title: First-in-Man Dose-Escalation Study of the Selective BRAF Inhibitor RG7256 in Patients with BRAF V600-Mutated Advanced Solid Tumors.
abstract: BACKGROUND
  BRAF mutations are a validated target for cancer therapy. A second-generation BRAF inhibitor with an improved preclinical safety profile (RG7256) was evaluated in a first-in-man study in order to determine the safety, efficacy, pharmacokinetics and pharmacodynamics in patients with BRAF V600-mutated advanced solid tumors.
  
  
  METHODS
  Patients received RG7256 orally over 8 dose levels from 200 mg once a day (QD) to 2400 mg twice a day (BID) (50-, 100- and 150-mg tablets) using a classic 3 + 3 dose escalation design.
  
  
  RESULTS
  In total, 45 patients were enrolled; most (87 %) had advanced melanoma (94 % BRAF V600E). RG7256 was rapidly absorbed, with limited accumulation and dose-proportional increase in exposure up to 1950 mg BID. The maximal tolerated dose (MTD) was not reached. The most common drug-related adverse events (AEs) were dyspepsia (20 %), dry skin (18 %), rash (18 %), fatigue (16 %) and nausea (13 %), mainly grade 1. Three patients (7 %) developed cutaneous squamous cell carcinoma. Photosensitivity, arthralgia and increased liver enzyme levels were each observed in only one patient each. Of 44 evaluable patients, 14 (32 %) had a partial response (melanoma and thyroid cancer). At high dose levels (>1200 mg BID), 10 of 16 (63 %) patients had a partial response. A decrease in maximum standardized uptake value (SUVmax) on FDG-PET of ≥25 % was observed in 19 of 37 patients. On-treatment reductions in pERK were documented in eight of ten paired tumor samples.
  
  
  CONCLUSIONS
  RG7256 has a favorable safety profile compared to other BRAF inhibitors while maintaining clinical activity, and MTD was not reached. The excessive pill burden needed to provide the desired exposure, and thus concerns about patient compliance, limited further development of this agent. Study Identifier: ClinicalTrials.gov (NCT01143753).
authors: Vall d'Hebron University Hospital, Medical Oncology, Barcelona, Spain. rdienstmann@vhio.net.|, P. Vall d'Hebron 119-129, 08035, Barcelona, Spain. rdienstmann@vhio.net.
authors: Rodrigo
authors: R
authors: Dienstmann
authors: Department of Oncology, Rigshospitalet, Copenhagen, Denmark.
authors: Ulrik
authors: U
authors: Lassen
authors: Austin Hospital, Oncology Unit, Heidelberg, Australia.
authors: Jonathan
authors: J
authors: Cebon
authors: Royal Melbourne Hospital, Parkville, Australia.
authors: Jayesh
authors: J
authors: Desai
authors: Cancer Clinical Trials Unit, Royal Adelaide Hospital, Centre for Cancer Biology, SA Pathology and University of South Australia, Adelaide, Australia.
authors: Michael P
authors: MP
authors: Brown
authors: Pharma Research & Early Development, Roche Innovation Center Zurich, Schlieren, Switzerland.
authors: Stefan
authors: S
authors: Evers
authors: Pharma Research & Early Development, Roche Innovation Center New York, New York, NY, USA.|Oncology Correlative Science Lead, Novartis Pharmaceutical Corporation, East Hanover, NJ, USA.
authors: Fei
authors: F
authors: Su
authors: Pharma Research & Early Development, Roche Innovation Center New York, New York, NY, USA.
authors: Weijiang
authors: W
authors: Zhang
authors: Pharma Research & Early Development, Roche Innovation Center New York, New York, NY, USA.
authors: Frederic
authors: F
authors: Boisserie
authors: Pharma Research & Early Development, Roche Innovation Center New York, New York, NY, USA.|Oncology Global Clinical Research, Bristol-Myers Squibb, New York, NY, USA.
authors: Brian
authors: B
authors: Lestini
authors: Pharma Research & Early Development, Roche Innovation Center New York, New York, NY, USA.|Global Development, Oncology, Bayer HealthCare Pharmaceuticals, Inc, Whippany, NJ, USA.
authors: Kathleen
authors: K
authors: Schostack
authors: Pharma Research & Early Development, Roche Innovation Center Basel, Basel, Switzerland.
authors: Valerie
authors: V
authors: Meresse
authors: Vall d'Hebron University Hospital, Medical Oncology, Barcelona, Spain. jtabernero@vhio.net.|, P. Vall d'Hebron 119-129, 08035, Barcelona, Spain. jtabernero@vhio.net.
authors: Josep
authors: J
authors: Tabernero
mesh_terms: D000328:Adult; D000368:Aged; D004305:Dose-Response Relationship, Drug; D005260:Female; D019788:Fluorodeoxyglucose F18 / Q000493:pharmacokinetics; D006801:Humans; D008297:Male; D008545:Melanoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D009154:Mutation; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000235:genetics; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D047428:Protein Kinase Inhibitors; D019275:Radiopharmaceuticals; D019788:Fluorodeoxyglucose F18; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf