At the 60th Annual Meeting of the American Hematology Society, there was an oral abstract session which focused on the novel immunotherapeutic agents in acute myeloid leukemia (AML). At this session, Jorge Cortes (member our North American Steering Committee) from the MD Anderson Cancer Center, Houston, US, presented data from an ongoing phase I dose-escalation study (NCT02674763), evaluating the safety and anti-leukemic activity of IMGN779,in patients with CD33+ relapsed/refractory (R/R) AML.
IMGN779 is a next-generation anti-CD33 antibody drug-conjugate (ADC) with a novel DNA-alkylating IGN (indolinobenzodiazepine pseudodimer) payload and a cleavable s-SPDB linker. In preclinical studies, IMGN779 has demonstrated potent anti-tumor activity in AML cell lines.
In this phase I study, 57 patients (median age = 68 years; range: 26–88) with CD33+ R/R AML received IMGN779 intravenously once every 2 weeks (Q2W; on days 1 and 15 of a 28-day cycle; n = 36) or once weekly (QW; days 1, 8, 15, and 22 of a 28-day cycle; n = 21). Dosing using the Q2W schedule began at 0.02 mg/kg and was escalated to 1.5 mg/kg (cohort 11). QW dosing was initiated at 0.39 mg/kg based on the safety data of Q2W and escalation has proceeded to 1.2 mg/kg. Patients received a median of four doses of IMGN779 (range: 1–40).
The primary objectives of this study were to establish the maximum tolerated dose and recommended phase II dose (RP2D) of IMGN779 administered as monotherapy using QW and Q2W. The secondary objectives of the study were to evaluate the safety, tolerability and preliminary efficacy of IMGN779.
Pharmacokinetics and pharmacodynamics
- Plasma IMGN779 concentrations indicate consistent and sustained exposure through seven days at doses ≥39 mg/kg
- The QW schedule provided a more consistent pharmacodynamic CD33 saturation compared to the Q2W schedule
- The most common treatment-emergent adverse events (AEs) occurring in > 15% of patients were febrile neutropenia, epistaxis, nausea, diarrhea, fatigue, abdominal pain, and hypokalemia
- The most frequent infection related serious AEs (SAEs) were febrile neutropenia (37%), bacteremia (14%), and pneumonia (14%)
- Three treatment-related SAEs were observed including grade 3 infusion-related reaction (n = 2), and febrile neutropenia (n = 1)
- One dose-limiting toxicity of veno-occlusive disease (VOD) with acute kidney injury (fatal) occurred in the 1.2 mg/kg QW
- Ten deaths occurred within 30 days after the last dose due to pneumonia/respiratory (n = 6), sepsis/multi-organ (n = 2), VOD (n = 1) and myocardial infarction (n = 1)
- Forty-one percent (12/29) of evaluable patients who received IMGN779 had a > 30% reduction in bone marrow blasts
- Eight patients had < 8% residual blasts
- Two patients had a complete response with incomplete count recovery (CRi)
In summary, IMGN779 demonstrates a manageable tolerability and anti-leukemic activity in patients with R/R AML. Jorge Cortes concluded by noting that “enrollment continues to identify the RP2D and schedule, which may warrant the further development as combination therapy in AML.”