title: Phase 1 trial of tivantinib in combination with sorafenib in adult patients with advanced solid tumors.
abstract: OBJECTIVE
  This phase I study evaluated the safety, tolerability, maximum tolerated dose (MTD), and recommended phase II dose (RP2D) of tivantinib combined with sorafenib in patients with advanced solid tumors.
  
  
  METHODS
  A standard 3 + 3 dose escalation design was used. At the RP2D, expansion cohorts in 5 tumor types could be enrolled. Pharmacogenetic and pharmacodynamic analysis were performed.
  
  
  RESULTS
  Eighty-seven patients received the study treatment. The combination had no unexpected toxicities. The most common treatment-related adverse events (AE) were rash (40 %), diarrhea (38 %), and anorexia (33 %). The RP2D was tivantinib 360 mg BID and sorafenib 400 mg BID for all cancer histologies, except in hepatocellular carcinoma (HCC) patients tivantinib was 240 mg BID plus sorafenib 400 mg BID. The overall response rate was 12 % in all patients, 26 % in melanoma, 15 % in renal cell carcinoma (RCC), 10 % in HCC, and 0 % in other patients. Disease control rate (CR, PR and SD ≥8 weeks) was 58 % in all patients, 90 % in RCC, 65 % in HCC, 63 % in melanoma, 40 % in breast cancer, and 8 % in NSCLC patients.
  
  
  CONCLUSIONS
  The combination treatment could be administered at full standard single-agent doses in all patients except those with HCC, where tivantinib was lowered to 240 mg BID. Preliminary evidence of anticancer activity was observed in patients with RCC, HCC, and melanoma, including patients refractory to sorafenib and/or other anti-VEGF pathway therapies. The combination treatment has therapeutic potential in treating a variety of solid tumors.
authors.affiliation: Vanderbilt University Medical Center, 2220 Pierce Avenue, 777 Preston Research Building, Nashville, TN, USA, igor.puzanov@vanderbilt.edu.
authors.forename: Igor
authors.initials: I
authors.lastname: Puzanov
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Sosman
authors.forename: Armando
authors.initials: A
authors.lastname: Santoro
authors.forename: Muhammad W
authors.initials: MW
authors.lastname: Saif
authors.forename: Laura
authors.initials: L
authors.lastname: Goff
authors.forename: Grace K
authors.initials: GK
authors.lastname: Dy
authors.forename: Paolo
authors.initials: P
authors.lastname: Zucali
authors.forename: Julie A
authors.initials: JA
authors.lastname: Means-Powell
authors.forename: Wen Wee
authors.initials: WW
authors.lastname: Ma
authors.forename: Matteo
authors.initials: M
authors.lastname: Simonelli
authors.forename: Robert
authors.initials: R
authors.lastname: Martell
authors.forename: Feng
authors.initials: F
authors.lastname: Chai
authors.forename: Maria
authors.initials: M
authors.lastname: Lamar
authors.forename: Ronald E
authors.initials: RE
authors.lastname: Savage
authors.forename: Brian
authors.initials: B
authors.lastname: Schwartz
authors.forename: Alex A
authors.initials: AA
authors.lastname: Adjei
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D065731:Cytochrome P-450 CYP2C19 / Q000235:genetics; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D009536:Niacinamide / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D011110:Polymorphism, Genetic; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism; D011760:Pyrrolidinones / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D011804:Quinolines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D000077157:Sorafenib; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: C551661:ARQ 197; D010671:Phenylurea Compounds; D011760:Pyrrolidinones; D011804:Quinolines; D009536:Niacinamide; D000077157:Sorafenib; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met