Interim Results of an Open-Label Phase IB/II Multi-Arm Study of OX40 Agonist Monoclonal Antibody (mAb), Anti-PDL1 Mab, Smoothened Inhibitor, Anti-CD33 Mab, Bcl-2 Inhibitor, and Azacitidine As Single-Agents and As Combinations for Relapsed/Refractory Acute Myeloid Leukemia
Authors: Short Nicholas J. , Kadia Tapan M. , DiNardo Courtney D. , Pemmaraju Naveen , Borthakur Gautam , Garcia-Manero Guillermo , Jabbour Elias , Sasaki Koji , Issa Ghayas C. , Montalban-Bravo Guillermo , Bose Prithviraj , Burger Jan A. , Miller Darla , Alexander-Williams Lynette , Ravandi Farhad , Konopleva Marina , Kantarjian Hagop M. , Daver Naval 
Published: November 2020

Background: Several novel agents, including venetoclax (VEN), gemtuzumab ozogamicin (GO), and glasdegib have shown promise in newly diagnosed AML. However, their role in relapsed/refractory (R/R) AML and their optimal combination with other agents has not been established. We therefore designed a multi-arm, parallel cohort, phase Ib/II study to evaluate various novel combinations of these agents in pts with R/R AML.
Methods: Adults ≥18 years of age with R/R AML or with AML from antecedent hematologic malignancy previously treated with hypomethylating agents (HMAs) who had performance status of ≤2 and adequate organ function were eligible. Pts were assigned at the treating physician's discretion to one of 5 concomitantly enrolling arms: A.) azacitidine (AZA) + VEN + GO, B.) AZA + VEN + avelumab (anti-PDL1 mAb), C.) AZA + avelumab + GO, D.) OX40 agonist mAb (PF-04518600), or E.) glasdegib + GO. Treatment regimens are shown in Table 1. In arms containing VEN, a bone marrow (BM) assessment was performed on cycle 1 day 21, and VEN was held if BM blasts were &lt;5% or aplastic BM. All arms had an initial 6 pt safety lead-in for assessment of DLTs, followed by a phase II expansion.
Results: As of 7/2020, 43 pts have been treated across the 5 arms.
The baseline characteristics of pts enrolled in the three triplet combination arms (Arm A, n=19; Arm C, n=9; Arm D, n=6) are shown in Table 2. More than half of the pts in each group had adverse risk cytogenetics. TP53 was the most commonly mutated gene, detected in 32%, 56%, and 33% of the pts in Arms A, B and C, respectively.
Nineteen pts received AZA + VEN + GO (Arm A); 18 were evaluable for response (1 pt too early). No DLTs were observed in the initial 6 pt safety lead-in. The 30-day and 60-day mortality rates were 11% and 21% in this R/R AML population. Overall, 4 pts achieved CR, 2 CRi, and 4 MLFS (CR rate: 22%; CR/CRi rate: 33%; CR/CRi/MLFS rate: 56%). Three pts proceeded to hematopoietic stem cell transplant. Eight pts (42%) had received prior VEN. The CR/CRi and CR/CRi/MLFS rates for pts without prior VEN exposure were 4/10 (40%) and 8/10 (80%), respectively. In contrast, the CR/CRi and CR/CRi/MLFS rates were both 2/8 (25%) for pts with prior VEN exposure. Five pts remain on study (3 with ongoing response). The median duration of response was 5.2 months (range, 3.1-6.3+ months), and the median overall survival (OS) was 7.3 months (median OS in VEN naïve: 7.3 months; median OS in prior VEN exposed: 3.2 months).
Nine pts received AZA + VEN + avelumab (Arm B); 8 were evaluable for response (1 pt too early). One pt developed a DLT of transient grade 3 possibly immune-related transaminase elevation; no other DLTs were observed. The 30-day and 60-day mortality rates were 0%. Two pts achieved CRi (25%), both of whom had prior VEN exposure. The median OS was 4.8 months.
Six pts received AZA + avelumab + GO (Arm C); 5 were evaluable for response (1 pt too early). No DLTs were observed, although one pt developed possibly immune-related grade 3 diarrhea in cycle 3 that resolved with holding avelumab. All enrolled pts had prior VEN exposure. The 30-day and 60-day mortality rates were 0%. One pt responded (20%). This pt had diploid NPM1-mutated AML with 4 prior therapies (including prior HMA + VEN) with only extramedullary disease (PET+ muscle involvement) at enrollment, and remains on study with ongoing PET-negative CR of 6+ months.
Four pts were treated with PF-04518600 monotherapy (Arm D). PF-04518600 was overall safe with no DLTs or immune-related AEs. However, none of the 4 pts responded. Five pts were treated with glasdegib + GO (Arm E). One pt developed grade 3 mucositis possibly related to GO and considered a DLT. No pts had a formal response, although one pt had a BM blast reduction from 20% to 9% after 1 cycle.
Conclusion: All 3 novel triplet combination regimens were safe and demonstrated preliminary efficacy even in pts with prior VEN exposure. Outcomes of AZA + VEN + GO in pts who had not received prior VEN were particularly promising with a CR/CRi/MLFS rate of 80%, which compares favorably to response rates of 50-55% with HMA + VEN in similar R/R pts, although numbers are still small. Future accrual will focus on these 3 triplet combination regimens. Evaluating the safety and early efficacy of multiple novel combinations in a single multi-arm study with clear "go" or "no go" signals is a feasible, more rapid and cost-efficient approach to be considered as multiple promising novel agents enter the AML space.

Disclosures
Short: AstraZeneca: Consultancy; Takeda Oncology: Consultancy, Honoraria, Research Funding; Astellas: Research Funding; Amgen: Honoraria. Kadia:Astra Zeneca: Research Funding; Astellas: Research Funding; Incyte: Research Funding; Celgene: Research Funding; Amgen: Research Funding; JAZZ: Honoraria, Research Funding; Genentech: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Pulmotec: Research Funding; Cellenkos: Research Funding; Abbvie: Honoraria, Research Funding; Novartis: Honoraria; Pfizer: Honoraria, Research Funding; Cyclacel: Research Funding; Ascentage: Research Funding. DiNardo:Agios: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; ImmuneOnc: Honoraria; MedImmune: Honoraria; Novartis: Consultancy; Takeda: Honoraria; Jazz: Honoraria; Syros: Honoraria; Calithera: Research Funding; Notable Labs: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding. Pemmaraju:Pacylex Pharmaceuticals: Consultancy; SagerStrong Foundation: Other: Grant Support; Stemline Therapeutics: Honoraria, Research Funding; Cellectis: Research Funding; Samus Therapeutics: Research Funding; Daiichi Sankyo: Research Funding; DAVA Oncology: Honoraria; Blueprint Medicines: Honoraria; Celgene: Honoraria; LFB Biotechnologies: Honoraria; AbbVie: Honoraria, Research Funding; Roche Diagnostics: Honoraria; Plexxikon: Research Funding; Incyte Corporation: Honoraria; Affymetrix: Other: Grant Support, Research Funding; Novartis: Honoraria, Research Funding; MustangBio: Honoraria. Borthakur:BioLine Rx: Consultancy; BioTherix: Consultancy; Nkarta Therapeutics: Consultancy; Treadwell Therapeutics: Consultancy; PTC Therapeutics: Consultancy; Argenx: Consultancy; FTC Therapeutics: Consultancy; Curio Science LLC: Consultancy; Oncoceutics: Research Funding; Xbiotech USA: Research Funding; Polaris: Research Funding; AstraZeneca: Research Funding; BMS: Research Funding; BioLine Rx: Research Funding; Cyclacel: Research Funding; GSK: Research Funding; Jannsen: Research Funding; Abbvie: Research Funding; Novartis: Research Funding; Incyte: Research Funding; PTC Therapeutics: Research Funding. Garcia-Manero:Astex Pharmaceuticals: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; H3 Biomedicine: Research Funding; Helsinn Therapeutics: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz Pharmaceuticals: Consultancy; Merck: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Amphivena Therapeutics: Research Funding; Acceleron Pharmaceuticals: Consultancy, Honoraria; Onconova: Research Funding; Novartis: Research Funding; AbbVie: Honoraria, Research Funding. Jabbour:Genentech: Other: Advisory role, Research Funding; Takeda: Other: Advisory role, Research Funding; AbbVie: Other: Advisory role, Research Funding; Adaptive Biotechnologies: Other: Advisory role, Research Funding; Pfizer: Other: Advisory role, Research Funding; BMS: Other: Advisory role, Research Funding; Amgen: Other: Advisory role, Research Funding. Sasaki:Novartis: Consultancy, Research Funding; Pfizer Japan: Consultancy; Otsuka: Honoraria; Daiichi Sankyo: Consultancy. Issa:Novartis: Membership on an entity's Board of Directors or advisory committees; Syndax: Research Funding; Celegene: Research Funding. Bose:NS Pharma: Research Funding; Blueprint Medicines Corporation: Honoraria, Research Funding; Pfizer, Inc.: Research Funding; Kartos Therapeutics: Honoraria, Research Funding; CTI BioPharma: Honoraria, Research Funding; Astellas Pharmaceuticals: Research Funding; Incyte Corporation: Consultancy, Honoraria, Research Funding, Speakers Bureau; Promedior, Inc.: Research Funding; Celgene Corporation: Honoraria, Research Funding; Constellation Pharmaceuticals: Research Funding. Burger:AstraZeneca: Consultancy; Janssen Pharmaceuticals: Consultancy, Speakers Bureau; Gilead Sciences: Consultancy, Research Funding; Beigene: Research Funding, Speakers Bureau; Pharmacyclics, an AbbVie company: Consultancy, Research Funding, Speakers Bureau; TG Therapeutics: Research Funding, Speakers Bureau. Ravandi:Macrogenics: Research Funding; AstraZeneca: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Orsenix: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Xencor: Consultancy, Honoraria, Research Funding. Konopleva:Agios: Research Funding; Forty-Seven: Consultancy, Research Funding; AstraZeneca: Research Funding; Kisoji: Consultancy; F. Hoffmann La-Roche: Consultancy, Research Funding; Eli Lilly: Research Funding; Rafael Pharmaceutical: Research Funding; Cellectis: Research Funding; Ablynx: Research Funding; Calithera: Research Funding; Reata Pharmaceutical Inc.;: Patents & Royalties: patents and royalties with patent US 7,795,305 B2 on CDDO-compounds and combination therapies, licensed to Reata Pharmaceutical; Stemline Therapeutics: Consultancy, Research Funding; Amgen: Consultancy; Genentech: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Sanofi: Research Funding; Ascentage: Research Funding. Kantarjian:Sanofi: Research Funding; Pfizer: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Jazz: Research Funding; Immunogen: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive biotechnologies: Honoraria; Aptitute Health: Honoraria; BioAscend: Honoraria; Delta Fly: Honoraria; Janssen: Honoraria; Oxford Biomedical: Honoraria; Daiichi-Sankyo: Honoraria, Research Funding; BMS: Research Funding; Abbvie: Honoraria, Research Funding; Ascentage: Research Funding; Amgen: Honoraria, Research Funding. Daver:Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Research Funding; Servier: Research Funding; Genentech: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novimmune: Research Funding; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Trovagene: Research Funding; Fate Therapeutics: Research Funding; ImmunoGen: Research Funding; Novartis: 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; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Trillium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Syndax: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; KITE: 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.

OffLabel Disclosure:
Azacitidine, gemtuzumab ozogamicin, glasdegib, avelumab, venetoclax and PF-04518600 in various combinations for relapsed/refractory AML