A Phase 1b/2 Study of IMGN632, a CD123-Targeting Antibody-Drug Conjugate (ADC), As Monotherapy or in Combination with Venetoclax and/or Azacitidine for Patients with CD123-Positive Acute Myeloid Leukemia

BACKGROUND: IMGN632 is a CD123-targeting ADC, comprised of a high affinity anti-CD123 antibody coupled to a DNA-alkylating payload of the novel IGN (indolinobenzodiazepine pseudodimer) class. An ongoing Phase I trial in patients with CD123-positive AML or BPDCN (NCT03386513) has reported encouraging efficacy and manageable tolerability with IMGN632 monotherapy. Preclinical data from AML mouse models demonstrate synergy in combinations with azacitidine and/or venetoclax1,2, supporting the clinical exploration of these combinations.

Here we describe the ongoing Phase 1b/2 study actively enrolling patients to determine the safety, tolerability, and preliminary anti-leukemia activity of IMGN632 when administered in combination with azacitidine and/or venetoclax to patients with relapsed and frontline CD123-positive AML, and the single-agent activity of IMGN632 in patients with minimal residual disease (MRD)-positive AML after frontline treatment.

METHODS AND STUDY DESIGN: Adult patients with CD123-positive relapsed or refractory (R/R) AML, who are deemed appropriate for experimental therapy, are eligible to enroll as part of the dose escalation phase. Key exclusion criteria for all regimens include active central nervous system disease, and history of sinusoidal obstruction syndrome/venous occlusive disease of the liver.

Three different combination regimens are being evaluated: Regimen A, IMGN632 plus azacitidine (632+AZA); Regimen B, IMGN632 plus venetoclax (632+VEN); and Regimen C, IMGN632 plus azacitidine and venetoclax (632+AZA+VEN). For each regimen, a Phase 1b dose escalation cohort in R/R patients will determine the recommended Phase 2 dose (RP2D) of IMGN632 for the specific combination. Escalation will follow a standard 3+3 design, with a starting dose for IMGN632 of 0.015 mg/kg administered intravenously on Day 7 of a 21- (632+VEN) or 28-day cycle (632+AZA, 632+AZA+VEN). Regimens A and B (the doublets) were initially explored to evaluate safety at increasing doses of IMGN632. Escalation of IMGN632 on Regimen C (the triplet) was allowed once the corresponding dose of IMGN632 was evaluated in each doublet combination (Figure). This will be followed by a Phase 2 dose expansion stage to further characterize the safety profile and assess antileukemia activity in frontline or relapsed AML patients, depending on the combination regimen. In addition, IMGN632 monotherapy is being explored in expansion cohorts of MRD-positive patients to assess conversion rate from MRD-positivity to MRD-negativity, in fit and unfit AML subpopulations. NCT04086264