title: A phase I study of daily everolimus plus low-dose weekly cisplatin for patients with advanced solid tumors.
abstract: OBJECTIVE
  Preclinical studies demonstrate synergistic anti-tumor activity with the combination of everolimus and cisplatin. We conducted a phase I study to establish the recommended phase II of oral everolimus to be given with low-dose weekly intravenous cisplatin.
  
  
  METHODS
  Part A used a standard 3 + 3 dose escalation scheme. There were 4 planned dose levels of everolimus: 2.5, 5, 7.5, and 10 mg/day. Subjects received oral everolimus during days 1-21 and cisplatin 20 mg/m(2) intravenously (fixed dose) on days 1, 8, and 15 of a 28-day cycle. Pharmacokinetic (PK) blood samples were collected on day 1 and day 8 of cycle 1 in Part A. After the phase II recommended dose was established (Part A), 6 additional subjects were enrolled in an expansion cohort (Part B). Response was assessed by RECIST q 2 cycles for all subjects.
  
  
  RESULTS
  Thirty patients were enrolled (18 male, 12 female) and 29 were treated. Median age was 61 years (31-79) and the median number of prior cytotoxic chemotherapy regimens was 2 (0-3). Eighty-three percent of subjects had received prior RT. DLTs occurred at dose level 1 (sudden death of unclear cause in a patient with melanoma metastatic to liver) and dose level 2 (bowel obstruction). No DLTs occurred at dose levels 3 and 4. The most common adverse events (≥grade 3) among 28 patients evaluable for toxicity were lymphopenia (36%), hyperglycemia (11%), fatigue (11%), and venous thrombosis (11%). PK analysis of everolimus demonstrated dose-proportional increases in C (max) (mean 91.9 ng/ml) and AUC(0-INF) (mean 680.5 h*ng/ml) at dose level 4. Three partial responses were seen (metastatic pulmonary carcinoid, n = 2; metastatic sinus carcinoma, n = 1). Prolonged stable disease ≥6 cycles occurred in subjects with pulmonary carcinoid, oropharyngeal squamous cell carcinoma, basal cell carcinoma, papillary thyroid carcinoma, and esthesioneuroblastoma (n = 1 each).
  
  
  CONCLUSIONS
  The phase II recommended dose is everolimus 10 mg/day (days 1-21) + cisplatin 20 mg/m(2) (days 1, 8, and 15) of a 28-day cycle. PK data demonstrate dose-proportional increases in exposure, as previously described for everolimus monotherapy. Anti-tumor activity was observed in several tumor types.
authors.affiliation: Department of Medicine, Head and Neck Medical Oncology Service, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, Box 532, New York, NY, 10021, USA. furym@mskcc.org
authors.forename: Matthew G
authors.initials: MG
authors.lastname: Fury
authors.forename: Eric
authors.initials: E
authors.lastname: Sherman
authors.forename: Sofia
authors.initials: S
authors.lastname: Haque
authors.forename: Susan
authors.initials: S
authors.lastname: Korte
authors.forename: Donna
authors.initials: D
authors.lastname: Lisa
authors.forename: Ronglai
authors.initials: R
authors.lastname: Shen
authors.forename: Nian
authors.initials: N
authors.lastname: Wu
authors.forename: David
authors.initials: D
authors.lastname: Pfister
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000627:therapeutic use; D002945:Cisplatin / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D000068338:Everolimus; D005260:Female; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D020123:Sirolimus / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives / Q000097:blood / Q000627:therapeutic use; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D016896:Treatment Outcome
chemical_list: D000068338:Everolimus; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D002945:Cisplatin; D020123:Sirolimus