title: Phase II study of the anti-cytotoxic T-lymphocyte-associated antigen 4 monoclonal antibody, tremelimumab, in patients with refractory metastatic colorectal cancer.
abstract: OBJECTIVE
  Safety and efficacy of tremelimumab (CP-675,206), a fully human anti-cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) monoclonal antibody, were assessed in patients with treatment-refractory colorectal cancer.
  
  
  METHODS
  A single-arm, multicenter, phase II trial was conducted in patients with Eastern Cooperative Oncology Group performance status <or= 1 and measurable colorectal carcinoma for whom standard treatments for metastatic disease had failed. Patients received 15 mg/kg tremelimumab intravenously every 90 days until progression. Primary end point was objective response status (per Response Evaluation Criteria in Solid Tumors). Secondary end points included safety, duration of response, progression-free survival, and overall survival.
  
  
  RESULTS
  Forty-seven patients who had received extensive prior therapies (all had received fluoropyrimidines, oxaliplatin, and irinotecan; most [91%] had also received cetuximab) were treated. Grade 3/4 treatment-related adverse events (AEs) were diarrhea (n = 5; 11%), ulcerative colitis (n = 1; 2%), fatigue (n = 1; 2%), autoimmune thrombocytopenia (n = 1; 2%), and hypokalemia (n = 1; 2%), which resolved spontaneously or with interventions. Six patients discontinued because of an AE; two were considered treatment related. Of 45 response-evaluable patients, 44 did not reach second dose (43 progressive disease; one discontinuation). Twenty-one patients (45%) lived >or= 180 days after enrollment. One patient (2%; 90% CI, < 1% to 10%) had a stable pelvic mass and substantial regression in an adrenal mass (partial response). This patient received five tremelimumab doses; response duration was 6 months (enrollment to disease progression, 15 months).
  
  
  CONCLUSIONS
  Tremelimumab did not demonstrate clinically meaningful single-agent activity in this patient population, although the number of survivors at 6 months and the one patient with confirmed partial response are potentially interesting. Further study of tremelimumab in combination with other agents may be warranted.
authors.affiliation: Gastrointestinal Medical Oncology Service, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA. chungk@mskcc.org
authors.forename: Ki Y
authors.initials: KY
authors.lastname: Chung
authors.forename: Ira
authors.initials: I
authors.lastname: Gore
authors.forename: Lawrence
authors.initials: L
authors.lastname: Fong
authors.forename: Alan
authors.initials: A
authors.lastname: Venook
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Beck
authors.forename: Prudence
authors.initials: P
authors.lastname: Dorazio
authors.forename: Peggy J
authors.initials: PJ
authors.lastname: Criscitiello
authors.forename: Diane I
authors.initials: DI
authors.lastname: Healey
authors.forename: Bo
authors.initials: B
authors.lastname: Huang
authors.forename: Jesus
authors.initials: J
authors.lastname: Gomez-Navarro
authors.forename: Leonard B
authors.initials: LB
authors.lastname: Saltz
mesh_terms: D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D015703:Antigens, CD / Q000276:immunology; D060908:CTLA-4 Antigen; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000401:mortality; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D015703:Antigens, CD; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C520704:tremelimumab