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

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 <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.