title: A phase I trial of everolimus in combination with 5-FU/LV, mFOLFOX6 and mFOLFOX6 plus panitumumab in patients with refractory solid tumors.
abstract: OBJECTIVE
  This phase I study investigated the safety, dose-limiting toxicity, and efficacy in three cohorts all treated with the mTOR inhibitor everolimus that was delivered (1) in combination with 5-fluorouracil with leucovorin (5-FU/LV), (2) with mFOLFOX6 (5-FU/LV + oxaliplatin), and (3) with mFOLFOX6 + panitumumab in patients with refractory solid tumors.
  
  
  METHODS
  Patients were accrued using a 3-patient cohort design consisting of two sub-trials in which the maximum tolerated combination (MTC) and dose-limiting toxicity (DLT) of everolimus and 5-FU/LV was established in Sub-trial A and of everolimus in combination with mFOLFOX6 and mFOLFOX6 plus panitumumab in Sub-trial B.
  
  
  RESULTS
  Thirty-six patients were evaluable for toxicity, 21 on Sub-trial A and 15 on Sub-trial B. In Sub-trial A, DLT was observed in 1/6 patients enrolled on dose level 1A and 2/3 patients in level 6A. In Sub-trial B, 2/3 patients experienced DLT on level 1B and subsequent patients were enrolled on level 1B-1 without DLT. Three of six patients in cohort 2B-1 experienced grade 3 mucositis, and further study of the combination of everolimus, mFOLFOX6 and panitumumab was aborted. Among the 24 patients enrolled with refractory metastatic colorectal cancer, the median time on treatment was 2.7 months with 45 % of patients remaining on treatment with stable disease for at least 3 months.
  
  
  CONCLUSIONS
  While a regimen of everolimus in addition to 5-FU/LV and mFOLFOX6 appears safe and tolerable, the further addition of panitumumab resulted in an unacceptable level of toxicity that cannot be recommended for further study. Further investigation is warranted to better elucidate the role which mTOR inhibitors play in patients with refractory solid tumors, with a specific focus on mCRC as a potential for the combination of this targeted and cytotoxic therapy in future studies.
authors.affiliation: Department of Medicine, Division of Hematology/Oncology, School of Medicine, The University of North Carolina at Chapel Hill, Physicians Office Building, 170 Manning Drive, Campus Box #7305, Chapel Hill, NC, 27599, USA, autumn_mcree@med.unc.edu.
authors.forename: Autumn J
authors.initials: AJ
authors.lastname: McRee
authors.forename: Janine M
authors.initials: JM
authors.lastname: Davies
authors.forename: Hanna G
authors.initials: HG
authors.lastname: Sanoff
authors.forename: Richard M
authors.initials: RM
authors.lastname: Goldberg
authors.forename: Stephen
authors.initials: S
authors.lastname: Bernard
authors.forename: E Claire
authors.initials: EC
authors.lastname: Dees
authors.forename: Kimberly
authors.initials: K
authors.lastname: Keller
authors.forename: Anastasia
authors.initials: A
authors.lastname: Ivanova
authors.forename: Bert H
authors.initials: BH
authors.lastname: O'Neil
mesh_terms: D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D015331:Cohort Studies; D015179:Colorectal Neoplasms / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D016903:Drug Monitoring; D057239:Early Termination of Clinical Trials; D000068338:Everolimus; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D006801:Humans; D002955:Leucovorin / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D052016:Mucositis / Q000139:chemically induced / Q000503:physiopathology; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000188:drug therapy; D009944:Organoplatinum Compounds / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D000077150:Oxaliplatin; D000077544:Panitumumab; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D012720:Severity of Illness Index; D020123:Sirolimus / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D047428:Protein Kinase Inhibitors; D000077150:Oxaliplatin; D000077544:Panitumumab; D000068338:Everolimus; D058570:TOR Serine-Threonine Kinases; D002955:Leucovorin; D005472:Fluorouracil; D020123:Sirolimus