MDX-1203

CD70 is a tumor necrosis factor (TNF)‐like type II integral membrane protein that is transiently expressed on activated T‐ and B‐lymphocytes. Aberrant expression of CD70 was identified in both solid tumors and haematologic malignancies. BMS‐936561 (αCD70_MED‐A) is an antibody‐drug conjugate composed of a fully human anti‐CD70 monoclonal antibody (αCD70) conjugated with a duocarmycin derivative, MED‐A, through a maleimide‐containing citrulline‐valine dipeptide linker. MED‐A is a carbamate prodrug that is activated by carboxylesterase to its active form, MED‐B, to exert its DNA alkylation activity. In vitro serum stability studies suggested the efficiencies of hydrolyzing the carbamate‐protecting group in αCD70_MED‐A followed a rank order of mouse > rat > > monkey > dog ~ human. Pharmacokinetics of αCD70_MED‐A was evaluated in mice, monkeys, and dogs after single intravenous doses. In mice, αCD70_MED‐A was cleared rapidly, with no detectable exposures after 15 min following dosing. In contrast, αCD70_MED‐A was much more stable in monkeys and dogs. The clearance of αCD70_MED‐A in monkeys was 58 mL/d/kg, ~2‐fold faster than that in dogs (31 mL/d/kg). The human PK profiles of the total αCD70 and αCD70_MED‐A were predicted using allometrically scaled monkeys PK parameters of αCD70 and the carbamate hydrolysis rate constant estimated in dogs. Comparing the predicted and observed human PK from the phase I study, the dose‐normalized concentration‐time profiles of αCD70_MED‐A and the total αCD70 were largely within the 5th‐95th percentile of the predicted profiles. Copyright © 2015 John Wiley & Sons, Ltd.

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

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.

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.

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.