Rodrigo Dienstmann1,2, Ulrik Lassen3, Jonathan Cebon4, Jayesh Desai5, Michael P Brown6, Stefan Evers7, Fei Su8,9, Weijiang Zhang8, Frederic Boisserie8, Brian Lestini8,10, Kathleen Schostack8,11, Valerie Meresse12, Josep Tabernero13,14. 1. Vall d'Hebron University Hospital, Medical Oncology, Barcelona, Spain. rdienstmann@vhio.net. 2. , P. Vall d'Hebron 119-129, 08035, Barcelona, Spain. rdienstmann@vhio.net. 3. Department of Oncology, Rigshospitalet, Copenhagen, Denmark. 4. Austin Hospital, Oncology Unit, Heidelberg, Australia. 5. Royal Melbourne Hospital, Parkville, Australia. 6. Cancer Clinical Trials Unit, Royal Adelaide Hospital, Centre for Cancer Biology, SA Pathology and University of South Australia, Adelaide, Australia. 7. Pharma Research & Early Development, Roche Innovation Center Zurich, Schlieren, Switzerland. 8. Pharma Research & Early Development, Roche Innovation Center New York, New York, NY, USA. 9. Oncology Correlative Science Lead, Novartis Pharmaceutical Corporation, East Hanover, NJ, USA. 10. Oncology Global Clinical Research, Bristol-Myers Squibb, New York, NY, USA. 11. Global Development, Oncology, Bayer HealthCare Pharmaceuticals, Inc, Whippany, NJ, USA. 12. Pharma Research & Early Development, Roche Innovation Center Basel, Basel, Switzerland. 13. Vall d'Hebron University Hospital, Medical Oncology, Barcelona, Spain. jtabernero@vhio.net. 14. , P. Vall d'Hebron 119-129, 08035, Barcelona, Spain. jtabernero@vhio.net.
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. 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).
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 % BRAFV600E). 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: Caroline Robert; Boguslawa Karaszewska; Jacob Schachter; Piotr Rutkowski; Andrzej Mackiewicz; Daniil Stroiakovski; Michael Lichinitser; Reinhard Dummer; Florent Grange; Laurent Mortier; Vanna Chiarion-Sileni; Kamil Drucis; Ivana Krajsova; Axel Hauschild; Paul Lorigan; Pascal Wolter; Georgina V Long; Keith Flaherty; Paul Nathan; Antoni Ribas; Anne-Marie Martin; Peng Sun; Wendy Crist; Jeff Legos; Stephen D Rubin; Shonda M Little; Dirk Schadendorf Journal: N Engl J Med Date: 2014-11-16 Impact factor: 91.245
Authors: Georgina V Long; Alexander M Menzies; Adnan M Nagrial; Lauren E Haydu; Anne L Hamilton; Graham J Mann; T Michael Hughes; John F Thompson; Richard A Scolyer; Richard F Kefford Journal: J Clin Oncol Date: 2011-02-22 Impact factor: 44.544
Authors: Georgia Hatzivassiliou; Kyung Song; Ivana Yen; Barbara J Brandhuber; Daniel J Anderson; Ryan Alvarado; Mary J C Ludlam; David Stokoe; Susan L Gloor; Guy Vigers; Tony Morales; Ignacio Aliagas; Bonnie Liu; Steve Sideris; Klaus P Hoeflich; Bijay S Jaiswal; Somasekar Seshagiri; Hartmut Koeppen; Marcia Belvin; Lori S Friedman; Shiva Malek Journal: Nature Date: 2010-02-03 Impact factor: 49.962
Authors: James Larkin; Michele Del Vecchio; Paolo A Ascierto; Ivana Krajsova; Jacob Schachter; Bart Neyns; Enrique Espinosa; Claus Garbe; Vanna Chiarion Sileni; Helen Gogas; Wilson H Miller; Mario Mandalà; Geke A P Hospers; Ana Arance; Paola Queirolo; Axel Hauschild; Michael P Brown; Lada Mitchell; Luisa Veronese; Christian U Blank Journal: Lancet Oncol Date: 2014-02-27 Impact factor: 41.316
Authors: Arnaud D Roth; Sabine Tejpar; Mauro Delorenzi; Pu Yan; Roberto Fiocca; Dirk Klingbiel; Daniel Dietrich; Bart Biesmans; György Bodoky; Carlo Barone; Enrique Aranda; Bernard Nordlinger; Laura Cisar; Roberto Labianca; David Cunningham; Eric Van Cutsem; Fred Bosman Journal: J Clin Oncol Date: 2009-12-14 Impact factor: 44.544
Authors: E A Eisenhauer; P Therasse; J Bogaerts; L H Schwartz; D Sargent; R Ford; J Dancey; S Arbuck; S Gwyther; M Mooney; L Rubinstein; L Shankar; L Dodd; R Kaplan; D Lacombe; J Verweij Journal: Eur J Cancer Date: 2009-01 Impact factor: 9.162
Authors: Helen Davies; Graham R Bignell; Charles Cox; Philip Stephens; Sarah Edkins; Sheila Clegg; Jon Teague; Hayley Woffendin; Mathew J Garnett; William Bottomley; Neil Davis; Ed Dicks; Rebecca Ewing; Yvonne Floyd; Kristian Gray; Sarah Hall; Rachel Hawes; Jaime Hughes; Vivian Kosmidou; Andrew Menzies; Catherine Mould; Adrian Parker; Claire Stevens; Stephen Watt; Steven Hooper; Rebecca Wilson; Hiran Jayatilake; Barry A Gusterson; Colin Cooper; Janet Shipley; Darren Hargrave; Katherine Pritchard-Jones; Norman Maitland; Georgia Chenevix-Trench; Gregory J Riggins; Darell D Bigner; Giuseppe Palmieri; Antonio Cossu; Adrienne Flanagan; Andrew Nicholson; Judy W C Ho; Suet Y Leung; Siu T Yuen; Barbara L Weber; Hilliard F Seigler; Timothy L Darrow; Hugh Paterson; Richard Marais; Christopher J Marshall; Richard Wooster; Michael R Stratton; P Andrew Futreal Journal: Nature Date: 2002-06-09 Impact factor: 49.962
Authors: Vlad Popovici; Eva Budinska; Fred T Bosman; Sabine Tejpar; Arnaud D Roth; Mauro Delorenzi Journal: BMC Cancer Date: 2013-09-27 Impact factor: 4.430