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

• Published in: Cancer chemotherapy and pharmacology 2016, Vol.77 (1), p.155-162
• Main Authors: Owonikoko, Taofeek Kunle, Hussain, Arif, Stadler, Walter Michael, Smith, David C., Kluger, Harriet, Molina, Ana M., Gulati, Parul, Shah, Aadhar, Ahlers, Christoph Matthias, Cardarelli, Pina M., Cohen, Lewis J.
• Format: Article
• Language: English
• Subjects: Aged; Antineoplastic Agents, Alkylating - administration & dosage; Antineoplastic Agents, Alkylating - adverse effects; Antineoplastic Agents, Alkylating - pharmacokinetics; Cancer Research; Carcinoma, Renal Cell - drug therapy; Carcinoma, Renal Cell - pathology; CD27 Ligand - immunology; Dose-Response Relationship, Drug; Female; Humans; Immunoconjugates - administration & dosage; Immunoconjugates - adverse effects; Immunoconjugates - pharmacokinetics; Indoles - administration & dosage; Indoles - adverse effects; Indoles - pharmacokinetics; Kidney Neoplasms - drug therapy; Kidney Neoplasms - pathology; Lymphoma, B-Cell - drug therapy; Lymphoma, B-Cell - pathology; Male; Maximum Tolerated Dose; Medicine; Medicine & Public Health; Middle Aged; Oncology; Original Article; Pharmacology/Toxicology
• ISSN: 0344-5704; 1432-0843
• DOI: 10.1007/s00280-015-2909-2

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.