title: Phase I trial of everolimus, gemcitabine and cisplatin in patients with solid tumors.
abstract: BACKGROUND
  A Phase I trial of the 2-drug regimen of everolimus plus gemcitabine (Cohort I) and the 3-drug regimen of everolimus plus gemcitabine and cisplatin (Cohort II) was performed to determine the maximally tolerated dose (MTD) of both combinations. An expansion cohort (Cohort III) of patients with cholangiocarcinoma or gallbladder carcinoma was treated at the MTD.
  
  
  METHODS
  A standard 3 + 3 design dose escalation was used. Everolimus was given on Monday/Wednesday/Friday or daily depending upon the dose level. Gemcitabine and cisplatin were administered on days 1 and 8 of each 21 day cycle.
  
  
  RESULTS
  Twelve patients were entered in Cohort I and 15 in Cohort II. The MTD for Cohort I was everolimus 5 mg on Monday/Wednesday/Friday and gemcitabine 800 mg/m(2). For Cohort II, it was everolimus 5 mg on Monday/Wednesday/Friday, gemcitabine 600 mg/m(2), and cisplatin 12.5 mg/m(2). All DLTs in this study were hematologic. Complete responses (CR) were seen in a patient with primary peritoneal carcinoma and another with recurrent pancreatic cancer. Partial responses (PR) were seen in 3 patients: breast, ampullary carcinoma and pheochromocytoma. Of 10 patients enrolled in Cohort III, six patients had stable disease and 4 had progressive disease.
  
  
  CONCLUSIONS
  This Phase I clinical trial has demonstrated that these 2-drug and 3-drug combinations are generally well tolerated and safely administered. The main DLTs in both regimens were hematologic, specifically thrombocytopenia. The 3-drug combination can be considered as a platform for future studies in specific tumor types.
authors.affiliation: Mayo Clinic Cancer Center, 200 First Street SW, Rochester, MN, 55905, USA, costello.brian@mayo.edu.
authors.forename: Brian A
authors.initials: BA
authors.lastname: Costello
authors.forename: Mitesh J
authors.initials: MJ
authors.lastname: Borad
authors.forename: Yingwei
authors.initials: Y
authors.lastname: Qi
authors.forename: George P
authors.initials: GP
authors.lastname: Kim
authors.forename: Donald W
authors.initials: DW
authors.lastname: Northfelt
authors.forename: Charles
authors.initials: C
authors.lastname: Erlichman
authors.forename: Steven R
authors.initials: SR
authors.lastname: Alberts
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage; D000970:Antineoplastic Agents / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D002945:Cisplatin / Q000008:administration & dosage; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D004334:Drug Administration Schedule; D000068338:Everolimus; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy; D009369:Neoplasms / Q000188:drug therapy*; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D003841:Deoxycytidine; D000068338:Everolimus; D002945:Cisplatin; D020123:Sirolimus; D000093542:Gemcitabine
references.citation: Clin Ther. 2013 Mar;35(3):215-25
references.pmid: 23453404
references.citation: Cancer Chemother Pharmacol. 2012 Mar;69(3):591-8
references.pmid: 21913034
references.citation: Ann Oncol. 1993 Aug;4(7):607-9
references.pmid: 8363992
references.citation: J Clin Oncol. 1996 Aug;14(8):2306-10
references.pmid: 8708721
references.citation: Oncology. 1994 Nov-Dec;51(6):515-7
references.pmid: 7970496
references.citation: N Engl J Med. 2010 Apr 8;362(14):1273-81
references.pmid: 20375404
references.citation: J Clin Oncol. 2008 Apr 1;26(10):1588-95
references.pmid: 18332470
references.citation: Int J Cancer. 2006 May 1;118(9):2337-43
references.pmid: 16331623
references.citation: Cancer. 1998 Feb 15;82(4):639-41
references.pmid: 9477094
references.citation: Oncol Rep. 1998 Jul-Aug;5(4):931-4
references.pmid: 9625849
references.citation: Cancer. 1998 Dec 1;83(11):2419-21
references.pmid: 9840543
references.citation: Anticancer Drugs. 2011 Jan;22(1):58-78
references.pmid: 20890178
references.citation: Clin Pharmacol Ther. 2001 Nov;70(5):425-30
references.pmid: 11719728
references.citation: Eur J Cancer Clin Oncol. 1983 Jun;19(6):721-3
references.pmid: 6307706
references.citation: J Clin Oncol. 2008 Apr 1;26(10):1596-602
references.pmid: 18332467