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Background Addition of temozolomide (TMZ) to radiotherapy (RT) improves overall survival (OS) in patients with glioblastoma (GBM), but previous studies suggest that patients with tumors harboring an unmethylated MGMT promoter derive minimal benefit. The aim of this open-label, phase III CheckMate 498 study was to evaluate the efficacy of nivolumab (NIVO) + RT compared with TMZ + RT in newly diagnosed GBM with unmethylated MGMT promoter. Methods Patients were randomized 1:1 to standard RT (60 Gy) + NIVO (240 mg every 2 weeks for eight cycles, then 480 mg every 4 weeks) or RT + TMZ (75 mg/m2 daily during RT and 150–200 mg/m2/day 5/28 days during maintenance). The primary endpoint was OS. Results A total of 560 patients were randomized, 280 to each arm. Median OS (mOS) was 13.4 months (95% CI, 12.6 to 14.3) with NIVO + RT and 14.9 months (95% CI, 13.3 to 16.1) with TMZ + RT (hazard ratio [HR], 1.31; 95% CI, 1.09 to 1.58; P = .0037). Median progression-free survival was 6.0 months (95% CI, 5.7 to 6.2) with NIVO + RT and 6.2 months (95% CI, 5.9 to 6.7) with TMZ + RT (HR, 1.38; 95% CI, 1.15 to 1.65). Response rates were 7.8% (9/116) with NIVO + RT and 7.2% (8/111) with TMZ + RT; grade 3/4 treatment-related adverse event (TRAE) rates were 21.9% and 25.1%, and any-grade serious TRAE rates were 17.3% and 7.6%, respectively. Conclusions The study did not meet the primary endpoint of improved OS; TMZ + RT demonstrated a longer mOS than NIVO + RT. No new safety signals were detected with NIVO in this study. The difference between the study treatment arms is consistent with the use of TMZ + RT as the standard of care for GBM. ClinicalTrials.gov NCT02617589

BackgroundThe phase 1 cohorts (1c+1d) of CheckMate 143 (NCT02017717) evaluated the safety/tolerability and efficacy of nivolumab plus radiotherapy (RT) ± temozolomide (TMZ) in newly diagnosed glioblastoma.MethodsIn total, 136 patients were enrolled. In part A (safety lead-in), 31 patients (n = 15, methylated/unknown MGMT promoter; n = 16, unmethylated MGMT promoter) received nivolumab and RT+TMZ (NIVO+RT+TMZ) and 30 patients with unmethylated MGMT promoter received NIVO+RT. In part B (expansion), patients with unmethylated MGMT promoter were randomized to NIVO+RT+TMZ (n = 29) or NIVO+RT (n = 30). Primary endpoint was safety/tolerability; secondary endpoint was overall survival (OS).ResultsNIVO+RT±TMZ was tolerable; grade 3/4 treatment-related adverse events occurred in 51.6% (NIVO+RT+TMZ) and 30.0% (NIVO+RT) of patients in part A and 46.4% (NIVO+RT+TMZ) and 28.6% (NIVO+RT) in part B. No new safety signals were detected. In part A, median OS (mOS) with NIVO+RT+TMZ was 33.38 months (95% CI, 16.2 to not estimable) in patients with methylated MGMT promoter. In patients with unmethylated MGMT promoter, mOS was 16.49 months (12.94–22.08) with NIVO+RT+TMZ and 14.41 months (12.55–17.31) with NIVO+RT. In part B, mOS was 14.75 months (10.01–18.6) with NIVO+RT+TMZ and 13.96 months (10.81–18.14) with NIVO+RT in patients with unmethylated MGMT promoter.ConclusionsCheckMate 143 was the first trial evaluating immune checkpoint inhibition with first-line treatment of glioblastoma. Results showed that NIVO can be safely combined with RT±TMZ, with no new safety signals. Toxicities, including lymphopenia, were more frequent with NIVO+RT+TMZ. OS was similar with or without TMZ in patients with unmethylated MGMT promoter, and differences by MGMT methylation status were observed.

Background: Prostate cancer is the 2nd leading cause of cancer-related deaths among men in the US. CREB binding protein (CBP) and paralog p300 are co-activators of androgen receptor (AR) relevant to metastatic castration-resistant prostate cancer (mCRPC) progression and AR therapy resistance. FT-7051 is an oral, potent and selective inhibitor of CBP/p300 bromodomain with activity in preclinical prostate cancer models, including those resistant to enzalutamide. Methods: The Courage Study (NCT04575766) is a first-in-human, multicenter, phase 1, open-label study to examine the safety, PK/PD, and preliminary anti-tumor activity of FT-7051 in mCRPC patients (pts) who have progressed despite prior therapy, including at least one AR pathway inhibitor. The study uses a Bayesian optimal interval (BOIN) design with an accelerated titration phase. FT-7051 is dosed on a 28-d cycle (21-d on/7-d off). Following accelerated titration, dose escalation/de-escalation decisions are made by comparing the observed dose-limiting toxicity (DLT) rate at the current dose with pre-specified dose escalation/de-escalation boundaries. The primary objectives are to evaluate safety and tolerability of FT-7051 and determine the recommended phase 2 dose. Key secondary endpoints include PSA at 12 wks, time to PSA progression, time to radiographic progression, overall response rate, and PK parameters. Biomarker analyses include PD assessments of CBP/p300 inhibition in surrogate tissues and genetic analyses in circulating tumor cells (AR, AR-v7) and peripheral blood. Results: As of 18-June-2021, a total of 5 pts were enrolled with exposure data entered into the database, with 2 pts ongoing and 3 pts discontinued (disease progression, n=1; no longer clinically benefitting, n=1; subject withdrawal, n=1). Pts had a median age of 71 yrs (range: 66-82) with a median time since first mCRPC diagnosis of 2.3 yrs (0.4-4.7) and a median of 3 (1-5) prior lines of mCRPC therapy. Mutations reported by the investigator for 3 pts included MYC, p53, RB1, AR, and PTEN loss. Preliminary PK analyses indicated that FT-7051 exposure increased with dose in a greater than dose-proportional manner. Importantly, observed FT-7051 exposures were consistent with the predicted efficacious exposure threshold derived from PK/efficacy modeling in preclinical studies. TEAEs were reported in 4 (80%) pts. Most TEAEs were mild (Gr1) or moderate (Gr2), ≥Gr3 TEAEs included one event of possibly related Gr3 hyperglycemia and one event of unrelated Gr5 disease progression. Conclusions: Preliminary safety and PK data from the accelerated titration phase of this BOIN study support the continued investigation of FT-7051 in men with mCRPC. Initial PK data confirm that FT-7051 exposure is consistent with the predicted efficacious exposure threshold determined by PK/efficacy modeling. Additional analyses of PSA, PD assessments, and genetic analyses, including AR-v7 status, will be reported. Citation Format: Andrew J. Armstrong, Michael S. Gordon, Melissa A. Reimers, Arif Hussain, Vaibhav G. Patel, Elaine T. Lam, Alex Sedkov, Von Potter, Neal Shore. Initial findings from an ongoing first-in-human phase 1 study of the CBP/p300 inhibitor FT-7051 in men with metastatic castration-resistant prostate cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P202.

Background Sickle cell disease (SCD) and thalassemia are inherited hemoglobinopathies characterized by lifelong anemia. In SCD, a single mutation in the β-globin gene results in sickle hemoglobin (HbS) that polymerizes upon deoxygenation, causing red blood cells (RBCs) to sickle leading to a variety of complications. In thalassemia, mutation(s) in α- or β-globin genes result in reduced or absent adult Hb causing ineffective erythropoiesis and downstream complications. The resultant anemias are exacerbated by impaired RBC function due to decreased ATP content. Supportive care and agents like hydroxyurea are used most in SCD, with a subset of patients (pts) on regular transfusions. Regular or episodic transfusions, with their own set of complications, are the mainstay of treatment for thalassemias. Etavopivat, a potent, selective, oral, small molecule activator of erythrocyte pyruvate kinase (PKR) increases ATP and decreases 2,3 diphosphoglycerate (2,3-DPG). In a Phase 1 study, etavopivat 300‒600 mg once daily in pts with SCD not regularly transfused was well-tolerated, improved hematological markers, decreased hemolysis, and improved markers of RBC functional health (Brown et al. EHA 2021 # EP1202). Etavopivat 200 and 400 mg once daily (dose levels predicted to provide the desired pharmacodynamic response profiles) is being evaluated in a Phase 2/3 study of pts with SCD who are not on chronic transfusions (The Hibiscus Study, NCT04624659). Herein we describe the design of a Phase 2, open-label, multicenter study (NCT04987489) evaluating the efficacy and safety of etavopivat in pts with: SCD on chronic transfusions (Cohort A), transfusion-dependent thalassemia (Cohort B), and non-transfusion-dependent thalassemia (Cohort C). Study Design and Methods Up to 20 pts aged 12-65 years will be enrolled in each of the three cohorts described above. Pts will receive etavopivat 400 mg once daily for 48-wks (Figure). In cohorts A and B, pts must have received ≥6 RBC units in the 24 wks before the first dose of etavopivat without a >35-day transfusion-free period during that period and be on iron chelation therapy for >3 months before enrollment. Additionally, pts in Cohort A should have received ≥24 monthly transfusions for the prevention or treatment of primary stroke. Pts in Cohort C should have a Hb ≤10 g/dL. Key exclusion criteria include significant infection, hepatic/renal dysfunction, history of malignancy/cardiac/pulmonary disease, a drug malabsorption disorder, prior/concomitant therapies ≤3 months before the first dose (eg, chronic systemic glucocorticoids, new chelation therapy). Baseline assessments will include medical, disease, transfusion, and medication histories. Transfusions received during the study (every ~3-5 wks) will be recorded and include Hb values before and ≥15 minutes after transfusion, number of RBC units, and volume of packed RBCs. If a pt has an increase in pre-transfusion Hb of ≥1.0 g/dL compared with their baseline pre-transfusion Hb, the Investigator may delay transfusion by 1 wk or reduce the number of RBC units transfused. In pts with SCD, RBC exchange may also be performed. The primary endpoint for Cohorts A/B is erythroid response defined as the proportion of pts with ≥20% reduction in transfusions over a continuous 12-wk treatment period versus baseline, and for Cohort C is Hb response at Wk 12 defined as an increase in Hb of ≥1.0 g/dL from baseline. For Cohorts A/B, secondary and exploratory endpoints include the proportion of pts with a reduction in transfusions over 12 wks of ≥33% and ≥50%, respectively, and a reduction in transfusions over 12, 24, and 48 wks; and for Cohort C, Hb response at Wks 24 and 48, and changes from baseline in Hb over 12, 24, and 48 wks. The following additional endpoints will be assessed for all cohorts: changes from baseline in quality of life as assessed via the Short Form Health Survey and Patient-Reported Outcome Measurement Information System Fatigue Scale; changes from baseline in the levels of serum ferritin at 12, 24, and 48 wks; liver iron at 48 wks; 2,3-DPG and ATP; pharmacokinetics; and safety. All primary endpoints will be analyzed using a 1-sided test at α=0.025. Summary Etavopivat is a novel, investigational, PKR activator designed to improve the functional health of RBCs. This Phase 2 study will assess the safety of etavopivat and its impact on Hb levels and transfusion burden in pts with SCD or thalassemia. Figure 1 Figure 1. Disclosures Lal: Chiesi: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; bluebird bio, Inc.: Research Funding; Protagonist Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Agios Pharmaceuticals: Consultancy; Insight Magnetics: Research Funding; Novartis: Research Funding; Terumo Corporations: Research Funding; La Jolla Pharmaceutical Company: Research Funding. Brown: Novo Nordisk: Consultancy; Novartis: Consultancy, Research Funding; Imara: Consultancy, Research Funding; Forma Therapeutics: Research Funding; Pfizer: Research Funding; Global Blood Therapeutics: Consultancy, Research Funding. Coates: Apo Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bluebird Bio: 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; Bristol Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Chiesi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Research Funding; Forma Pharma: Consultancy; Sangamo: Consultancy; UpToDate: Patents & Royalties; Vifor Pharma: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Kalfa: Agios Pharmaceuticals, Inc.: Other: Steering Committee, Research Funding; FORMA Therapeutics, Inc: Research Funding. Kwiatkowski: Bioverativ: Research Funding; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Agios Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; CRISPR: Research Funding; Imara: Consultancy, Research Funding; Silence Therapeutics: Consultancy; Sangamo: Research Funding; bluebird bio: Consultancy, Research Funding; Chiesi: Research Funding; Vertex: Research Funding. Brevard: Forma Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company, Current holder of stock options in a privately-held company. Potter: Forma Therapeutics, Inc: Current Employment, Current equity holder in publicly-traded company; Bristol Myers Squibb: Ended employment in the past 24 months. Wood: Forma Therapeutics, Inc: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months. Sheth: Bluebird bio: Consultancy; CRISPR: Consultancy; Bristol Myers Squibb: Consultancy, Research Funding; Imara: Research Funding; Chiesi: Consultancy; Agios: Consultancy; Dispersol: Research Funding.

3560 Background: The role of immunotherapy in the treatment of pMMR/MSS metastatic CRC is not established. A Japanese phase 1b trial in this setting showed the combination of regorafenib (multikinase inhibitor with immunomodulatory activity) plus nivolumab (anti PD-1) had encouraging activity and manageable safety (Fukuoka, 2020). This study further assessed the safety and efficacy of this combination. Methods: Patients (pts) from the US aged ≥18 years who progressed on/were intolerant to standard chemotherapy were enrolled. Regorafenib was given orally, once daily in 28-day (D) cycles (21D on/7D off) plus IV nivolumab 480 mg on D1. Regorafenib starting dose was 80 mg; if well tolerated, it could be escalated to 120 mg in Cycle 2. Primary endpoint was overall response rate (ORR; RECIST 1.1); secondary aims included disease control rate (DCR), overall survival (OS), progression-free survival (PFS), and safety (NCI-CTCAE v5.0 grade). Biomarker analysis was exploratory. Results: 70 pts (59% male) started treatment. At baseline, median age was 57 years (range 34–85), ECOG PS 0/1 was 51%/49%, 67% had liver metastases (mets), and the primary tumor site was right-sided colon in 36% and rectum in 17%. Median number of cycles was 3.0 (range 1–13); 41% of pts escalated regorafenib to 120 mg. Five pts (7.1%) had a partial response (PR) lasting ≥16 weeks (wks) and 22 (31.4%) had stable disease (SD); pts without liver mets had a higher ORR (21.7%). In pts with tumor samples (n = 40), higher baseline expression (IHC) of cytotoxic T cells (CD3+/CD8+/GranzymeB+), Tregs (FoxP3+), and macrophages (CD68+) trended with clinical benefit (PR/SD ≥16 wks/PFS); pts with liver mets had lower expression. Lower plasma levels of biomarkers of vascular biology (e.g. VEGF-D, Ang-2, VWF) trended with longer PFS. Grade (Gr) 3 treatment-emergent adverse events (TEAEs) occurred in 53% of pts and Gr 4 in 10%. Three pts had a Gr 5 TEAE: n = 1 related to the combination (sepsis); n = 1 related to nivolumab only by investigator (sepsis); n = 1 unrelated to treatment (respiratory failure). Most common Gr 3/4 TEAEs: maculopapular rash (14%), fatigue (7%), pneumonia (6%), increased bilirubin (6%). Conclusions: Combination treatment with regorafenib (up to 120 mg/day) and nivolumab (480 mg every 28D) has manageable safety. Efficacy of this combination in the North American population did not emulate results in the Japanese population. Absence of liver mets and expression of specific biomarkers indicate a better response and may warrant further analysis. Clinical trial information: NCT04126733. [Table: see text]

BACKGROUND Current therapies for recurrent glioblastoma provide limited survival benefit. In the open-label, phase 3 CheckMate 143 study (NCT02017717), although the primary endpoint was not met, the median overall survival (mOS) was comparable between nivolumab (anti–PD-1) and bevacizumab in the overall population of patients with glioblastoma at first recurrence after temozolomide chemoradiotherapy (Reardon et al, WFNOS 2017). Exploratory subgroup analyses were conducted to evaluate the association of O-6-methylguanine DNA methyltransferase (MGMT) promoter methylation status and corticosteroid use at baseline with mOS. METHODS Prespecified patient subgroups included MGMT promoter status (methylated vs unmethylated) and baseline corticosteroid use (yes [within 5 days of first dose] vs no). FINDINGS: Methylation status was available for 102/184 (55%) nivolumab-treated and 109/185 (59%) bevacizumab-treated patients. Using a multivariable Cox proportional hazards model analysis, no baseline corticosteroid use (HR, 0.59 [95% CI, 0.36–0.95]) and methylated MGMT status (HR, 0.47 [95% CI, 0.29–0.78]) were each associated with longer mOS among nivolumab-treated patients. Among patients with methylated MGMT and no baseline corticosteroid use, mOS was 17.0 months with nivolumab (n=31) and 10.1 months with bevacizumab (n=22; HR, 0.58 [95% CI, 0.30–1.11]). In patients with methylated tumors and baseline corticosteroids, mOS was 7.7 months with nivolumab (n=12) and 13.5 months with bevacizumab (n=17). Among patients with unmethylated tumors and no baseline corticosteroids, mOS was 8.3 months with nivolumab (n=30) and 10.3 months with bevacizumab (n=29). In patients with unmethylated tumors and baseline corticosteroids, mOS was 5.6 months with nivolumab (n=28) and 8.3 months with bevacizumab (n=28). CONCLUSION A trend toward longer mOS with nivolumab was observed in a subgroup of patients with methylated MGMT and no baseline corticosteroid use. These findings suggest that MGMT methylation status and corticosteroid use at baseline could be used to identify patients who may benefit from nivolumab and thus warrant further study.

Monoclonal antibodies (MAbs) targeting epidermal growth factor receptor (EGFR) are effective in treatment of metastatic colorectal cancer (mCRC). Cetuximab, a chimeric MAb targets EGFR. Even with premedication, cetuximab can cause a hypersensitivity reaction (HSR). In case of severe HSR, further therapy with cetuximab is contraindicated, thus preventing these patients from receiving potentially beneficial anti-EGFR therapy. Panitumumab is a fully human MAb also targets EGFR. To date, no human antihuman Ab have been detected, and unlike CET, HSR are infrequent, and no premedication is required. Safety of panitumumab in patients with a previous severe HSR with cetuximab is not fully known. We present three patients with GI cancers who tolerated panitumumab without HSR after experiencing severe HSR to cetuximab. Three patients were challenged with standard dose of panitumumab (6 mg/kg) after experiencing grade 3 HSR to standard dose of cetuximab under strict observation and no premedication. First patient, a 58-year-old male with mCRC developed grade 3 HSR during 8th dose of cetuximab. Second patient was a 58-year-old female with mCRC developed grade 3 HSR during 12th dose of cetuximab. Third patient was a 61-year-old male with pancreatic cancer who experienced grade 3 HSR during loading dose of cetuximab. Charts were reviewed to find history of prior allergy, including H1 blocker use, drug allergy, bee sting allergy, eczema, allergic reactive airways disease, or food allergy. All patients were Caucasians with an average age of 59 year with no history of prior allergy. No patient received any premedication. First patient received panitumumab for 2 months, second patient was treated for 6 months, and third patient who was rechallenged 1 week after HSR to cetuximab had a partial response following 6 months of therapy. HSR are serious complications associated with MAbs. Thanks to hybridoma technology that newer generations of MAbs contain less or no mouse-specific protein sequences, hence reducing the risk of HSR. Identification of individuals likely to develop severe and sometimes life-threatening HSR is challenging. Our report of three patients successfully treated with panitumumab after they had severe HSR to cetuximab warrant further investigation.

Abstract 2816 Background: Vorinostat is a histone deacetylase inhibitor with activity in lymphoma and leukemia. Vorinostat has been reported to act synergistically with topoisomeraseII inhibitors such as anthracyclines (Ac) by facilitating an open chromatin configuration thus enhancing double-strand DNA breaks and apoptosis. We conducted a phase 1 study of escalating doses of vorinostat with pegylated liposomal doxorubicin (V+PLD) in patients with relapsed or refractory lymphoma. The primary objective was to determine the maximum tolerated dose (MTD). Other endpoints included safety, tolerability, and activity of V+PLD. Methods: Patients age ≥18 years with relapsed or refractory lymphoma were enrolled sequentially into 1 of 3 dosing levels using a standard 3+3 design for up to 8 cycles. The study was conducted in accordance with the Declaration of Helsinki, good clinical practice and regulatory guidelines. Vorinostat 200 (dose level 1), 300 (dose level 2), or 400mg (dose level 3) twice daily on days 1–7 and PLD 30mg/m2 on day 3 of a 21-day cycle were administered to eligible and consenting patients. CTCAE v.3.0 was used to determine toxicities, and the revised criteria for malignant lymphoma were used to determine response. Results: 14 patients have been enrolled; 2 men and 12 women; median age 69 years [range 27–88]; median prior therapies (4) [1-11]; prior Ac (13); median prior Ac dose (300mg/m2) [108-440mg/m2]; prior HDACi (1); Dose level 1 (7); Dose level 2 (4); Dose level 3 (3). Lymphoma subtypes included: Hodgkin's lymphoma (HL)(4), peripheral T-cell lymphoma (3), diffuse large B-cell lymphoma (DLBCL)(5), grey zone lymphoma (1), lymphoplasmacytic lymphoma (1). Median number of study cycles was two [1-8](2). Grade 3–4 hematologic toxicities included: neutropenia (3) and thrombocytopenia (1). Grade 3–4 non-hematologic toxicities included: fatigue (2), nausea (1), anorexia (1), dehydration (1), AST/ALT elevation (1), amylase/lipase elevation (1). No cardiac toxicities were observed. There was one death attributed to disease progression. Partial responses (PR) were documented in two HL patients, stable disease (SD) in one HL and one DLBCL patient. Three patients continued therapy beyond 2 cycles. One HL patient with a PR tolerated 8 cycles despite a prior anthracycline dose of 350mg/m2 and 9 prior systemic treatments including ABVD, ICE, GND, DICEP, BEAM and autologous stem cell transplant, Gem and C-MOPP. Another HL patient with a PR after 2 cycles is currently on cycle 3 at dose level 3 and had 5 prior treatments including autologous transplant. One other HL patient with SD discontinued therapy after 2 cycles to proceed with alternative chemotherapy including allogeneic stem cell transplant. One patient with cutaneous DLBCL obtained a skin response but had overall stable disease and completed 6 cycles before disease progression; prior treatment included R-CHOP, R-ICE, CEPP, and GemOx. In addition, one patient with lymphoplasmacytic lymphoma had a clinical response after 1 cycle but therapy was discontinued because of neutropenia and her disease progressed. Conclusions: The combination of V+PLD is well tolerated even among older and heavily pretreated patients. There were no cardiac toxicities even in patients heavily pretreated with anthracyclines. The MTD has not been reached and enrollment to dose level 3 is ongoing. Disease control was achieved in 4 of 14 patients (2 PR and 2 SD). Of interest, 3 of 4 patients with HL achieved disease control (2 PR and one SD), and treatment with vorinostat in combination with anthracycline-based therapy warrants further investigation in HL. Disclosures: Lansigan: Merck: Speakers Bureau. Off Label Use: Vorinostat in combination with pegylated doxorubicin is considered experimental in lymphoma. Foss:Merck: Speakers Bureau.

20744 Background: Monoclonal antibodies (Mabs) targeting epidermal growth factor receptor (EGFR) are effective in treatment of metastatic colorectal cancer (mCRC). CET, a human-murine chimeric Mab ...