, 3+3 dose escalation trial is testing ORIN1001 administered PO daily to patients (pts) with advanced solid tumors (single agent) or relapsed refractory breast cancer (in combination with Abraxane). The phase 1 dose escalation part of the trial evaluates the safety, tolerability, pharmacokinetics and preliminary efficacy of ORIN1001. After identification of the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) for the single agent, the dose expansion part of the trial will test ORIN1001 in combination with Abraxane. Results: As of Jan 25, 2021, 22 patients with advanced cancer have received ORIN1001 dosed at 100mg, 200mg or 300mg per day in 21-day continuous cycles with a median age of 61 (range 42-77). The pts had received a median of 4 prior line of treatments. Two DLTs were observed at 200 mg with thrombocytopenia and rash. MTD has not been reached. Common (>15%) treatment-emergent adverse events (TEAEs) included nausea, vomiting, rash, fatigue, and hypokalaemia. The vast majority of these events were Grade 1-2 in severity. Seven (32%) pts had at least 1 TRAE grade≥ 3, the most frequent of which were thrombocytopenia (N=3) and rash (N=3). Preliminary pharmacokinetic analysis showed ORIN1001 exposure to increase in a dose proportional manner. Mean t1/2 at steady state was 18 hrs. Thirteen pts were evaluated for preliminary efficacy. Best response, per RECIST 1.1, was stable disease (SD) in 8 pts while 5 pts had progressive disease (PD). For 2 ongoing patients with advanced liver or colorectal cancer, duration of treatment has exceeded 300 days and 570 days, respectively. Conclusions: To date, the phase 1 part of the first-in-human trial has demonstrated a reasonable safety and pharmacokinetic profile for ORIN1001 at 100mg and 200mg dose levels. While efficacy data have yet to mature, chronic dosing achieved in pts with heavily treated advanced solid tumors, suggests clinical potential for in the setting of advanced solid cancers. The phase 2 part of the trial testing ORIN1001 in combination with Abraxane is currently enrolling pts with advanced breast cancer. Clinical trial information: NCT03950570.

Ian D Schnadig1, Richy Agajanian2, Christopher Dakhil3, Nashat Gabrail4, Jeffrey Vacirca5, Charles Taylor6, Sharon Wilks7, Eduardo Braun8, Michael C Mosier9, Robert B Geller10, Lee Schwartzberg11, NicholasVogelzang12 1Compass Oncology, US Oncology Research, Tualatin, OR, 2The Oncology Institute of Hope and Innovation, Whittier, CA, 3Cancer Center of Kansas, Wichita, KS, 4Gabrail Cancer Center, Canton, OH, 5North Shore Hematology Oncology, East Setauket, NY, 6Tulsa Cancer Institute, Tulsa, OK, 7Cancer Care Centers of South Texas, San Antonio, TX, 8Michiana Hematology Oncology, Westville, IN, 9Biostatistics, EMB Statistical Solutions, LLC, Overland Park, KS, 10Medical Affairs, Heron Therapeutics, Inc., San Diego, CA, 11West Cancer Center, Germantown, TN, 12Comprehensive Cancer Centers of Nevada, Las Vegas, NV, USA Background: APF530, a novel extended-release granisetron injection, was superior to ondansetron in a guideline-recommended three-drug regimen in preventing delayed-phase chemotherapy-induced nausea and vomiting (CINV) among patients receiving highly emetogenic chemotherapy (HEC) in the double-blind Phase III Modified Absorption of Granisetron In the prevention of CINV (MAGIC) trial.Patients and methods: This MAGIC post hoc analysis evaluated CINV prevention efficacy and safety of APF530 versus ondansetron, each with fosaprepitant and dexamethasone, in patient subgroup receiving an anthracycline plus cyclophosphamide (AC) regimen. Patients were randomized 1:1 to APF530 500mg subcutaneously (granisetron 10mg) or ondansetron 0.15mg/kg intravenously (IV) (≤16mg); stratification was by planned cisplatin ≥50mg/m2 (yes/no). Patients were to receive fosaprepitant 150mg IV and dexamethasone 12mg IV on day1, then dexamethasone 8mg orally once daily on day 2 and twice daily on days 3 and 4. Patients were mostly younger females (APF530 arm, mean age 54.1years, female, 99.3%; ondansetron arm, 53.8years, female 98.3%). The primary end point was delayed-phase (>24–120 hours) complete response (CR). Results: APF530 versus ondansetron regimens achieved numerically better CINV control in delayed and overall (0–120 hours) phases for CR, complete control, total response, rescue medication use, and proportion with no nausea. APF530 trends are consistent with the overall population, although not statistically superior given the underpowered AC subgroup analysis. The APF530 regimen in this population was generally well tolerated, with safety comparable to that of the overall population.Conclusion: APF530 plus fosaprepitant and dexamethasone effectively prevented CINV among patients receiving AC-based HEC, a large subgroup in whom CINV control has traditionally been challenging. Keywords: APF530, extended release granisetron, chemotherapy-induced nausea and vomiting (CINV), highly emetogenic chemotherapy (HEC), anthracycline, cyclophosphamide

Purpose: The high fatality-to-case ratio of ovarian cancer is directly related to platinum resistance. Exportin-1 (XPO1) is a nuclear exporter that mediates nuclear export of multiple tumor suppressors. We investigated possible clinicopathologic correlations of XPO1 expression levels and evaluated the efficacy of XPO1 inhibition as a therapeutic strategy in platinum-sensitive and -resistant ovarian cancer. Experimental Design: XPO1 expression levels were analyzed to define clinicopathologic correlates using both TCGA/GEO datasets and tissue microarrays (TMA). The effect of XPO1 inhibition, using the small-molecule inhibitors KPT-185 and KPT-330 (selinexor) alone or in combination with a platinum agent on cell viability, apoptosis, and the transcriptome was tested in immortalized and patient-derived ovarian cancer cell lines (PDCL) and platinum-resistant mice (PDX). Seven patients with late-stage, recurrent, and heavily pretreated ovarian cancer were treated with an oral XPO1 inhibitor. Results: XPO1 RNA overexpression and protein nuclear localization were correlated with decreased survival and platinum resistance in ovarian cancer. Targeted XPO1 inhibition decreased cell viability and synergistically restored platinum sensitivity in both immortalized ovarian cancer cells and PDCL. The XPO1 inhibitor–mediated apoptosis occurred through both p53-dependent and p53-independent signaling pathways. Selinexor treatment, alone and in combination with platinum, markedly decreased tumor growth and prolonged survival in platinum-resistant PDX and mice. In selinexor-treated patients, tumor growth was halted in 3 of 5 patients, including one with a partial response, and was safely tolerated by all. Conclusions: Taken together, these results provide evidence that XPO1 inhibition represents a new therapeutic strategy for overcoming platinum resistance in women with ovarian cancer. Clin Cancer Res; 23(6); 1552–63. ©2016 AACR.

Background: Seviteronel (Sevi), a CYP17-lyase (L) inhibitor (reduces testosterone (T) and estradiol (E2) biosynthesis) and a competitive AR antagonist, has activity in castration resistant prostate cancer at a dose of 600mg nightly. Sevi potently inhibits the growth of ER(+)/AR(+) MCF7, tamoxifen-resistant (TAMR) MCF7, and ER(-)/AR(+) MDA-MB-453 cells. In a TAMR xenograft BC model, Sevi decreases tumor growth greater than enzalutamide (Enza), an AR antagonist (Ellison et al, SABCS 2015). Nearly all subtypes of BC, including AR(+) TNBC, are potential targets for Sevi based on its mechanism of action (MOA). Phase (Ph) 1 of this study established the recommended Ph 2 dose (RP2D) of Sevi in women with BC as 450mg once nightly, based upon preliminary tolerability and pharmacokinetics (PK) (Bardia et al, ASCO 2016). The primary objective of Ph 2 is to estimate the activity of Sevi, as measured by clinical benefit rate (CBR) at 16 and 24 weeks (wks) for AR(+) TNBC and ER(+) BC, respectively. The secondary objectives include an estimation of Sevi tolerability and pharmacodynamics (PD) (NCT02580448). Methods: Women with advanced AR(+) TNBC (stratified by prior Enza use) or ER(+) BC were enrolled using 3 parallel Simon's 2-stage designs powered to evaluate CBR. ER(+) BC patients must have had ≥1 prior line of endocrine therapy; no limit to prior treatment for TNBC. AR(+) status was confirmed using central IHC analysis in all patients, with a ≥10% tumor cell nuclear staining cutoff for evaluable TNBC patients. Sevi was administered once nightly with dinner at 450mg (28d cycle). Tumor and blood samples were collected for PK and PD analysis (circulating tumor cells, ctDNA, sex steroids). Response was assessed every 8 wks for 52 wks, then every 12 wks thereafter. Current tolerability and PD results are presented herein for this ongoing Ph 2 study. Results: As of June 7, 2016, 17 patients received Sevi at 450mg nightly between Ph1 and Ph2 with 10 in screening. 14 patients are currently on study in Cycles 1-6. The most common adverse events (AEs > 10% regardless of causality or grade) were tremor (24%), pain (18%), fatigue (18%) and dyspnea (18%), nausea (12%), AST increase (12%), ALT increase (12%) and abdominal pain (12%), all of which were Grade 1 or 2 except for Grade 3 dyspnea (n=1; unrelated). No dose reductions were reported and there were no drug-related discontinuations. Nine patients underwent central AR testing (4 AR(+) of 6 TNBC; 3 AR(+) of 3 ER(+) BC). Median AR tumor cell nuclear staining was 90% (15-100%). Preliminary sex steroid analyses from 6 Ph 1 patients receiving Sevi at 450, 600, or 750mg nightly (n=2 at each dose) for 1 cycle showed a median decline in E2 concentration of 52% (-29 to -87%) to 12.4pmol/L (4 to 33pmol/L) from baseline. There was a similar magnitude of decline for T. Conclusions: Sevi was well-tolerated at 450mg nightly with exposures similar to the RP2D in men (600mg nightly). The CYP17-L inhibition activity of Sevi was demonstrated with an early and potent reduction in E2 and T. Sevi's unique CYP17-L and AR antagonist MOA may provide a new novel treatment option for AR(+) TNBC or ER(+) BC. Citation Format: Gucalp A, Bardia A, Gabrail N, DaCosta N, Danso M, Elias AD, Ali H, Lemon SJ, Riley EC, Eisner JR, Fleming RA, Kurman MR, Moore WR, Traina TA. Phase 1/2 study of oral seviteronel (VT-464), a dual CYP17-lyase inhibitor and androgen receptor (AR) antagonist, in patients with advanced AR positive triple negative (TNBC) or estrogen receptor (ER) positive breast cancer (BC) [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-08-04.

Aim: To evaluate real-world effectiveness of guideline-recommended palonosetron-containing antiemetic regimens in patients receiving highly (HEC) or moderately emetogenic (MEC) chemotherapy. Patients & methods: This retrospective analysis used records of adults receiving first-line chemotherapy and a three-drug palonosetron-containing antiemetic regimen for HEC or palonosetron-containing antiemetic regimen for MEC (carboplatin). Results: A total of 1587 records were evaluated. For HEC and MEC, respectively, chemotherapy-induced nausea and vomiting (CINV) occurred in 40 versus 44% of patient cycles (p = 0.01), and unscheduled iv. antiemetics in 41 versus 35% (p Conclusion: Palonosetron-containing antiemetic regimens may provide insufficient CINV control. Alternative regimens may improve patient quality of life and reduce healthcare resource utilization.

TPS185 Background: LIV-1 is a transmembrane protein expressed in a variety of cancer types. SGN-LIV1A, or ladiratuzumab vedotin (LV), is a novel investigational humanized IgG1 antibody-drug conjugate (ADC) directed against LIV-1. LV mediates delivery of monomethyl auristatin E (MMAE), which drives antitumor activity through cytotoxic cell killing and induces immunogenic cell death. In a phase 1 study, LV was tolerable and active in heavily pretreated patients with metastatic breast cancer (Modi 2017). This study is currently evaluating the safety and efficacy of LV in different advanced solid tumors with various LIV-1 expression, including metastatic castration-resistant prostate cancer (mCRPC), advanced gastric and gastroesophageal junction (GEJ) adenocarcinoma, esophageal squamous cell carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (squamous and nonsquamous), head and neck squamous cell carcinoma, and melanoma. Methods: SGNLVA-005 (NCT04032704) is an open-label, phase 2 study evaluating LV monotherapy in patients with previously treated, locally advanced unresectable or metastatic advanced solid tumors, including mCRPC. Patients with mCRPC will receive LV administered as a 30 minute intravenous infusion (IV) at 1.25 mg/kg every 1 week. Up to 30 patients with mCRPC will be enrolled. Patients in the mCRPC cohort must have metastatic castration-resistant disease, have received no more than 1 prior line of androgen receptor-targeted therapy, have ≥28 days between androgen receptor-targeted therapy and start of study treatment, an Eastern Cooperative Oncology Group (ECOG) score of 0 or 1, and adequate organ function. In addition, mCRPC patients with measurable and non-measurable disease are eligible if the protocol-defined criteria are met. mCRPC patients must not have BRCA gene mutations, prior cytotoxic chemotherapy in the metastatic mCRPC setting, prior radioisotope therapy, or radiotherapy to ≥30% of bone marrow. Patients are not preselected based on tumor LIV-1 expression. Their tumor samples will be analyzed for correlation between LIV-1 expression and response. Safety and efficacy will be monitored throughout the study. Study objectives include objective tumor response rate per RECIST 1.1 and prostate-specific antigen (PSA) response rate per Prostate Cancer Clinical Trials Working Group 3 (both primary); safety and tolerability, disease control rate, duration of response, progression-free and overall survival, and pharmacokinetics and immunogenicity (all secondary); and pharmacodynamics. Study accrual is ongoing in the USA, Italy, South Korea, Taiwan, Australia, and the UK. Clinical trial information: NCT04032704.

99 Background: GT0918, an androgen receptor (AR) antagonist, is a new chemical entity with reduced drug accumulation in the CNS. In a phase I dose escalation trial (NCT02826772), GT0918 was well tolerated with some durable responses in mCRPC patients (pts) who had progressed on ≥2 lines of standard and experimental therapies. This Phase 2 was designed to study the safety and efficacy of GT0918 400 mg vs. 500 mg oral daily in mCRPC pts who had progressed on either Abi or Enza with or without prior docetaxel. Methods: Pts with histologically confirmed mCRPC who had progressed on either Abi or Enza with or without prior docetaxel were eligible and randomized to 400 mg or 500 mg of GT0918 administered once daily orally. Pts continued treatment with GT0918 at their assigned dose until disease progression, intolerable toxicities or withdrawal of consent. PSA and labs were checked monthly. Imaging scans (CT/MRI and bone scan), circulating tumor cells and cf-DNA/RNA were performed every 3 months. Results: 61 pts were enrolled at 9 US sites and randomized 1:1 to 400 mg (n = 31) or 500 mg (n = 30) daily dose. All pts had progressed on either Abi (n = 34) or Enza (n = 27). Most of the reported AEs related to GT0918 were grade 1 or 2 as per CTCAE v4.03, but 22 AEs (5.3%) were reported as grade ≥ 3, such as fatigue, increase ALT/AST, rhabdomyolysis, or muscle weakness. Some AEs were due to drug-drug interaction with lipid-lowering medications leading to early discontinuation (26.2%). As of 5 October 2020, twelve pts finished 6 cycles. Among them, three finished 12 cycles and remained on the treatment. Treatment duration showed more pts in the 400 mg cohort with stable disease (SD) on imaging (9/31 finished 6 cycles) compared to the 500 mg cohort (3/30 finished 6 cycles). Further, all three pts who finished 12 cycles had progressed on Abi indicating that GT0918 might be a good treatment option for pts who had progressed on Abi. Conclusions: Proxalutamide (GT0918) administrated orally once a day is well tolerated and resulted in SD in pts who had progressed on either Abi or Enza. The 400 mg/day will be considered as the recommended phase II dose for further clinical trials. GT0918 is warranted for pts failed either Abi or Enza. Clinical trial information: NCT03899467.

TPS256 Background: LIV-1 is a transmembrane protein expressed in a variety of cancer types. SGN-LIV1A, or ladiratuzumab vedotin (LV), is a novel investigational humanized IgG1 antibody-drug conjugate (ADC) directed against LIV-1. LV mediates delivery of monomethyl auristatin E (MMAE), which drives antitumor activity through cytotoxic cell killing and induces immunogenic cell death. In a phase 1 study, LV was tolerable and active in heavily pretreated patients with metastatic breast cancer at a recommended dose of 2.5 mg/kg every 21 days (Modi 2017). More frequent, fractionated dosing has improved the activity and/or safety of other ADCs. Thus, this study is currently evaluating the safety and efficacy of weekly LV dosing (Days 1, 8, and 15 of every 3-week cycle) in different advanced solid tumors with various LIV-1 expression, including advanced gastric and gastroesophageal junction (GEJ) adenocarcinoma, esophageal squamous cell carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (squamous and nonsquamous), head and neck squamous cell carcinoma, castration resistant prostate cancer, and melanoma. Methods: SGNLVA-005 (NCT04032704) is an open-label, phase 2 study evaluating LV monotherapy in patients with 8 different advanced solid tumors in two parts (administered as a 30 minute intravenous infusion [IV]: Part A LV 2.5 mg/kg IV every 3 weeks [up to n = 72 total]; Part B LV 1.0 or 1.25 mg/kg every 1 week [up to n = 252 total]). The study is enrolling previously treated patients with unresectable locally advanced or metastatic disease. Patients must have measurable disease per RECIST v1.1, an Eastern Cooperative Oncology Group (ECOG) score of 0 or 1, and adequate organ function. Cohort specific inclusion criteria require that patients in the gastric and GEJ adenocarcinoma and esophageal squamous cell carcinoma cohorts must have received and progressed during or after no more than 1 prior line of platinum based cytotoxic chemotherapy. Patients in the gastric and GEJ adenocarcinoma cohort may have received prior anti-programmed cell death (ligand) 1 (anti-PD[L]1) therapy (unless contraindicated), and patients with known human epidermal growth factor receptor 2 (HER2) overexpression must have received prior HER2-targeted therapy. Patients are not preselected based on tumor LIV-1 expression. Tumor samples will be analyzed for correlation between LIV-1 expression and tumor response. Safety and efficacy will be monitored throughout the study. Study objectives include objective response rate (primary); safety and tolerability, disease control rate, duration of response, progression-free and overall survival, and pharmacokinetics and immunogenicity (all secondary); and pharmacodynamics. Study accrual is ongoing in the USA, Italy, South Korea, Taiwan, Australia, and the UK. Clinical trial information: NCT04032704.

PURPOSE: Pralatrexate is a folate analogue indicated for the treatment of relapsed or refractory peripheral T-cell lymphoma. It has not been formally tested in patients with renal impairment. This study evaluated the pharmacokinetic (PK) profile of pralatrexate in patients with renal impairment and with relapsed/refractory advanced solid tumors and lymphoma. METHODS: This was an open-label, nonrandomized, phase 1 study. Eligible patients received pralatrexate administered as an IV push over 3–5 min once weekly for 6 weeks in 7-week cycles until progressive disease or intolerable toxicity. Four cohorts of 6 patients were planned for a total of 24 patients. Patients with normal renal function (Cohort A), mild (Cohort B), and moderate renal impairment (Cohort C) received 30 mg/m(2) pralatrexate once weekly for 6 weeks in 7-week cycles, and patients with severe renal impairment (Cohort D) were to be administered 20 mg/m(2) once weekly for 6 weeks. Plasma and urine samples were collected at pre-specified time points to determine the PK profile of pralatrexate in each treatment cohort. Patients were followed for safety and tolerability. RESULTS: A total of 29 patients were enrolled and 27 patients (14 male) received at least 1 dose of pralatrexate. Because of a qualifying toxicity in Cohort C, the starting dose for Cohort D was reduced to 15 mg/m(2). Chronic renal impairment led to a decrease in renal clearance of the pralatrexate diastereomers, PDX-10a and PDX-10b, but systemic exposure to these diastereomers was not dramatically affected by renal impairment. Pralatrexate exposure in Cohort D (15 mg/m(2)) was similar to the exposure in other cohorts (30 mg/m(2)). No apparent difference in toxicity between the four treatment cohorts was observed, except for an increase in cytopenias in patients with severe renal impairment. CONCLUSION: Pralatrexate exposure, at a dose of 30 mg/m(2), in patients with mild or moderate renal impairment was similar to the exposure in patients with normal renal function. For patients with severe renal impairment only, a pralatrexate dose of 15 mg/m(2) is recommended.

Aim: APF530, extended-release granisetron, provides sustained release for ≥5 days for acute- and delayed-phase chemotherapy-induced nausea and vomiting (CINV). We compared efficacy and safety of APF530 versus ondansetron for delayed CINV after highly emetogenic chemotherapy (HEC), following a guideline-recommended three-drug regimen. Methods: HEC patients received APF530 500 mg subcutaneously or ondansetron 0.15 mg/kg intravenously, with dexamethasone and fosaprepitant. Primary end point was delayed-phase complete response (no emesis or rescue medication). Results: A higher percentage of APF530 versus ondansetron patients had delayed-phase complete response (p = 0.014). APF530 was generally well tolerated; treatment-emergent adverse event incidence was similar across arms, mostly mild-to-moderate injection-site reactions. Conclusion: APF530 versus the standard three-drug regimen provided superior control of delayed-phase CINV following HEC. ClinicalTrials.gov : NCT02106494.

Purpose The US community-based, phase IIIB UPFRONT trial was designed to compare three frontline bortezomib-based regimens in transplantation-ineligible patients with myeloma. Patients and Methods Patients (N = 502) were randomly assigned 1:1:1 to 24 weeks (eight 21-day cycles) of induction with bortezomib-dexamethasone (VD; n = 168; intravenous bortezomib 1.3 mg/m2, days 1, 4, 8, and 11 plus oral dexamethasone 20 mg, days 1, 2, 4, 5, 8, 9, 11, and 12 [cycles 1 to 4], or 1, 2, 4, and 5 [cycles 5 to 8]), bortezomib-thalidomide-dexamethasone (VTD; n = 167; bortezomib and dexamethasone as before plus oral thalidomide 100 mg, days 1 to 21), or bortezomib-melphalan-prednisone (VMP; n = 167; bortezomib as before plus oral melphalan 9 mg/m2 and oral prednisone 60 mg/m2, days 1 to 4, every other cycle), followed by 25 weeks (five 35-day cycles) of bortezomib maintenance (1.6 mg/m2, days 1, 8, 15, and 22). The primary end point was progression-free survival. Results After 42.7 months' median follow-up, median progression-free survival with VD, VTD, and VMP was 14.7, 15.4, and 17.3 months, respectively; median overall survival was 49.8, 51.5, and 53.1 months, with no significant differences among treatments for either end point (global P = .46 and P = .79, respectively, Wald test). Overall response rates were 73% (VD), 80% (VTD), and 70% (VMP). Adverse events were more common with VTD than VD or VMP. Bortezomib maintenance was feasible without producing cumulative toxicity. Conclusion Although all bortezomib-containing regimens produced good outcomes, VTD and VMP did not appear to offer an advantage over VD in transplantation-ineligible patients with myeloma treated in US community practice.

Background: Enhancer of zeste homolog 2 (EZH2) is an epigenetic regulator that is essential for BCL6-driven germinal center (GC) formation. Relapsed/refractory (R/R) follicular lymphoma (FL) is derived from GC B-cells and is generally dependent on EZH2 function. EZH2 mutations are observed in ∼20% of patients with FL; however, as FL is commonly reliant on other epigenetic modulator mutations, EZH2 is relevant in both mutant (MT) and wild-type (WT) EZH2 FL. Tazemetostat (TAZ), a selective, oral EZH2 inhibitor, has demonstrated durable single-agent antitumor activity in MT or WT EZH2 R/R FL. Aims: Study EZH-302 (NCT04224493) will determine the recommended phase 3 dose (RP3D) and assess efficacy and safety of rituximab, lenalidomide, and TAZ (R2+TAZ) versus rituximab, lenalidomide, and placebo (R2) in R/R FL. Methods: Patients aged ≥18 years with histologically confirmed FL (grades 1–3A; WT or MT EZH2 status) previously treated with ≥1 line of chemotherapy, immunotherapy, or chemoimmunotherapy will be enrolled. Phase 1b (safety run-in; stage 1) will evaluate safety and tolerability and establish the maximum tolerated and/or RP3D of TAZ+R2 in 3–18 patients. TAZ will be evaluated at 3 escalating dose levels (400 mg, 600 mg, and 800 mg orally twice daily) if no dose-limiting toxicities are observed. Rituximab (375 mg/m2) will be administered intravenously on days 1, 8, 15, and 22 of cycle 1, then day 1 of cycles 2–5. Lenalidomide (20 mg) will be administered orally once daily on days 1–21 every 28 days for up to 12 cycles. Phase 3 (stage 2) will be a 1:1 randomized study of ∼500 patients receiving TAZ (twice daily at the RP3D)+R2 (dosed per stage 1) or placebo+R2. Enrollment with MT EZH2 status will be capped at 150–210 patients (≤30%) to reflect real-world prevalence. Randomization will be stratified by EZH2 status (WT or MT), response to prior systemic therapy (sensitive or refractory), and number of prior treatment lines (1 or ≥2). Primary endpoint is investigator-assessed progression-free survival per 2014 Lugano Classification. An interim futility analysis will be initiated when 100 patients are evaluable for objective response rate.

Despite progress of immune checkpoint therapies, many cases of non-small cell lung cancer (NSCLC) are refractory or acquire resistance to current therapies. Antibody blockade of semaphorin 4D (SEMA4D, CD100) can overcome resistance mechanisms of immune exclusion and myeloid suppression. Importantly, combinations of anti-SEMA4D with various immunotherapies enhanced T cell infiltration and activity, leading to durable tumor regression in preclinical models. Pepinemab (VX15/2503) is a first-in-class humanized monoclonal antibody targeting SEMA4D. The CLASSICAL-Lung clinical trial tests the combination of pepinemab with avelumab to couple immune activation via checkpoint inhibition with beneficial modifications of the tumor immune microenvironment via pepinemab. Here, we present interim results of the Phase 2 portion of the CLASSICAL-Lung study. This phase 1b/2, open label, single arm, first-in-human combination study is designed to evaluate the safety, tolerability and efficacy of pepinemab in combination with avelumab in 62 subjects with advanced stage (IIIB/IV) NSCLC, including immunotherapy-naïve (ION) patients and patients whose tumors progressed during or following immunotherapy (IOF). Dose escalation was successfully completed, presented previously, and no concerning safety signals have been identified to date. Among 29 evaluable IOF patients, 2 experienced confirmed partial response (PR) with 66% and 52% tumor reduction following acquired resistance to prior treatment with pembrolizumab, 15 additional patients experienced stable disease (SD), and at least 7 patients had durable clinical benefit of ≥ 23 weeks. Among 21 evaluable ION patients, 5 experienced PR, and 3 patients had clinical benefit ≥ 1 year. The disease control rate was 81%. Analysis of pre- and on-treatment biopsies demonstrated increased CD8+ T cell density correlating with response, with reduction or elimination of tumor in 10/11 biopsies from subjects with PR or SD. It was notable that 79% of patients who experienced PR or SD were reported to have tumors with negative or low PD-L1 expression. Enrollment is complete and this interim analysis suggest the combination of pepinemab plus avelumab is well tolerated and shows initial clinical signals of antitumor activity. Updated clinical response data, as well as additional immunophenotyping of both inflammatory and suppressive myeloid cells will be presented. Citation Format: Jonathan W. Goldman, Terrence L. Fisher, Elizabeth Evans, John E. Leonard, Desa Rae Pastore, Crystal Mallow, Ernest Smith, Andreas Schröeder, Kevin Chin, Michael Shafique, Thaddeus Beck, Megan A. Baumgart, Ramaswamy Govindan, Nashat Gabrail, Rachel E. Sanborn, Alexander I. Spira, Nagashree Seetharamu, Yanyan Lou, Aaron S. Mansfield, Maurice Zauderer. Interim results from CLASSICAL-Lung, phase 1b/2 study of pepinemab (VX15/2503) in combination with avelumab in advanced NSCLC [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT191.

TPS9637 Background: Repotrectinib is a next-generation ROS1/TRK inhibitor with > 90-fold greater potency than crizotinib against ROS1 and > 100-fold greater potency than larotrectinib against TRK. Preclinical studies demonstrated inhibitory activity of repotrectinib against ROS1 resistance mutations, including the solvent-front mutation (SFM) G2032R. In the phase 1 portion of the study, repotrectinib was found to be well tolerated with encouraging antitumor activity including a 91% confirmed overall response (cORR) in TKI-naïve ROS1+ NSCLC pts. In ROS1+ NSCLC pts who received 1 prior chemo and 1 prior TKI, the cORR was 57% at the clinical dose of 160 mg QD or above. Intra-cranial (IC) activity was observed in ROS1+ NSCLC pts with measurable CNS disease (100% IC-ORR in TKI-naïve and 75% IC-ORR in patients with 1 prior TKI). Encouraging antitumor activity was observed in pts with NTRK+ solid tumors. Methods: A global phase 2 study was initiated and is actively enrolling. The primary endpoint for the Phase 2 study is cORR assessed by BICR (Blinded Independent Central Review) using RECIST v1.1, in each expansion cohort in pts with advanced solid tumors that harbor a ROS1 or NTRK1/2/3 gene fusion. Secondary endpoints include duration of response (DOR), progression-free survival (PFS), overall survival (OS), IC-ORR, IC-PFS, and quality of life assessments. All pts need to have RECIST 1.1 measurable disease confirmed by BICR and ECOG performance score ≤1. Repotrectinib is administered at 160 mg QD for 14 days and, if tolerated, the dose can be increased to 160 mg BID. Approximately 320 pts (≥12 years old) will be enrolled into 6 defined expansion cohorts, depending on the status of previous treatment with TKIs and cancer types (see table below). Clinical trial information: NCT03093116 . [Table: see text]

e17578 Background: Both abiraterone and enzalutamide have been approved for the treatment of mCRPC. GT0918 (proxalutamide) is a novel second-generation androgen receptor (AR) antagonist binding directly to the androgen receptor, impairing nuclear translocation and decreasing AR protein expression. This phase II portion of the Ph I/II study is being conducted to further evaluate safety and tolerability of GT0918 at 400 mg or 500 mg daily dosing. Methods: All eligible mCRPC pts with progressive disease based on rising prostate-specific antigen (PSA) or/and imaging while on either abiraterone or enzalutamide, but not both. One line of prior chemotherapy was allowed. Pts (n = 60) will be randomized to GT0918 either 400 mg or 500 mg po once daily for 6 months. The primary endpoint is safety and tolerability. Secondary endpoints are PSA reduction at 12 weeks, % radiographic progression at 6-month, time to imaging progression, and exploratory biomarker CTC & cf-DNA/RNA. PSA is assessed every 4 wks and tumor imaging is done every 12 wks. Results: 56 pts were screened June 2019 to January 15, 2020 and 40 pts were randomized to receive GT0918 either 400 mg or 500 mg po daily. 22 pts (55%) had enzalutamide as prior therapy and 18 pts (45%) had abiraterone as prior therapy. 17 pts (43%) had one or more lines of chemotherapy. The median age was 72 years (range 53-89) and median baseline PSA was 162 ng/mL (0.3-4195). 10 pts had 1 cycle or less of study drug due to rapid PSA progression, AEs and/or withdrawal of consent. The most common treatment-related AEs were fatigue (48%), loss of appetite/anorexia (25%), nausea (20%), lower leg extremity edema (18%), constipation (15%), weight loss (13%), vomiting (10%), and headache (8%). 8 pts (6 in 500 mg vs. 2 in 400 mg) required dose reduction due to AE. No seizures have been observed. As Jan 30, 2020, 3 pts (8%) and 8 pts (20%) had PSA reduction at 12 weeks and 4 weeks, respectively, but no 50% PSA reduction was observed. 2 pts (5%) received study drug treatment over 24 weeks and 10 pts (25%) received study drug over 16 weeks based on stable disease (SD) on imaging. Conclusions: GT0918 administrated orally once a day is well tolerated and first 40-pts taking GT0918 show some anti-tumor activities. Dose of 400 mg po daily is recommended for GT 0918 for further clinical trials. Clinical trial information: NCT03899467 .

3011 Background: Antibody blockade of semaphorin 4D (SEMA4D, CD100) promotes tumoral dendritic cell and CD8+ T cell infiltration and reduces function and recruitment of immunosuppressive myeloid cells. Importantly, these mechanisms to overcome immune exclusion and suppression have been shown to complement immune checkpoint therapies in preclinical models. Pepinemab is an IgG4 humanized monoclonal antibody targeting semaphorin 4D. The CLASSICAL-Lung clinical trial tests the combination of pepinemab with avelumab to couple T cell activation via checkpoint inhibition with beneficial modifications of the immune microenvironment via pepinemab. Methods: This phase 1b/2, single arm, first-in-human study is designed to evaluate the safety, tolerability and efficacy of pepinemab with avelumab in 62 patients (pts) with advanced (stage IIIB/IV) non-small cell lung cancer (NSCLC), including immunotherapy-naïve (ION) pts and pts whose tumors progressed following immunotherapy (IOF). Results: Among 21 evaluable ION pts, 5 experienced partial response (PR), 3 pts had clinical benefit ≥ 1 year, and the disease control rate (DCR) is 81%. Pts enrolled in this study were observed to have lower PD-L1 expression relative to prior single agent studies (likely due to approval of pembrolizumab for first line therapy). We, therefore, performed subgroup analysis for response by PD-L1 status. The objective tumor response (ORR) in the PD-L1 negative and low population ( < 80% TPS by Dako 73-10 assay) appears to be approximately 2-2.5 fold greater with combination therapy than with historical single agent immune checkpoint controls. Notably, 97% of pts who experienced PR or SD were reported to have tumors with negative or low PD-L1 expression. Among 29 evaluable IOF pts, the combination resulted in 59% DCR, including 2 PR and 7 patients with durable clinical benefit of ≥ 23 weeks. Biomarker analysis of pre- and on-treatment biopsies confirmed increased CD8+ T cell density correlating with response. Surprisingly, analysis of myeloid-derived suppressor cells (MDSCs) revealed a relative paucity of these cells in pretreatment NSCLC biopsies as compared to other cancer indications such as HNSCC. Conclusions: This trial is nearing completion with only 5 of 62 subjects remaining on study. Preliminary data suggest the combination is well tolerated and shows signs of increased antitumor activity, particularly in PD-L1 negative or low tumors. Updated clinical response data and immunophenotypic analyses will be presented. Clinical trial information: NCT03268057 .

75 Background: Despite progress of immune checkpoint therapies, many cases of non-small cell lung cancer (NSCLC) are refractory or acquire resistance to current therapies. Antibody blockade of semaphorin 4D (SEMA4D, CD100) can overcome resistance mechanisms of immune exclusion and myeloid suppression. Importantly, combinations of anti-SEMA4D with various immunotherapies enhanced T cell infiltration and activity, as well as durable tumor regression in preclinical models. Pepinemab (VX15/2503) is a first-in-class humanized monoclonal antibody targeting SEMA4D. Methods: The CLASSICAL-Lung clinical trial (NCT03268057) evaluates the combination of pepinemab with anti-PD-L1 antibody avelumab to couple beneficial modifications of the immune microenvironment via pepinemab with immune activation via checkpoint inhibition. This ongoing study evaluates the safety, tolerability and efficacy of the combination in patients with advanced (stage IIIB/IV) NSCLC, including immunotherapy-naïve (ION) patients and patients whose tumors progressed during or following immunotherapy (IOF). Results: The combination was well tolerated with no major safety signals identified. Among 29 evaluable IOF patients, two experienced confirmed partial response (PR) with 63% and 52% tumor reduction on study following acquired resistance to prior treatment with pembrolizumab, 15 additional patients experienced stable disease, and at least 5 patients with durable clinical benefit of ≥ 23 weeks. Among 21 evaluable ION patients, 5 experienced PR, clinical benefit ≥ 1 year was observed in 3 patients, and Disease Control Rate was 81%. Analysis of pre- and on-treatment biopsies demonstrated increased CD8+ T cell density correlating with response, reduction or elimination of tumor in 11/13 biopsies from subjects with PR or SD. Conclusions: Interim analysis suggests the combination of pepinemab plus avelumab is well tolerated and shows initial clinical signals of antitumor activity. Updated clinical response data (minimum of 6 mo. follow-up), as well as additional immunophenotyping of both inflammatory and suppressive myeloid cells will be presented. Clinical trial information: NCT03268057.

Aim: Real-world palonosetron effectiveness was evaluated in an antiemetic regimen with highly emetogenic chemotherapy (HEC). Patients & methods: In this Phase IV, prospective, multicenter observational study, HEC-treated cancer patients received palonosetron, a neurokinin 1 receptor antagonist, and dexamethasone. Primary objective was to assess complete response (CR) for acute (≤24 h), delayed and overall (≤120 h) chemotherapy-induced nausea and vomiting. Results: Of 159 patients, 65.4% had breast cancer, 64.8% received anthracycline (doxorubicin)-plus-cyclophosphamide-containing chemotherapy; 155 completed one HEC cycle. CR was 60.0% acute, 39.4% delayed and 34.8% overall, and then increased (all phases) in 69 patients completing four HEC cycles. Anthracycline (doxorubicin) plus cyclophosphamide-receiving patients had especially low CR. Conclusion: Even within a recommended three-drug antiemetic regimen, palonosetron may provide suboptimal chemotherapy-induced nausea and vomiting control with HEC in real-world settings.

Objectives: Tissue factor overexpression is associated with tumor progression, venous thromboembolism, and worsened survival in patients with cancer. Tissue factor and activated factor VII (FVIIa) complex may contribute to tumor invasiveness by promoting cell migration and angiogenesis. The study objective was to evaluate safety, pharmacokinetics, and efficacy of PCI-27483, a selective FVIIa inhibitor. Methods: This was an open-label, multicenter phase 2 trial of patients with advanced pancreatic cancer. Part A of the study was an intrapatient dose escalation lead-in portion in patients concurrently receiving gemcitabine, and in part B, patients were randomized 1: 1 to the recommended phase 2 dose combination PCI-27483–gemcitabine versus gemcitabine alone. Results: Target international normalized ratio (between 2.0–3.0) was achieved following PCI-27483 treatment. Overall safety of PCI-27483–gemcitabine (n = 26) was similar to gemcitabine alone (n = 16), with a higher incidence of mostly low-grade bleeding events (65% vs. 19%). Progression-free survival (PFS) and overall survival (OS) were not significantly different between patients treated with PCI-27483–gemcitabine (PFS: 3.7 months, OS: 5.7 months) and those treated with gemcitabine alone (PFS: 1.9 months, OS: 5.6 months). Conclusions: Targeted inhibition of the coagulation cascade was achieved by administering PCI-27483. PCI-27483–gemcitabine was well tolerated, but superiority to single agent gemcitabine was not demonstrated.

Introduction: Hypomethylating agents (HMAs) such as decitabine (DEC) or azacitidine (AZA) are FDA approved therapies for patients with different myeloid malignancies as single agent or in combination with venetoclax. Both DEC and AZA require IV infusion for 1 hour or subcutaneous (SC) injections daily for 5-7 days of every 28-day treatment cycle. They both have limited oral bioavailability due to rapid degradation by cytidine deaminase (CDA) in the gut and liver. An orally bioavailable HMA option could reduce clinic visit frequency and reduce infusions/injections related adverse events and burden. ASTX727 is an oral tablet comprised of a fixed-dose combination (FDC) of CDA inhibitor cedazuridine (C) at 100 mg with DEC at 35 mg. In a phase 2 study, C-DEC (ASTX727) demonstrated pharmacokinetic (PK) AUC exposure similar to IV-DEC at 20mg/m2 with comparable clinical activity and safety (Garcia-Manero, et al, 15th Int'l MDS Symposium, 2019). We describe here the results of a phase 3 study designed to demonstrate exposure bioequivalence of oral C-DEC and IV-DEC and generate clinical data using C-DEC in a larger population (ASCERTAIN study). Methods: The study used a randomized cross over design where patients were randomized 1:1 to either Sequence A: C-DEC (100 mg/35 mg respectively) in Cycle 1 followed by IV-DEC at 20 mg/m2 in Cycle 2, or Sequence B receiving IV-DEC in Cycle 1 followed by C-DEC on Cycle 2 to compare PK (primary endpoint AUC equivalence over 5 days of dosing) and pharmacodynamic (PD) of DNA demethylation using LINE-1 assay. All patients received C-DEC in all subsequent cycles from Cycle 3 onwards until treatment discontinuation to study clinical efficacy and safety of C-DEC. Patients were eligible as per the FDA-approved label (MDS IPSS Intermediate [Int]-1,-2 or high risk[HR] and CMML patients). Clinical responses were assessed by an independent expert panel according to International Working Group (IWG) 2006 response criteria. Adverse events (AEs) were graded by Common Terminology Criteria for Adverse Events (CTCAE) v 4.03. Results: 138 patients were randomized, of whom 133 were treated with median age of 71.0 years (range 44-88), median weight was 83.1 kg (range 45-158), and median BSA was 1.99 m2 (range 1.4-2.9 m2). The IPSS status of the patients were Int-1 in 44%, Int-2 in 20%, and HR in 16%, and 12% of pts had CMML. Patients in the two arms were well balanced regarding cytogenetic risk, baseline hemoglobin, neutrophils, platelets, or red blood cell or platelet transfusion dependence. For the primary end point, the decitabine AUC0-24 (h*ng/mL) 5-Day geometric mean estimate was 856 from the C-DEC and 865 from IV-DEC resulting in an oral/IV AUC ratio of 98.9% (90% CI of 92.7-105.6%). All sensitivity and secondary exposure analyses confirmed the primary results. Comparison of hypomethylating activity as measured by LINE-1 demethylation showed difference between oral C-DEC and IV-DEC demethylation of Summary/Conclusions: This randomized phase 3 study demonstrates that C-DEC, the oral FDC of cedazuridine/decitabine (100 mg/35 mg) resulted in an equivalent DEC exposure to IV-DEC at 20 mg/m2 over 5 days. Safety findings are consistent with those anticipated with IV-DEC with no clinically significant GI toxicity. Preliminary clinical activity is also consistent with published data from IV-DEC. C-DEC is an oral HMA alternative to IV-DEC. Combination studies with other oral agents are being planned. Disclosures Garcia-Manero: Amphivena: Consultancy, Research Funding; Helsinn: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Celgene: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding. Griffiths:New Link Genetics: Consultancy; Astex Phramaceuticals/Otsuka Pharmaceuticals: Consultancy, Research Funding; Persimmune: Consultancy; Boston Scientific: Consultancy; Genentech, Inc.: Research Funding; Genentech, Inc.: Research Funding; Novartis Inc.: Consultancy; Novartis Inc.: Consultancy; Partner Therapeutics: Consultancy; Astex Phramaceuticals/Otsuka Pharmaceuticals: Consultancy, Research Funding; Onconova Therapeutics: Other: PI on a clinical trial; Celgene, Inc: Consultancy, Research Funding; Abbvie, Inc.: Consultancy; Celgene, Inc: Consultancy, Research Funding; Persimmune: Consultancy; Partner Therapeutics: Consultancy; Boston Scientific: Consultancy; New Link Genetics: Consultancy; Onconova Therapeutics: Other: PI on a clinical trial; Abbvie, Inc.: Consultancy, PI on a clinical trial; Appelis Pharmaceuticals: Other: PI on a clinical trial; Appelis Pharmaceuticals: Other: PI on a clinical trial. Yee:Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Zeidan:Ariad: Honoraria; Acceleron Pharma: Consultancy, Honoraria, Research Funding; Celgene Corporation: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Otsuka: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Medimmune/AstraZeneca: Research Funding; Astellas: Honoraria; Seattle Genetics: Honoraria; Cardinal Health: Honoraria; Novartis: Honoraria; Agios: Honoraria; Daiichi Sankyo: Honoraria; BeyondSpring: Honoraria; Boehringer-Ingelheim: Consultancy, Honoraria, Research Funding; Trovagene: Consultancy, Honoraria, Research Funding; Incyte: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; ADC Therapeutics: Research Funding; Jazz: Honoraria. Al-Kali:Astex Pharmaceuticals, Inc.: Research Funding. Dao:Incyte Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding. Patel:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Dava Oncology: Honoraria; France Foundation: Honoraria. Sabloff:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; ASTX: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi Canada: Research Funding; Actinium Pharmaceuticals, Inc: Membership on an entity's Board of Directors or advisory committees; Pfizer Canada: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas Pharma Canada: Honoraria, Membership on an entity's Board of Directors or advisory committees. Keating:Sanofi: Membership on an entity's Board of Directors or advisory committees; Hoffman La Roche: Membership on an entity's Board of Directors or advisory committees; Shire: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria. Fazal:Janssen: Honoraria, Speakers Bureau; Takeda: Honoraria, Speakers Bureau; Gilead: Consultancy, Honoraria, Speakers Bureau; Pfizer: Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Incyte: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; Jazz: Consultancy, Honoraria, Speakers Bureau; Celgene: Speakers Bureau; Karyopharm: Honoraria, Speakers Bureau. Odenike:AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen Oncology: Research Funding; Astra Zeneca: Research Funding; Gilead Sciences: Research Funding; Agios: Research Funding; CTI/Baxalta: Research Funding; Astex Pharmaceuticals: Research Funding; Incyte: Research Funding; NS Pharma: Research Funding; Oncotherapy: Research Funding. DeZern:Astex Pharmaceuticals, Inc.: Consultancy; Celgene: Consultancy. O'Connell:Astex: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Shionogi: Membership on an entity's Board of Directors or advisory committees. Roboz:Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Orsenix: Consultancy, Membership on an entity's Board of Directors or advisory committees; Otsuka: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Trovagene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sandoz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Eisai: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celltrion: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Actinium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amphivena: Consultancy, Membership on an entity's Board of Directors or advisory committees; Argenx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astex: Consultancy, Membership on an entity's Board of Directors or advisory committees. Oganesian:Astex Pharmaceuticals, Inc.: Employment. Hao:Astex Pharmaceuticals, Inc.: Employment. Keer:Astex Pharmaceuticals, Inc.: Employment. Azab:Astex Pharmaceuticals, Inc.: Employment. Savona:Incyte Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Patents & Royalties; Sunesis: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Selvita: Membership on an entity's Board of Directors or advisory committees; Karyopharm Therapeutics: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees.

Background: Polycythemia vera (PV) is a myeloproliferative neoplasm (MPN) characterized by clonal stem cell proliferation of the erythroid, myeloid, and megakaryocytic lines. The predominant clinical characteristic is an increase in red cell mass, resulting in hyperviscosity of the blood, which is responsible for most symptoms during early stages of disease. Disease progression typically results in symptomatic splenomegaly and severe constitutional symptoms, causing significant morbidity and a shortened life expectancy. Patients with PV may develop cardiovascular complications, myelofibrosis (MF), myelodysplasia, or acute myeloid leukemia (AML). Long-term (20-year) survival for PV is 18%, highlighting the poor long-term prognosis and need for additional therapies. Phlebotomy and low-dose aspirin are the standard of care for initial treatment; hydroxyurea (HU) remains the myelosuppressive agent of choice, despite the increased potential for leukemic transformation, estimated at 10% after 13 years of exposure. The Janus kinase (JAK) inhibitor ruxolitinib is approved in the US and Europe for the treatment of patients who have had an inadequate response to or are intolerant of HU. In clinical trials, ruxolitinib produced responses in 23% of patients, compared with The tumor suppressor protein p53 is the master regulator of cell-cycle arrest and apoptosis in response to cellular stress or DNA damage. Murine double minute 2 (MDM2) is a key regulator of p53, inhibiting its activity via ubiquitination, nuclear export, and direct inhibition of transcriptional activity. MDM2 is upregulated in PV CD43+ stem/progenitor cells, making the p53-MDM2 axis an attractive target in PV. In PV, TP53 is observed to be wild-type in 94% of patients, suggesting MDM2 inhibition as a potentially successful strategy (Raza, et al. Am. J. Hematol. 2012). KRT-232 is a potent and selective oral small-molecule drug that targets MDM2 and prevents MDM2-mediated p53 inhibition, allowing p53 to mediate tumor cell-cycle arrest and apoptosis. In a phase 1 dose-finding study, clinical responses were observed in 7/12 (58%) of PV patients treated with an alternative MDM2 inhibitor (Mascarenhas, et al. Blood, 2019). KRT-232 has been investigated as monotherapy and in combination with trametinib or dabrafenib in phase I studies of AML and melanoma; the most common treatment-related adverse events (TRAEs) observed in these studies were nausea, diarrhea, vomiting, decreased appetite, anemia, leukopenia, thrombocytopenia, and fatigue. The majority of TRAEs were grade 1 or 2. Methods: This randomized, open-label study aims to evaluate the efficacy, safety, and pharmacokinetics of KRT-232 compared with ruxolitinib in up to 320 patients with phlebotomy-dependent PV (Figure). The study will be conducted in 2 parts. Part A will identify the recommended dose and schedule by testing 4 treatment cohorts. In Part B, patients will be randomized 1:1 to either KRT-232 or ruxolitinib in order to evaluate safety and efficacy using the recommended dose/schedule for KRT-232 from part A. This study will enroll patients ≥ 18 years of age with PV and an ECOG performance status ≤ 2. In Part A, patients who are phlebotomy dependent with and without splenomegaly are eligible and patients must be resistant to or intolerant of HU or have undergone treatment with interferon. In Part B, only phlebotomy-dependent patients with splenomegaly are eligible, and patients must be resistant or intolerant to HU. The primary endpoint is proportion of patients with splenomegaly achieving a response at Week 32, defined as having achieved both of the following: 1) the absence of phlebotomy eligibility from Week 8 through Week 32, with no more than one phlebotomy eligibility occurring after randomization and before the Week 8 visit and 2) a reduction in spleen volume as assessed by MRI (or CT) ≥ 35% from baseline at Week 32. Secondary endpoints include response rate, duration of response and improvement in patient-reported outcomes. Exploratory endpoints include molecular and biomarker analysis including TP53 mutational status. This trial is enrolling at multiple sites in the United States and Europe (NCT03669965, EduraCT: 2018-001672-38). Figure Disclosures Gotlib: Deceiphera: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Research Funding; Pharmacyclics: Research Funding; Promedior: Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Blueprint Medicines: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Allakos: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. O'Connell:Pfizer: Membership on an entity's Board of Directors or advisory committees; Astex: Membership on an entity's Board of Directors or advisory committees, Research Funding; Shionogi: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding. Garcia-Delgado:Celgene: Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Hospital Virgen De La Victoria Malaga: Employment. Sbardellati:Kartos Therapeutics: Employment, Equity Ownership. Rothbaum:Kartos Therapeutics: Employment, Patents & Royalties: Pending; Quogue Bioventures LLC: Equity Ownership, Membership on an entity's Board of Directors or advisory committees. McGreivy:Kartos Therapeutics: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Harrison:Janssen: Speakers Bureau; Gilead: Speakers Bureau; CTI: Speakers Bureau; Roche: Honoraria; Sierra Oncology: Honoraria; AOP: Honoraria; Novartis: Honoraria, Research Funding, Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Promedior: Honoraria; Shire: Speakers Bureau; Incyte: Speakers Bureau. Kiladjian:AOP Orphan: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Celgene: Consultancy. OffLabel Disclosure: Yes, KRT-232 is an investigational small molecule MDM2 inhibitor. This trial-in-progress abstract describes a registered clinical trial that will evaluate the safety and efficacy of KRT-232 for patients with polycythemia vera.

To evaluate the safety and efficacy of mocetinostat (a Class I/IV HDAC inhibitor) in combination with gemcitabine in patients with solid tumors, including pancreatic cancer. In this open-label, non-randomized Phase I/II study (NCT00372437) sequential cohorts of patients with solid tumors received gemcitabine (1000 mg/m2, day 1 of three consecutive weeks, 4-week cycles) and oral mocetinostat [50–110 mg, three times per week (TIW)]. The maximum tolerated dose (MTD) and recommended Phase II dose (RP2D) was determined based on dose-limiting toxicities in Cycle 1 (Phase I study). The MTD/RP2D was further evaluated in patients with advanced pancreatic cancer (Phase II study) using a two-stage design. The Phase II primary endpoint was overall response rate (ORR). Forty-eight patients were enrolled into the Phase I (n = 25) and Phase II (n = 23) studies. In the Phase I study, the MTD/RP2D was mocetinostat 90 mg TIW + gemcitabine 1000 mg/m2. Grade ≥ 3 treatment-related adverse events (AEs) were reported by 81% of all patients, the most frequent being fatigue (38%) and thrombocytopenia (19%). The ORR was 11% in the Phase I study (n = 2 patients with pancreatic cancer, responses lasting for 16.8 and 4.0 months, respectively). As no responses were seen in the Phase II cohort, the study was terminated. Mocetinostat TIW in combination with gemcitabine was associated with significant toxicities in patients with advanced pancreatic cancer. The level of clinical activity of this treatment combination was not considered high enough to merit further testing in this setting.

Background\ud \ud Patients with relapsed or refractory lymphoma or chronic lymphocytic leukaemia have a poor prognosis. Therapies targeting more than one isoform of PI3K, as well as mTOR, might increase antitumour activity. We aimed to investigate the efficacy and safety of voxtalisib (also known as XL765 or SAR245409), a pan-PI3K/mTOR inhibitor, in patients with relapsed or refractory lymphoma, or chronic lymphocytic leukaemia/small lymphocytic lymphoma.\ud Methods\ud \ud We did a non-randomised, open-label, phase 2 trial at 30 oncology clinics in the USA, Belgium, Germany, France, the Netherlands, and Australia. Patients aged 18 years or older with Eastern Cooperative Oncology Group (EGOG) performance status score of 2 or lower and relapsed or refractory mantle cell lymphoma, follicular lymphoma, diffuse large B-cell lymphoma, or chronic lymphocytic leukaemia/small lymphocytic lymphoma were enrolled and treated with voxtalisib 50 mg orally twice daily in 28-day continuous dosing cycles until progression or unacceptable toxicity. The primary endpoint was the proportion of patients in each disease-specific cohort who achieved an overall response, defined as a complete response or partial response. All patients who received more than 4 weeks of treatment and who completed a baseline and at least one post-baseline tumour assessment were analysed for efficacy and all patients were analysed for safety. This study is registered with ClinicalTrials.gov, number NCT01403636, and has been completed.\ud Findings\ud \ud Between Oct 19, 2011, and July 24, 2013, 167 patients were enrolled (42 with mantle cell lymphoma, 47 with follicular lymphoma, 42 with diffuse large B-cell lymphoma, and 36 with chronic lymphocytic leukaemia/small lymphocytic lymphoma. The median number of previous anticancer regimens was three (IQR 2–4) for patients with lymphoma and four (2–5) for patients with chronic lymphocytic leukaemia/small lymphocytic lymphoma. Of 164 patients evaluable for efficacy, 30 (18·3%) achieved an overall response (partial, n=22; complete, n=8); 19 (41·3%) of 46 with follicular lymphoma, five (11·9%) of 42 with mantle cell lymphoma, two (4·9%) of 41 with diffuse large B-cell lymphoma, and four (11·4%) of 35 with chronic lymphocytic leukaemia/small lymphocytic lymphoma. The safety profile was consistent with that of previous studies of voxtalisib. The most frequently reported adverse events were diarrhoea (in 59 [35%] of 167 patients), fatigue (in 53 [32%]), nausea (in 45 [27%]), pyrexia (in 44 [26%,]), cough (in 40 [24%]), and decreased appetite (in 35 [21%]). The most frequently reported grade 3 or worse adverse events were anaemia (in 20 [12%] of 167 patients), pneumonia (in 14 [8%]), and thrombocytopenia (in 13 [8%]). Serious adverse events occurred in 97 (58·1%) of 167 patients.\ud Interpretation\ud \ud Voxtalisib 50 mg given orally twice daily had an acceptable safety profile, with promising efficacy in patients with follicular lymphoma but limited efficacy in patients with mantle cell lymphoma, diffuse large B-cell lymphoma, or chronic lymphocytic leukaemia/small lymphocytic lymphoma.

Novel therapies are needed for patients with relapsed or refractory multiple myeloma (MM). We conducted a multicenter, phase 1 study in advanced hematological malignancies to assess the safety, efficacy, and recommended phase 2 dose (RP2D) of oral selinexor, a selective inhibitor of the nuclear export protein XPO1. In the dose-escalation phase, 25 patients with heavily pretreated MM (22) or Waldenstrom macroglobulinemia (3) were administered selinexor (3-60 mg/m2) in 8 or 10 doses per 28-day cycle. In the dose-expansion phase, 59 patients with MM received selinexor at 45 or 60 mg/m2 with 20 mg dexamethasone, twice weekly in 28-day cycles, or selinexor (40 or 60 mg flat dose) without corticosteroids in 21-day cycles. The most common nonhematologic adverse events (AEs) were nausea (75%), fatigue (70%), anorexia (64%), vomiting (43%), weight loss (32%), and diarrhea (32%), which were primarily grade 1 or 2. The most common grade 3 or 4 AEs were hematologic, particularly thrombocytopenia (45%). Single-agent selinexor showed modest efficacy with an objective response rate (ORR) of 4% and clinical benefit rate of 21%. In contrast, the addition of dexamethasone increased the ORR with all responses of ≥partial response occurring in the 45 mg/m2 selinexor plus 20 mg dexamethasone twice weekly cohort (ORR = 50%). Furthermore, 46% of all patients showed a reduction in MM markers from baseline. Based on these findings, we conclude that selinexor in combination with dexamethasone is active in heavily pretreated MM and propose a RP2D of 45 mg/m2 (80 mg) plus 20 mg dexamethasone given twice weekly. This trial was registered at clinicaltrials.gov as #NCT01607892.

Purpose Subcutaneous APF530 provides controlled sustained release of granisetron to prevent acute (0–24 h) and delayed (24–120 h) chemotherapy-induced nausea and vomiting (CINV). This randomized, double-blind phase 3 trial compared APF530 and palonosetron in preventing acute and delayed CINV after moderately (MEC) or highly emetogenic chemotherapy (HEC). Methods Patients receiving single-day MEC or HEC received single-dose APF530 250 or 500 mg subcutaneously (SC) (granisetron 5 or 10 mg) or intravenous palonosetron 0.25 mg. Primary objectives were to establish APF530 noninferiority to palonosetron for preventing acute CINV following MEC or HEC and delayed CINV following MEC and to determine APF530 superiority to palonosetron for preventing delayed CINV following HEC. The primary efficacy end point was complete response (CR [using CI difference for APF530 − palonosetron]). A lower confidence bound greater than −15 % indicated noninferiority. Results In the modified intent-to-treat population (MEC = 634; HEC = 707), both APF530 doses were noninferior to palonosetron in preventing acute CINV after MEC (CRs 74.8 % [−9.8, 9.3] and 76.9 % [−7.5, 11.4], respectively, vs. 75.0 % palonosetron) and after HEC (CRs 77.7 % [−11.5, 5.5] and 81.3 % [-7.7, 8.7], respectively, vs. 80.7 % palonosetron). APF530 500 mg was noninferior to palonosetron in preventing delayed CINV after MEC (CR 58.5 % [−9.5, 12.1] vs. 57.2 % palonosetron) but not superior in preventing delayed CINV after HEC. Adverse events were generally mild and unrelated to treatment, the most common (excluding injection-site reactions) being constipation. Conclusions A single subcutaneous APF530 injection offers a convenient alternative to palonosetron for preventing acute and delayed CINV after MEC or HEC.

Patients with relapsed or refractory (R/R) non-Hodgkin lymphoma (NHL) have a poor prognosis and limited treatment options. We evaluated selinexor, an orally bioavailable, first-in-class inhibitor of the nuclear export protein XPO1, in this phase 1 trial to assess safety and determine a recommended phase 2 dose (RP2D). Seventy-nine patients with various NHL histologies, including diffuse large B-cell lymphoma, Richter’s transformation, mantle cell lymphoma, follicular lymphoma, and chronic lymphocytic leukemia, were enrolled. In the dose-escalation phase, patients received 3 to 80 mg/m2 of selinexor in 3- or 4-week cycles and were assessed for toxicities, pharmacokinetics, and antitumor activity. In the dose-expansion phase, patients were treated with selinexor at 35 or 60 mg/m2. The most common grade 3 to 4 drug-related adverse events were thrombocytopenia (47%), neutropenia (32%), anemia (27%), leukopenia (16%), fatigue (11%), and hyponatremia (10%). Tumor biopsies showed decreases in cell-signaling pathways (Bcl-2, Bcl-6, c-Myc), reduced proliferation (Ki67), nuclear localization of XPO1 cargos (p53, PTEN), and increased apoptosis after treatment. Twenty-two (31%) of the 70 evaluable patients had an objective responses, including 4 complete responses and 18 partial responses, which were observed across a spectrum of NHL subtypes. A dose of 35 mg/m2 (60 mg) was identified as the RP2D. These findings suggest that inhibition of XPO1 with oral selinexor at 35 mg/m2 is a safe therapy with encouraging and durable anticancer activity in patients with R/R NHL. The trial was registered at www.clinicaltrials.gov as #NCT01607892.

Selinexor is a novel, first-in-class, selective inhibitor of nuclear export compound, which blocks exportin 1 (XPO1) function, leads to nuclear accumulation of tumor suppressor proteins, and induces cancer cell death. A phase 1 dose-escalation study was initiated to examine the safety and efficacy of selinexor in patients with advanced hematological malignancies. Ninety-five patients with relapsed or refractory acute myeloid leukemia (AML) were enrolled between January 2013 and June 2014 to receive 4, 8, or 10 doses of selinexor in a 21- or 28-day cycle. The most frequently reported adverse events (AEs) in patients with AML were grade 1 or 2 constitutional and gastrointestinal toxicities, which were generally manageable with supportive care. The only nonhematological grade 3/4 AE, occurring in >5% of the patient population, was fatigue (14%). There were no reported dose-limiting toxicities or evidence of cumulative toxicity. The recommended phase 2 dose was established at 60 mg (∼35 mg/m2) given twice weekly in a 4-week cycle based on the totality of safety and efficacy data. Overall, 14% of the 81 evaluable patients achieved an objective response (OR) and 31% percent showed ≥50% decrease in bone marrow blasts from baseline. Patients achieving an OR had a significant improvement in median progression-free survival (PFS) (5.1 vs 1.3 months; P = .008; hazard ratio [HR], 3.1) and overall survival (9.7 vs 2.7 months; P = .01; HR, 3.1) compared with nonresponders. These findings suggest that selinexor is safe as a monotherapy in patients with relapsed or refractory AML and have informed subsequent phase 2 clinical development. This trial was registered at www.clinicaltrials.gov as #NCT01607892.