Updated Results from a Phase 1 Study of APVO436, a Novel Bispecific Anti-CD123 x Anti-CD3 Adaptir™ Molecule, in Relapsed/Refractory Acute Myeloid Leukemia and Myelodysplastic Syndrome

Introduction Acute myeloid leukemia (AML) is a clonal disease characterized by the rapid proliferation of immature myeloid cells in the bone marrow with impaired differentiation. Despite major progress in AML therapy and high rates of complete remission (CR) after intensive chemotherapy, many patients will eventually relapse and die from the disease. Immunotherapy offers the promise of a new paradigm for patients with relapsed/refractory (R/R) acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). APVO436, a novel bispecific anti-CD123 x anti-CD3 ADAPTIR™ molecule, has shown pre-clinical proof of concept and is being further evaluated in the clinic. Results from the APVO436-5001 dose-escalation phase were previously reported (Watts et al, ASH 2021). Herein, we report preliminary data from the dose-expansion phase of the study of APVO436 at the RP2D in patients with primary and secondary AML. Methods APVO436-5001 (NCT03647800) is an ongoing 2-part, phase 1b dose-escalation and -expansion study. The expansion phase is evaluating the safety and tolerability of APVO436 at the RP2D level when it is used as an adjunct to the standard of care to obtain a preliminary assessment of the anti-leukemia activity of APVO436-containing experimental monotherapy (Cohorts 3 and 5) and combination therapy modalities (Cohort 1 with MEC chemotherapy, Cohort 2 with venetoclax and azacitidine, and Cohort 4 with oral azacitidine). The expansion phase will enroll a total of 90 patients with AML at different disease stages into 5 different cohorts of 18 patients each. Specifically, Cohort 1 patients had fit primary or secondary AML in 1st or 2nd relapse with last complete response (CR) <1 year or primary refractory disease; Cohort 2 patients had fit primary or secondary AML who were either treatment-naïve with adverse risk genetics by ELN criteria, in 1st relapse, or had primary refractory disease; Cohort 3 patients had fit primary or secondary AML with intermediate or adverse risk AML, who were in 1st relapse with a duration of CR<1 year, or had primary refractory disease; Cohort 4 patients had MRD-positive high-risk 1st remission AML; and, Cohort 5 patients had MRD-positive AML and were in 2nd remission post-induction with a standard of care regimen. In Cohorts 1-4, APVO436 was administered at a fixed dosage of 18 mcg after weekly ramp up during Cycle 1 (Cohorts, 1, 3, 4) or Cycle 1-2 (Cohort 2). In Cohort 5, APVO436 was administered at a fixed dose of 18 mcg twice weekly after a weekly ramp up during Cycle 1. The primary safety endpoints included Grade 3-4 AEs, SAEs and AESIs. Secondary efficacy endpoints included the incidence of composite response rate [defined as CR + CR with incomplete hematologic recovery (CRi) + morphologic leukemia-free state (MLFS)] and incidence of patients who were able to achieve MRD-negative CR and undergo hematopoietic stem cell transplantation (HSCT) after protocol treatment. Results Through July 11, 2022, 30 primary/secondary AML patients with a median age of 60 years and 10% with an ECOG performance status of 2 were treated across 4 Cohorts: Cohort 1, n=14; Cohort 2 n=7; Cohort 3 n=7; Cohort 4, n=0; Cohort 5, n=2. Treatment-emergent AEs ≥ Grade 3 were reported in 53% of patients across Cohorts; the most common (reported in ≥10%) were anemia (20%), neutropenia (17%), thrombocytopenia (17%) and sepsis (17%). Treatment-emergent SAEs were reported in 20% of patients across Cohorts; events occurred in no more than 1 patient each. Treatment-emergent infusion-related reactions (IRRs) and cytokine release syndrome (CRS) were reported for 7% and 23% of patients, respectively, across all Cohorts with no IRRs and only 1 CRS at Grade ≥ 3. There was 1 death in Cohort 2; this was unrelated to the study drug or procedures. The composite response rate based on Investigator assessment which includes CR, CRi and MLFS for the efficacy evaluable population, defined as patients who received APVO436 and had a post-baseline response assessment, was 4/12 (33%), 2/5 (40%) and 1/5 (20%) for Cohorts 1, 2, and 3, respectively. Two patients, 1 in CR and 1 with substantial blast reduction, received an allogeneic transplant in Cohorts 1 and 3, respectively. Conclusions Preliminary results from the dose-expansion phase indicate that APVO436 is well tolerated and safe as single agent and in combination across cohorts with different underlying leukemic conditions. Furthermore, anti-leukemic activity has been observed.