PMID- 26310975
OWN - NLM
STAT- MEDLINE
DCOM- 20170227
LR  - 20181113
IS  - 1776-260X (Electronic)
IS  - 1776-2596 (Linking)
VI  - 11
IP  - 2
DP  - 2016 Apr
TI  - First-in-Man Dose-Escalation Study of the Selective BRAF Inhibitor RG7256 in 
      Patients with BRAF V600-Mutated Advanced Solid Tumors.
PG  - 149-56
LID - 10.1007/s11523-015-0381-x [doi]
AB  - 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. PATIENTS AND 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).
FAU - Dienstmann, Rodrigo
AU  - Dienstmann R
AD  - Vall d'Hebron University Hospital, Medical Oncology, Barcelona, Spain. 
      rdienstmann@vhio.net.
AD  - , P. Vall d'Hebron 119-129, 08035, Barcelona, Spain. rdienstmann@vhio.net.
FAU - Lassen, Ulrik
AU  - Lassen U
AD  - Department of Oncology, Rigshospitalet, Copenhagen, Denmark.
FAU - Cebon, Jonathan
AU  - Cebon J
AD  - Austin Hospital, Oncology Unit, Heidelberg, Australia.
FAU - Desai, Jayesh
AU  - Desai J
AD  - Royal Melbourne Hospital, Parkville, Australia.
FAU - Brown, Michael P
AU  - Brown MP
AD  - Cancer Clinical Trials Unit, Royal Adelaide Hospital, Centre for Cancer Biology, 
      SA Pathology and University of South Australia, Adelaide, Australia.
FAU - Evers, Stefan
AU  - Evers S
AD  - Pharma Research & Early Development, Roche Innovation Center Zurich, Schlieren, 
      Switzerland.
FAU - Su, Fei
AU  - Su F
AD  - Pharma Research & Early Development, Roche Innovation Center New York, New York, 
      NY, USA.
AD  - Oncology Correlative Science Lead, Novartis Pharmaceutical Corporation, East 
      Hanover, NJ, USA.
FAU - Zhang, Weijiang
AU  - Zhang W
AD  - Pharma Research & Early Development, Roche Innovation Center New York, New York, 
      NY, USA.
FAU - Boisserie, Frederic
AU  - Boisserie F
AD  - Pharma Research & Early Development, Roche Innovation Center New York, New York, 
      NY, USA.
FAU - Lestini, Brian
AU  - Lestini B
AD  - Pharma Research & Early Development, Roche Innovation Center New York, New York, 
      NY, USA.
AD  - Oncology Global Clinical Research, Bristol-Myers Squibb, New York, NY, USA.
FAU - Schostack, Kathleen
AU  - Schostack K
AD  - Pharma Research & Early Development, Roche Innovation Center New York, New York, 
      NY, USA.
AD  - Global Development, Oncology, Bayer HealthCare Pharmaceuticals, Inc, Whippany, 
      NJ, USA.
FAU - Meresse, Valerie
AU  - Meresse V
AD  - Pharma Research & Early Development, Roche Innovation Center Basel, Basel, 
      Switzerland.
FAU - Tabernero, Josep
AU  - Tabernero J
AD  - Vall d'Hebron University Hospital, Medical Oncology, Barcelona, Spain. 
      jtabernero@vhio.net.
AD  - , P. Vall d'Hebron 119-129, 08035, Barcelona, Spain. jtabernero@vhio.net.
LA  - eng
SI  - ClinicalTrials.gov/NCT01143753
PT  - Clinical Trial, Phase I
PT  - Journal Article
PT  - Multicenter Study
PL  - France
TA  - Target Oncol
JT  - Targeted oncology
JID - 101270595
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (Radiopharmaceuticals)
RN  - 0Z5B2CJX4D (Fluorodeoxyglucose F18)
RN  - EC 2.7.11.1 (BRAF protein, human)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins B-raf)
SB  - IM
MH  - Adult
MH  - Aged
MH  - Dose-Response Relationship, Drug
MH  - Female
MH  - Fluorodeoxyglucose F18/pharmacokinetics
MH  - Humans
MH  - Male
MH  - Melanoma/drug therapy/genetics/metabolism
MH  - Middle Aged
MH  - Mutation
MH  - Neoplasms/*drug therapy/genetics/metabolism
MH  - Protein Kinase Inhibitors/*administration & dosage/adverse 
      effects/pharmacokinetics
MH  - Proto-Oncogene Proteins B-raf/*antagonists & inhibitors/genetics
MH  - Radiopharmaceuticals/pharmacokinetics
MH  - Treatment Outcome
MH  - Young Adult
EDAT- 2015/08/28 06:00
MHDA- 2017/02/28 06:00
CRDT- 2015/08/28 06:00
PHST- 2015/08/28 06:00 [entrez]
PHST- 2015/08/28 06:00 [pubmed]
PHST- 2017/02/28 06:00 [medline]
AID - 10.1007/s11523-015-0381-x [pii]
AID - 10.1007/s11523-015-0381-x [doi]
PST - ppublish
SO  - Target Oncol. 2016 Apr;11(2):149-56. doi: 10.1007/s11523-015-0381-x.