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Title: First-in-Man Dose-Escalation Study of the Selective BRAF Inhibitor RG7256 in Patients with BRAF V600-Mutated Advanced Solid Tumors.
Austin Authors: Dienstmann, Rodrigo;Lassen, Ulrik;Cebon, Jonathan S ;Desai, Jayesh;Brown, Michael P;Evers, Stefan;Su, Fei;Zhang, Weijiang;Boisserie, Frederic;Lestini, Brian;Schostack, Kathleen;Meresse, Valerie;Tabernero, Josep
Affiliation: Global Development, Oncology, Bayer HealthCare Pharmaceuticals, Inc, Whippany, NJ, USA
P. Vall d'Hebron 119-129, 08035, Barcelona, Spain
Vall d'Hebron University Hospital, Medical Oncology, Barcelona, Spain
Department of Oncology, Rigshospitalet, Copenhagen, Denmark
Department of Medical Oncology, Austin Health, Heidelberg, Victoria, Australia
Royal Melbourne Hospital, Parkville, Australia
Cancer Clinical Trials Unit, Royal Adelaide Hospital, Centre for Cancer Biology, SA Pathology and University of South Australia, Adelaide, Australia
Pharma Research & Early Development, Roche Innovation Center Zurich, Schlieren, Switzerland
Pharma Research & Early Development, Roche Innovation Center New York, New York, NY, USA
Oncology Correlative Science Lead, Novartis Pharmaceutical Corporation, East Hanover, NJ, USA
Oncology Global Clinical Research, Bristol-Myers Squibb, New York, NY, USA
Pharma Research & Early Development, Roche Innovation Center Basel, Basel, Switzerland
Issue Date: Apr-2016
Publication information: Targeted oncology 2016; 11(2): 149-56
Abstract: 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 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. 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. 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: (NCT01143753).
DOI: 10.1007/s11523-015-0381-x
PubMed URL: 26310975
Type: Journal Article
Appears in Collections:Journal articles

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