Tees, Michael

Abstract Introduction: Bruton tyrosine kinase inhibitors (BTKi) have revolutionized the treatment of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and certain B-cell neoplasms. However, resistance to BTKi develops primarily through mutations at the cysteine binding site (C481) or PLCγ2 mutations. MK-1026 (formerly ARQ-531) is a non-covalent, potent inhibitor of both wild type and C481- mutated BTK. In the phase 1/2 dose escalation and dose expansion study NCT03162536, the preliminary recommended phase 2 dose (RP2D) of MK-1026 was determined to be 65 mg once daily. The efficacy and safety of MK-1026 in participants with CLL/SLL and B-cell non-Hodgkin lymphoma (NHL) were also evaluated at a higher dose during the dose expansion phase. Methods: In this open-label, single-arm phase 2 study, 9 expansion cohorts were initiated following determination of preliminary MK-1026 RP2D. Approximately 10-25 eligible participants were enrolled into Cohort A (relapsed/refractory (r/r) CLL/SLL, with ≥2 prior therapies including covalent BTKi, with documented C481 mutation), Cohort B (r/r CLL/SLL progressed on/intolerant to a BTKi, with ≥2 prior therapies without C481 mutation), Cohort C (participants with Richter transformation [RT] with ≥1 prior therapy), Cohort D-H (participants with follicular lymphoma (FL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), high-grade B cell lymphoma (BCL) with known MYC, BCL-2 or BCL-6 translocations, and Waldenström macroglobulinemia (WM), respectively, who received ≥2 prior therapies), Cohort I (food effect cohort including participants with B-cell NHL, CLL/SLL, and WM). Treatment continued until unacceptable toxicity, clinical or radiological progression, participant/physician withdrawal. Primary endpoint was overall response rate (per iwCLL criteria, by investigator) for participants with CLL/SLL. Secondary endpoints included duration of response and safety and tolerability. The data cut-off date for this analysis was April 7, 2021. Results: Among 118 participants enrolled, 44 had B-cell NHL (including 6 with DLBCL, 11 with FL, 3 with high-grade BCL, 6 with MCL, 2 with MZL, 16 with RT), 68 CLL/SLL, and 4 WM. Of these, 94 (79.6%) were treated at the preliminary RP2D, including 51 (54.3%) participants with CLL/SLL. Participants with CLL/SLL had a median (range) number of prior therapies of 4 (1-18), 43 (84%) had prior BTKi therapy, 12 (23%) had del17p, 26 (51%) had IGHV unmutated status, and 32 (63%) had C481S BTK mutation. At data cut-off, median (range) follow-up was 4.56 months (0.1-26.7) for all treated participants. ORR was 57.9% (N = 22 of 38; 1 CR, 21 PR/PRL) per iwCLL criteria in the efficacy evaluable population of participants with CLL/SLL treated at preliminary RP2D. The median duration of response in these participants was not estimable [NE] (range, 8.3 months-NE). At data cut-off, the median duration of treatment exposure was 3.2 months (range, 0-35.9). Among all treated participants, 114 (97%) had a treatment-emergent adverse event (TEAE), with 78 (66%) having a drug-related TEAE, and 9 (8%) having a drug-related TEAE that led to discontinuation. Common TEAEs (≥ 20%) included fatigue (33%), constipation (31%), dysgeusia (28%), cough (25%), nausea (25%), pyrexia (25%), dizziness (23%), hypertension (23%), peripheral edema (22%), arthralgia (20%), and diarrhea (21%). Grade ≥3 TEAEs occurred in 80 (68%) participants. Grade 5 TEAEs occurred in 7 (6%) participants and included death following disease progression in 3 (3%), sepsis 1 (1%), dyspnea 1 (1%), and respiratory failure 2 (2%) participants. Common drug-related TEAEs (≥10%) included dysgeusia (15%), nausea (11%), fatigue (11%), and decreased neutrophil count (10%). Grade 3-4 drug-related TEAEs occurred in 31 (26%) participants. No drug-related TEAEs led to death. Conclusion: MK-1026 has promising antitumor activity with a manageable safety profile in participants with CLL/SLL exposed to multiple lines of therapy, including in those who had progression of disease on prior covalent BTKi. Further evaluation of MK-1026 in B-cell malignancies is ongoing. Disclosures Woyach: AbbVie Inc, ArQule Inc, Janssen Biotech Inc, AstraZeneca, Beigene: Other: Advisory Committee; AbbVie Inc, ArQule Inc, AstraZeneca Pharmaceuticals LP, Janssen Biotech Inc, Pharmacyclics LLC, an AbbVie Company,: Consultancy; AbbVie Inc, Loxo Oncology Inc, a wholly owned subsidiary of Eli Lilly & Company: Research Funding; Gilead Sciences Inc: Other: Data & Safety. Flinn: Verastem: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Genentech: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; IGM Biosciences: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Gilead Sciences: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Juno Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Yingli Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Constellation Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Loxo: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Kite, a Gilead Company: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Novartis: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; AbbVie: Consultancy, Other: All Consultancy and Research Funding payments made to Sarah Cannon Research Institute, Research Funding; AstraZeneca: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Great Point Partners: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Iksuda Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; BeiGene: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Forty Seven: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Calithera Biosciences: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Roche: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Unum Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; MorphoSys: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Merck: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; TG Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Janssen: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Teva: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Takeda: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Seagen: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Karyopharm Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Celgene: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Incyte: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Infinity Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Agios: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Curis: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Acerta Pharma: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; ArQule: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Pfizer: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Forma Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Nurix Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Portola Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Rhizen Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Trillium Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Triphase Research & Development Corp.: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Century Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Hutchison MediPharma: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Vincerx Pharma: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Sarah Cannon Research Institute: Current Employment; Servier Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Yingli Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Seagen: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Servier Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Unum Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute, Research Funding; Johnson & Johnson: Current holder of individual stocks in a privately-held company; Seattle Genetics: Research Funding. Awan: Verastem: Consultancy; Incyte: Consultancy; Dava Oncology: Consultancy; MEI Pharma: Consultancy; Beigene: Consultancy; Celgene: Consultancy; Johnson and Johnson: Consultancy; Karyopharm: Consultancy; Kite pharma: Consultancy; Gilead sciences: Consultancy; Pharmacyclics: Consultancy; Janssen: Consultancy; BMS: Consultancy; Merck: Consultancy; Cardinal Health: Consultancy; ADCT therapeutics: Consultancy; Abbvie: Consultancy; Astrazeneca: Consultancy; Genentech: Consultancy. Eradat: AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Beigene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Speakers Bureau; Juno: Research Funding; Kite: Research Funding; Genentech: Research Funding. Brander: Pfizer: Consultancy, Other: Biosimilars outcomes research panel; Juno Therapeutics/Celgene/Bristol Myers Squibb: Research Funding; ArQule: Research Funding; Ascentage: Research Funding; AstraZeneca: Research Funding; BeiGene: Research Funding; DTRM: Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; MEI Pharma: Research Funding; TG Therapeutics: Consultancy, Research Funding; Novartis: Research Funding; LOXO: Research Funding; Verastem: Consultancy; ArQule/Merck: Consultancy; Genentech: Consultancy, Research Funding; NCCN: Other: panel member; AbbVie: Consultancy, Other: informCLL registry steering committee, Research Funding. Parikh: Pharmacyclics, MorphoSys, Janssen, AstraZeneca, TG Therapeutics, Bristol Myers Squibb, Merck, AbbVie, and Ascentage Pharma: Research Funding; Pharmacyclics, AstraZeneca, Genentech, Gilead, GlaxoSmithKline, Verastem Oncology, and AbbVie: Membership on an entity's Board of Directors or advisory committees. Phillips: BMS: Consultancy, Research Funding; AstraZeneca: Consultancy; Incyte: Consultancy, Other: received travel expenses from Incyte, Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Research Funding; ADCT, BeiGene, Bristol Myers Squibb, Cardinal Health, Incyte, Karyopharm, Morphosys, Pharmacyclics, Seattle Genetics: Consultancy; Bayer: Consultancy, Research Funding. Reddy: Merck & Co., Inc.: Current Employment. Farooqui: Merck & Co., Inc.: Current Employment, Other: Current Stockholder. Byrd: Vincerx Pharmaceuticals: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Novartis, Trillium, Astellas, AstraZeneca, Pharmacyclics, Syndax: Consultancy, Honoraria; Newave: Membership on an entity's Board of Directors or advisory committees. Stephens: CSL Behring: Consultancy; Innate Pharma: Membership on an entity's Board of Directors or advisory committees; Beigene: Membership on an entity's Board of Directors or advisory committees; Epizyme: Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees; Adaptive: Membership on an entity's Board of Directors or advisory committees; Arqule: Research Funding; Mingsight: Research Funding; JUNO: Research Funding; Novartis: Research Funding; Abbvie: Consultancy; AstraZeneca: Consultancy; Celgene: Consultancy; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Abstract Background Allogeneic (off the shelf) chimeric antigen receptor (CAR) T-cell therapy addresses the logistical challenges, availability (including insufficient T-cell yields from low baseline absolute lymphocyte count), and variable product quality of autologous CAR T therapy. ALLO-501A is a genetically modified anti-CD19 AlloCAR T™ cell product that uses TALEN ® gene editing to disrupt the T-cell receptor alpha constant gene (TRAC) and the CD52 gene to reduce the risk of graft-versus-host disease (GvHD) and permit the use of ALLO-647, an anti-CD52 monoclonal antibody (mAb), for selective and transitory host lymphodepletion (LD). Here we present an update on the preliminary safety, efficacy, and correlative data. ALLO-501A uses Cellectis technologies. Methods ALPHA2 (NCT04416984) is a single-arm, open-label, Phase 1/2 trial of ALLO-501A in patients (pts) with relapsed/refractory (R/R) large B-cell lymphoma (LBCL including [R/R] diffuse LBCL [DLBCL], transformed follicular lymphoma [tFL], marginal zone lymphoma [tMZL], primary mediastinal B-cell lymphoma [PMBCL], follicular lymphoma grade 3B [FL3B]) who received ≥2 prior lines of therapy (including an anthracycline and anti-CD20 mAb), have an ECOG performance status of 0 or 1. Subjects with donor specific antibodies are excluded. Following LD with ALLO-647, fludarabine 30 mg/m 2/d x 3d (F), and cyclophosphamide 300 or 500 mg/m 2/d x 3d (C), either a single (40 [DL1] or 120 [DL2] x 10 6 viable CAR T cells) or consolidation dose of ALLO-501A (DL2) are given. For consolidation dose, pts with ≥stable disease (SD) at day 28 receive consolidation with second ALLO-647 (no chemo) for LD and ALLO-501A (DL2) cell infusion. Results As of July 9, 2021, 20 pts were enrolled; 15 pts were treated with ALLO-501A (12 evaluable and 3 pending D28 assessment); 3 pts pending treatment; 2 pts withdrew due to adverse event (AE)/progressing disease (PD) prior to dosing. Patients were heavily pretreated with advanced-stage disease (Stage III: 4 [22.2%], Stage IV: 8 [44.4%]), median number of prior treatments was 3 with a high of 7. Three pts (16.7%) had primary refractory disease. Safety profile was manageable in both single dose and consolidation cohorts. Events of interest in the single dose cohort have been previously reported (ASCO 2021). In the consolidation cohort (13 enrolled, 9 pts dosed thus far), no cytokine release syndrome (CRS), no GvHD, no immune effector cell-associated neurotoxicity syndrome (ICANS), no dose-limiting toxicities (DLTs), no dose reductions, no Grade (Gr) 3+ infections and no related serious adverse events (SAEs) occurred, and infusion-related reactions were Gr 1. Among all treated, cytopenias were the most common AE and occurred in 72% of pts. Of the 12 evaluable pts (6 each treated in the single dose and consolidation dose cohort), both the overall response rate (ORR) and complete response (CR) were 50% (95% CI: 21.1, 78.9). In the consolidation cohort, both ORR and CR rate were 66.7% (95% CI: 22.3, 95.7) with 3/3 partial responses (PRs) converting to CR after consolidation; 1 pt had CR at days 28 and 56 post consolidation and 2 pts had PD at month 1 and did not receive consolidation. In single dose cohort, 2 pts have ongoing CR at 9 and 12+ months. CAR T expansion was greater in pts who achieved a CR with a geometric mean area under the curve (AUC) at D1-28 of 206,990 copies/ug*days (n=6; GSD 4.94) compared to pts who did not achieve a CR with AUC at D1-28 of 3,571 copies/ug*days (n=3; GSD 2.41). Pts who received the consolidation dose continued to have CAR T expansion after the 2 nd CAR T infusion with geometric mean AUC from D30-56 of 92,893 copies/ug*days (n=4; GSD 5.42). Conclusions ALLO-501A with consolidation dosing demonstrated comparable safety and an improved efficacy profile compared to single dosing with all 4 pts who received consolidation remaining in CR. Persistence of CAR T at D28 and expansion after consolidation dose was observed in addition to the observed deepening of responses in pts whose initial response was PR. Additional follow up is needed to determine whether consolidation also improves the durability of response. Consolidation was well tolerated and given the generally favorable overall safety profile, ALLO-501A may have the potential to be given in the outpatient setting. Enrollment is ongoing. Updated efficacy and follow-up will be presented at the meeting. Currently, an ALLO-501A Phase 2 trial is planned. Disclosures Locke: Cowen: Consultancy; Umoja: Consultancy, Other; Wugen: Consultancy, Other; Takeda: Consultancy, Other; Novartis: Consultancy, Other, Research Funding; Janssen: Consultancy, Other: Scientific Advisory Role; Bluebird Bio: Consultancy, Other: Scientific Advisory Role; BMS/Celgene: Consultancy, Other: Scientific Advisory Role; Calibr: Consultancy, Other: Scientific Advisory Role; Amgen: Consultancy, Other: Scientific Advisory Role; GammaDelta Therapeutics: Consultancy, Other: Scientific Advisory Role; Cellular Biomedicine Group: Consultancy, Other: Scientific Advisory Role; Kite, a Gilead Company: Consultancy, Other: Scientific Advisory Role, Research Funding; Legend Biotech: Consultancy, Other; Iovance Biotherapeutics: Consultancy, Other: Scientific Advisory Role; EcoR1: Consultancy; Allogene Therapeutics: Consultancy, Other: Scientific Advisory Role, Research Funding; Emerging Therapy Solutions: Consultancy; Gerson Lehrman Group: Consultancy; Moffitt Cancer Center: Patents & Royalties: field of cellular immunotherapy. Neelapu: Kite, a Gilead Company, Merck, Bristol Myers Squibb, Novartis, Celgene, Pfizer, Allogene Therapeutics, Cell Medica/Kuur, Incyte, Precision Biosciences, Legend Biotech, Adicet Bio, Calibr, Unum Therapeutics and Bluebird Bio: Honoraria; Kite, a Gilead Company, Merck, Bristol Myers Squibb, Novartis, Celgene, Pfizer, Allogene, Kuur, Incyte, Precision BioSciences, Legend, Adicet Bio, Calibr, and Unum Therapeutics: Other: personal fees; Kite, a Gilead Company, Bristol Myers Squibb, Merck, Poseida, Cellectis, Celgene, Karus Therapeutics, Unum Therapeutics (Cogent Biosciences), Allogene, Precision BioSciences, Acerta and Adicet Bio: Research Funding; Takeda Pharmaceuticals and related to cell therapy: Patents & Royalties. Hamadani: Janssen, Incyte, ADC Therapeutics, Omeros, Morphosys, Kite: Consultancy; Sanofi, Genzyme, AstraZeneca, BeiGene: Speakers Bureau; Takeda, Spectrum Pharmaceuticals and Astellas Pharma: Research Funding. Frank: Allogene Therapeutics: Research Funding; Kite-Gilead: Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Research Funding. Popplewell: Novartis: Other: Travel; Pfizer: Other: Travel; Hoffman La Roche: Other: Food. Abramson: Bluebird Bio: Consultancy; Kymera: Consultancy; BeiGene: Consultancy; Incyte Corporation: Consultancy; Astra-Zeneca: Consultancy; Allogene Therapeutics: Consultancy; Seagen Inc.: Research Funding; AbbVie: Consultancy; Karyopharm: Consultancy; Novartis: Consultancy; Morphosys: Consultancy; Kite Pharma: Consultancy; C4 Therapeutics: Consultancy; Genmab: Consultancy; EMD Serono: Consultancy; Bristol-Myers Squibb Company: Consultancy, Research Funding; Genentech: Consultancy. Munoz: Pharmacyclics/Abbvie: Consultancy, Research Funding, Speakers Bureau; Bayer: Consultancy, Research Funding, Speakers Bureau; Gilead/Kite Pharma: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy; Janssen: Consultancy, Research Funding, Speakers Bureau; Juno/Celgene: Consultancy, Research Funding, Speakers Bureau; BMS: Consultancy, Speakers Bureau; Kyowa: Consultancy, Honoraria, Speakers Bureau; Alexion: Consultancy; Beigene: Consultancy, Speakers Bureau; Fosunkite: Consultancy; Innovent: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding, Speakers Bureau; Debiopharm: Consultancy; Karyopharm: Consultancy; Genmab: Consultancy; ADC Therapeutics: Consultancy; Epizyme: Consultancy; Servier: Consultancy; Merck: Research Funding; Portola: Research Funding; Incyte: Research Funding; Genentech: Research Funding, Speakers Bureau; Millennium: Research Funding; Targeted Oncology: Honoraria; OncView: Honoraria; Physicians' Education Resource: Honoraria; Roche: Speakers Bureau; AstraZeneca: Speakers Bureau; Verastem: Speakers Bureau; Acrotech/Aurobindo: Speakers Bureau. Shin: Allogene Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company. Loomis-Navale: Allogene: Current Employment, Current equity holder in publicly-traded company. Miklos: Pharmacyclics, Amgen, Kite, a Gilead Company, Novartis, Roche, Genentech, Becton Dickinson, Isoplexis, Miltenyi, Juno-Celgene-Bristol Myers Squibb, Allogene, Precision Biosciences, Adicet, Adaptive Biotechnologies: Research Funding; Kite, a Gilead Company, Amgen, Atara, Wugen, Celgene, Novartis, Juno-Celgene-Bristol Myers Squibb, Allogene, Precision Bioscience, Adicet, Pharmacyclics, Janssen, Takeda, Adaptive Biotechnologies and Miltenyi Biotechnologies: Consultancy; Adaptive Biotechnologies, Novartis, Juno/Celgene-BMS, Kite, a Gilead Company, Pharmacyclics-AbbVie, Janssen, Pharmacyclics, AlloGene, Precision Bioscience, Miltenyi Biotech, Adicet, Takeda: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Patents & Royalties. OffLabel Disclosure: Discussion of fludarabine and cyclophosphamide in combination with ALLO-647 as conditioning regimen prior to administration of ALLO-501A in patients with R/R LBCL.