IMGN632 is a CD123-targeting antibody-drug conjugate comprising a novel humanized anti-CD123 antibody coupled, via a peptide linker, to a unique DNA-alkylating payload of the recently developed IGN (indolinobenzodiazepine pseudodimer) class of cytotoxic compounds. In preclinical studies, IMGN632 displayed antileukemic activity in acute myeloid leukemia (AML) models.
At the 60th American Society of Hematology Annual Meeting & Exposition, Naval Daver from the MD Anderson Cancer Center, Houston, US, presented data from an ongoing first-in-human phase I dose-escalation study (NCT03386513), evaluating the safety and anti-leukemic activity of IMGN632, in patients with relapsed/refractory (R/R) AML or other CD123+ hematologic malignancies. The primary objectives of this ongoing phase I study were to determine the maximum tolerated dose and the recommended Phase 2 dose of IMGN632 when administered as a single agent. The secondary objectives included dose-limiting toxicity (DLT), safety, pharmacokinetics, pharmacodynamics, and preliminary antileukemic activity of IMGN632.
In this phase I study, 33 patients (median age = 70 years; range: 40–80) with CD123+ R/R AML (n = 30) or blastic plasmacytoid dendritic cell neoplasm (BPDCN; n = 3) with no more than three lines of prior therapy were enrolled. IMGN632 was administered intravenously every three weeks (Q3W) using a standard 3+3 design. The starting dose of IMGN632 was 0.015 mg/kg, with escalation following a modified Fibonacci schema. Doses between 0.015–0.45 mg/kg were explored with four doses expanded for further efficacy and safety assessment. Patients received a median of two Q3W IMGN632 doses (range, 1–6).
Pharmacokinetics and pharmacodynamics
- Pharmacokinetic exposures and pharmacodynamic CD123 saturation increase with dose
- The most common treatment-emergent adverse events (AEs) occurring in > 10% of patients were febrile neutropenia, nausea, diarrhea, fatigue, lung infection, and decreased appetite
- Three treatment-related serious AEs (SAEs) of febrile neutropenia occurred
- One DLT of prolonged neutropenia occurred in the 0.3 mg/kg after two doses
- Two DLTs of veno-occlusive disease occurred in the 0.45 mg/kg and 0.18 mg/kg doses, respectively
- Three deaths occurred within 30 days after the last dose of IMGN632 due to disease progression (n = 2) and unknown cause (n = 1)
Efficacy in R/R AML patients
- Twenty-six percent (6/23) of evaluable patients with AML who received IMGN632 achieved complete response (CR)/CR with incomplete count recovery (CRi)
- CR/CRi were seen across a wide range of doses, 0.015–0.3 mg/kg
- Two patients had a complete response with incomplete count recovery (CRi)
In summary, IMGN632 demonstrates an initial safety and anti-leukemic activity in patients with R/R AML. Enrollment into the expansion cohorts and the use of fractionated doses is ongoing.