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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.

Background: Intravenous infusion of ixabepilone is Food and Drug Administration-approved for treatment of patients with metastatic breast cancer. The aim of this study was to establish the maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), safety, and pharmacokinetics (PK) of a novel oral formulation of ixabepilone in patients with advanced solid tumors., Patients and Methods: Forty-four patients received one of six daily doses of oral ixabepilone (5, 10, 15, 20, 25, or 30 mg) on days 1-5 of a 21-day cycle. PK parameters were evaluated in cycle 1 for all treated patients and in cycle 1 and cycle 2 for patients participating in assessments of food and gastric pH effects., Results: The most common DLTs (reported in at least one patient) were neutropenia, neutropenic fever, diarrhea, ileus, and hypokalemia. The MTD of oral ixabepilone was 25 mg. Plasma concentrations of ixabepilone showed high variability; coefficients of variation for the area under the curve and the peak plasma concentration ranged from 61 to 131 % and from 17 to 172 %, respectively. The mean half-life of ixabepilone calculated after day 5 of cycle 1 ranged from 24 to 47 h. Ixabepilone exposure was higher when administered with a low-fat meal compared with the fasted state, and when administered 2 h after the histamine H2 receptor antagonist famotidine., Conclusions: The MTD of oral ixabepilone when administered once daily for five consecutive days every 21 days was 25 mg. Ixabepilone exposure was highly variable; therefore, safety and efficacy of this novel oral formulation might not be reliably predicted.