First-in-human multicenter phase I study of BMS-936561 (MDX-1203), an antibody-drug conjugate targeting CD70

Purpose: The study evaluated the safety, tolerability, and pharmacokinetics of BMS-936561, a fully human monoclonal antibody-drug conjugate targeting CD70 cell-surface protein.

Methods: Eligible patients had ECOG performance status 0-2 and received ≤3 prior chemotherapy regimens. An initial accelerated titration design enrolling one patient per dose level was followed by 3 + 3 dose escalation with the first observation of a grade ≥2 adverse event (AE). We tested escalating doses of BMS-936561 (0.5, 1, 2, 4, 8, 15 mg/kg) administered every 21 days in a 42 day cycle for a maximum of 17 cycles. Pharmacokinetic samples were collected in cycle 1.

Results: A total of 26 patients enrolled; 16 and 10 for the escalation and expansion cohorts, respectively. Median age was 63 years (48-74); 18 males and 25 Caucasians. There was no defined MTD per protocol, but a DLT of grade 3 hypersensitivity was recorded in 2 of 16 (13%) subjects at the highest dose of 15 mg/kg. The most frequent AEs were: fatigue (85%), nausea (54%), and decreased appetite (39%). Delayed toxicities (facial edema and pleural/pericardial effusions) occurred in 6 of 16 (38%) subjects at the 15 mg/kg dose. PK analysis showed a dose-proportional increase in active drug levels with increasing doses. There was disease stabilization in 18 of 26 patients (69%) without correlation with received dose.

Conclusions: BMS-936561 is well tolerated over a wide range of doses in patients with advanced ccRCC and B-NHL. The 8 mg/kg dose was the highest best tolerated dose and the recommended dose for future studies.

Antibody-drug conjugate; BMS-936561; CD70; Pharmacokinetic; Phase.