ASH 2018 | IMGN632, a CD123-targeting antibody-drug conjugate, in patients with relapsed/refractory acute myeloid leukemia

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 60^th 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).

Key findings:

Pharmacokinetics and pharmacodynamics

• Pharmacokinetic exposures and pharmacodynamic CD123 saturation increase with dose

Safety

• 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.