title: First-in-human multicenter phase I study of BMS-936561 (MDX-1203), an antibody-drug conjugate targeting CD70.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Hematology/Medical Oncology, The Winship Cancer Institute of Emory University, 1365 Clifton Road, NE, Atlanta, GA, 30322, USA. towonik@emory.edu.
authors.forename: Taofeek Kunle
authors.initials: TK
authors.lastname: Owonikoko
authors.affiliation: University of Maryland Cancer Center, Baltimore, MD, USA.
authors.forename: Arif
authors.initials: A
authors.lastname: Hussain
authors.affiliation: The University of Chicago Medicine and Biological Sciences, Chicago, IL, USA.
authors.forename: Walter Michael
authors.initials: WM
authors.lastname: Stadler
authors.affiliation: University of Michigan Comprehensive Cancer Center, Ann Arbor, MI, USA.
authors.forename: David C
authors.initials: DC
authors.lastname: Smith
authors.affiliation: Yale University, New Haven, CT, USA.
authors.forename: Harriet
authors.initials: H
authors.lastname: Kluger
authors.affiliation: Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
authors.forename: Ana M
authors.initials: AM
authors.lastname: Molina
authors.affiliation: Bristol-Myers Squibb, New York, NY, USA.
authors.forename: Parul
authors.initials: P
authors.lastname: Gulati
authors.affiliation: Bristol-Myers Squibb, New York, NY, USA.
authors.forename: Aadhar
authors.initials: A
authors.lastname: Shah
authors.affiliation: Bristol-Myers Squibb, New York, NY, USA.
authors.forename: Christoph Matthias
authors.initials: CM
authors.lastname: Ahlers
authors.affiliation: Bristol-Myers Squibb, New York, NY, USA.
authors.forename: Pina M
authors.initials: PM
authors.lastname: Cardarelli
authors.affiliation: Bristol-Myers Squibb, New York, NY, USA.
authors.forename: Lewis J
authors.initials: LJ
authors.lastname: Cohen
mesh_terms: D000368:Aged; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D053282:CD27 Ligand / Q000276:immunology; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D018796:Immunoconjugates / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D007211:Indoles / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000473:pathology; D016393:Lymphoma, B-Cell / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged
chemical_list: D018906:Antineoplastic Agents, Alkylating; D053282:CD27 Ligand; D018796:Immunoconjugates; D007211:Indoles; C585822:MDX-1203
keywords: Antibody-drug conjugate; BMS-936561; CD70; Pharmacokinetic; Phase