Skip to main content
Log in

First-in-Man Dose-Escalation Study of the Selective BRAF Inhibitor RG7256 in Patients with BRAF V600-Mutated Advanced Solid Tumors

  • Original Research Article
  • Published:
Targeted Oncology Aims and scope Submit manuscript

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)

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S et al (2002) Mutations of the BRAF gene in human cancer. Nature 417:949–54

    Article  CAS  PubMed  Google Scholar 

  2. Wan PTC, Garnett MJ, Roe SM, Lee S, Niculescu-Duvaz D, Good VM et al (2004) Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF. Cell 116:855–67

    Article  CAS  PubMed  Google Scholar 

  3. Long GV, Menzies AM, Nagrial AM, Haydu LE, Hamilton AL, Mann GJ et al (2011) Prognostic and clinicopathologic associations of oncogenic BRAF in metastatic melanoma. J Clin Oncol 29:1239–46

    Article  PubMed  Google Scholar 

  4. Dienstmann R, Tabernero J (2011) BRAF as a target for cancer therapy. Anticancer Agents Med Chem 11:285–95

    Article  CAS  PubMed  Google Scholar 

  5. Elisei R, Ugolini C, Viola D, Lupi C, Biagini A, Giannini R et al (2008) BRAF(V600E) mutation and outcome of patients with papillary thyroid carcinoma: a 15-year median follow-up study. J Clin Endocrinol Metab 93:3943–9

    Article  CAS  PubMed  Google Scholar 

  6. Roth AD, Tejpar S, Delorenzi M, Yan P, Fiocca R, Klingbiel D et al (2010) Prognostic role of KRAS and BRAF in stage II and III resected colon cancer: results of the translational study on the PETACC-3, EORTC 40993, SAKK 60-00 trial. J Clin Oncol 28:466–74

    Article  CAS  PubMed  Google Scholar 

  7. Popovici V, Budinska E, Bosman FT, Tejpar S, Roth AD, Delorenzi M (2013) Context-dependent interpretation of the prognostic value of BRAF and KRAS mutations in colorectal cancer. BMC Cancer 13:439

    Article  PubMed  PubMed Central  Google Scholar 

  8. Chapman PB, Hauschild A, Robert C, Haanen JB, Ascierto P, Larkin J et al (2011) Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 364:2507–16

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Hauschild A, Grob J-J, Demidov LV, Jouary T, Gutzmer R, Millward M et al (2012) Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet 380:358–65

    Article  CAS  PubMed  Google Scholar 

  10. Larkin J, Del Vecchio M, Ascierto PA, Krajsova I, Schachter J, Neyns B et al (2014) Vemurafenib in patients with BRAF(V600) mutated metastatic melanoma: an open-label, multicentre, safety study. Lancet Oncol 15:436–44

    Article  CAS  PubMed  Google Scholar 

  11. McArthur GA, Chapman PB, Robert C, Larkin J, Haanen JB, Dummer R et al (2014) Safety and efficacy of vemurafenib in BRAF(V600E) and BRAF(V600K) mutation-positive melanoma (BRIM-3): extended follow-up of a phase 3, randomised, open-label study. Lancet Oncol 15:323–32

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Ascierto PA, Minor D, Ribas A, Lebbe C, O’Hagan A, Arya N et al (2013) Phase II trial (BREAK-2) of the BRAF inhibitor dabrafenib (GSK2118436) in patients with metastatic melanoma. J Clin Oncol 31:3205–11

    Article  CAS  PubMed  Google Scholar 

  13. Su F, Xu L, Higgings B, Yang H, Packman K, Hilton H et al (2012) Preclinical Characterization of RG7256, a Potent and Selective BRAF Inhibitor with Differentiation From Vemurafenib. Eur J Cancer 48(Supplement 6):114

    Article  Google Scholar 

  14. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R et al (2009) New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 45:228–47

    Article  CAS  PubMed  Google Scholar 

  15. Hatzivassiliou G, Song K, Yen I, Brandhuber BJ, Anderson DJ, Alvarado R et al (2010) RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth. Nature 464:431–5

    Article  CAS  PubMed  Google Scholar 

  16. Poulikakos PI, Zhang C, Bollag G, Shokat KM, Rosen N (2010) RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF. Nature 464:427–30

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Robert C, Karaszewska B, Schachter J, Rutkowski P, Mackiewicz A, Stroiakovski D et al (2015) Improved Overall Survival in Melanoma with Combined Dabrafenib and Trametinib. N Engl J Med 372:30–9

    Article  PubMed  Google Scholar 

  18. Basile KJ, Le K, Hartsough EJ, Aplin AE (2014) Inhibition of mutant BRAF splice variant signaling by next-generation, selective RAF inhibitors. Pigment Cell Melanoma Res 27:479–84

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Nakamura A, Arita T, Tsuchiya S, Donelan J, Chouitar J, Carideo E et al (2013) Antitumor activity of the selective pan-RAF inhibitor TAK-632 in BRAF inhibitor-resistant melanoma. Cancer Res 73:7043–55

    Article  CAS  PubMed  Google Scholar 

  20. Girotti M, Lopes F, Preece N, Niculescu-Duvaz D, Zambon A, Davies L, et al. Novel panRAF inhibitors active in melanomas that are resistant to BRAF-selective, or BRAF-selective/MEK inhibitor combinations. Cancer Res. 2014;74:Abst #3074.

  21. Morris EJ, Jha S, Restaino CR, Dayananth P, Zhu H, Cooper A et al (2013) Discovery of a novel ERK inhibitor with activity in models of acquired resistance to BRAF and MEK inhibitors. Cancer Discov 3:742–50

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We thank the patients and their families who participated in this study, Mei Liu for bioanalysis of PK samples, and Sarah MacKenzie for medical writing assistance. RG7256/PLX3603 was developed in collaboration with Plexxikon.

Conflict of Interest

This study was funded by Hoffmann-La Roche, which provided institutional research support to UL, JD, MPB and JT. RD and JC have no conflicts of interest to declare. SE, FS, WZ, FB, BL, and KS, and VM are employees of Hoffmann-La Roche. SE, WZ, FB, BL, and KS hold stock of Hoffman-La Roche as an employment benefit.

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Rodrigo Dienstmann or Josep Tabernero.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary Fig. 1

A Representative images showing changes in proliferation (Ki-67) and MAPK pathway activity (pERK) with RG7256 treatment. Tumor sample sections from a 37-year-old woman with acral lentiginous malignant melanoma who started treatment at 1950 mg BID, had a partial response (non-confirmed) at cycle 3, and progressed at cycle 5. Strong inhibition of proliferation (Ki-67) and MAPK signaling (pERK) is seen at cycle 1 day 8 (C1D8) relative to baseline, with a return to baseline levels at cycle 5 correlating with disease progression. 1 B Correlation between changes in Ki-67 or pERK concentrations at cycle 1 day 8 compared to baseline, according to the AUC at day 15 (steady state) and RECIST response. Tumor sections were stained with anti-phosphorylated ERK (anti-pERK) or anti-Ki-67 antibodies, and percentage change in H-score was calculated. Eight of the ten patients with available paired samples showed a reduction in pERK and Ki-67. (PPTX 724 kb)

Supplementary Table 1

(DOCX 20 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Dienstmann, R., Lassen, U., Cebon, J. et al. First-in-Man Dose-Escalation Study of the Selective BRAF Inhibitor RG7256 in Patients with BRAF V600-Mutated Advanced Solid Tumors. Targ Oncol 11, 149–156 (2016). https://doi.org/10.1007/s11523-015-0381-x

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11523-015-0381-x

Keywords

Navigation