A phase 1 dose-escalation and expansion study of binimetinib (MEK162), a potent and selective oral MEK1/2 inhibitor

Johanna C. Bendell, Milind Javle, Tanios S. Bekaii-Saab, Richard S. Finn, Zev A. Wainberg, Daniel Laheru, Colin D. Weekes, Benjamin R. Tan, Gazala N. Khan, Mark M. Zalupski, Jeffrey R. Infante, Suzanne Jones, Kyriakos P. Papadopoulos, Anthony W. Tolcher, Renae E. Chavira, Janna L. Christy-Bittel, Emma Barrett, Amita Patnaik

Research output: Contribution to journalArticle

Abstract

Background:Binimetinib (MEK162; ARRY-438162) is a potent and selective oral MEK 1/2 inhibitor. This phase 1 study determined the maximum tolerated dose (MTD), safety, pharmacokinetic and pharmacodynamic profiles, and preliminary anti-tumour activity of binimetinib in patients with advanced solid tumours, with expansion cohorts of patients with biliary cancer or KRAS-or BRAF-mutant colorectal cancer.Methods:Binimetinib was administered twice daily. Expansion cohorts were enroled after MTD determination following a 3+3 dose-escalation design. Pharmacokinetic properties were determined from plasma samples. Tumour samples were assessed for mutations in RAS, RAF, and other relevant genes. Pharmacodynamic properties were evaluated in serum and skin punch biopsy samples.Results:Ninety-three patients received binimetinib (dose-escalation phase, 19; expansion, 74). The MTD was 60 mg twice daily, with dose-limiting adverse events (AEs) of dermatitis acneiform and chorioretinopathy. The dose for expansion patients was subsequently decreased to 45 mg twice daily because of the frequency of treatment-related ocular toxicity at the MTD. Common AEs across all dose levels included rash (81%), nausea (56%), vomiting (52%), diarrhoea (51%), peripheral oedema (46%), and fatigue (43%); most were grade 1/2. Dose-proportional increases in binimetinib exposure were observed and target inhibition was demonstrated in serum and skin punch biopsy samples. Three patients with biliary cancer had objective responses (one complete and two partial).Conclusions:Binimetinib demonstrated a manageable safety profile, target inhibition, and dose-proportional exposure. The 45 mg twice daily dose was identified as the recommended phase 2 dose. The three objective responses in biliary cancer patients are encouraging and support further evaluation in this population.

Original languageEnglish (US)
Pages (from-to)575-583
Number of pages9
JournalBritish Journal of Cancer
Volume116
Issue number5
DOIs
StatePublished - Feb 28 2017

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Maximum Tolerated Dose
Biliary Tract Neoplasms
Pharmacokinetics
Biopsy
Safety
Neoplasms
Skin
Mitogen-Activated Protein Kinase Kinases
Dermatitis
MEK162
Exanthema
Serum
Nausea
Vomiting
Fatigue
Colorectal Neoplasms
Diarrhea
Edema
Mutation
Population

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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A phase 1 dose-escalation and expansion study of binimetinib (MEK162), a potent and selective oral MEK1/2 inhibitor. / Bendell, Johanna C.; Javle, Milind; Bekaii-Saab, Tanios S.; Finn, Richard S.; Wainberg, Zev A.; Laheru, Daniel; Weekes, Colin D.; Tan, Benjamin R.; Khan, Gazala N.; Zalupski, Mark M.; Infante, Jeffrey R.; Jones, Suzanne; Papadopoulos, Kyriakos P.; Tolcher, Anthony W.; Chavira, Renae E.; Christy-Bittel, Janna L.; Barrett, Emma; Patnaik, Amita.

In: British Journal of Cancer, Vol. 116, No. 5, 28.02.2017, p. 575-583.

Research output: Contribution to journalArticle

Bendell, JC, Javle, M, Bekaii-Saab, TS, Finn, RS, Wainberg, ZA, Laheru, D, Weekes, CD, Tan, BR, Khan, GN, Zalupski, MM, Infante, JR, Jones, S, Papadopoulos, KP, Tolcher, AW, Chavira, RE, Christy-Bittel, JL, Barrett, E & Patnaik, A 2017, 'A phase 1 dose-escalation and expansion study of binimetinib (MEK162), a potent and selective oral MEK1/2 inhibitor', British Journal of Cancer, vol. 116, no. 5, pp. 575-583. https://doi.org/10.1038/bjc.2017.10
Bendell, Johanna C. ; Javle, Milind ; Bekaii-Saab, Tanios S. ; Finn, Richard S. ; Wainberg, Zev A. ; Laheru, Daniel ; Weekes, Colin D. ; Tan, Benjamin R. ; Khan, Gazala N. ; Zalupski, Mark M. ; Infante, Jeffrey R. ; Jones, Suzanne ; Papadopoulos, Kyriakos P. ; Tolcher, Anthony W. ; Chavira, Renae E. ; Christy-Bittel, Janna L. ; Barrett, Emma ; Patnaik, Amita. / A phase 1 dose-escalation and expansion study of binimetinib (MEK162), a potent and selective oral MEK1/2 inhibitor. In: British Journal of Cancer. 2017 ; Vol. 116, No. 5. pp. 575-583.
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T1 - A phase 1 dose-escalation and expansion study of binimetinib (MEK162), a potent and selective oral MEK1/2 inhibitor

AU - Bendell, Johanna C.

AU - Javle, Milind

AU - Bekaii-Saab, Tanios S.

AU - Finn, Richard S.

AU - Wainberg, Zev A.

AU - Laheru, Daniel

AU - Weekes, Colin D.

AU - Tan, Benjamin R.

AU - Khan, Gazala N.

AU - Zalupski, Mark M.

AU - Infante, Jeffrey R.

AU - Jones, Suzanne

AU - Papadopoulos, Kyriakos P.

AU - Tolcher, Anthony W.

AU - Chavira, Renae E.

AU - Christy-Bittel, Janna L.

AU - Barrett, Emma

AU - Patnaik, Amita

PY - 2017/2/28

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N2 - Background:Binimetinib (MEK162; ARRY-438162) is a potent and selective oral MEK 1/2 inhibitor. This phase 1 study determined the maximum tolerated dose (MTD), safety, pharmacokinetic and pharmacodynamic profiles, and preliminary anti-tumour activity of binimetinib in patients with advanced solid tumours, with expansion cohorts of patients with biliary cancer or KRAS-or BRAF-mutant colorectal cancer.Methods:Binimetinib was administered twice daily. Expansion cohorts were enroled after MTD determination following a 3+3 dose-escalation design. Pharmacokinetic properties were determined from plasma samples. Tumour samples were assessed for mutations in RAS, RAF, and other relevant genes. Pharmacodynamic properties were evaluated in serum and skin punch biopsy samples.Results:Ninety-three patients received binimetinib (dose-escalation phase, 19; expansion, 74). The MTD was 60 mg twice daily, with dose-limiting adverse events (AEs) of dermatitis acneiform and chorioretinopathy. The dose for expansion patients was subsequently decreased to 45 mg twice daily because of the frequency of treatment-related ocular toxicity at the MTD. Common AEs across all dose levels included rash (81%), nausea (56%), vomiting (52%), diarrhoea (51%), peripheral oedema (46%), and fatigue (43%); most were grade 1/2. Dose-proportional increases in binimetinib exposure were observed and target inhibition was demonstrated in serum and skin punch biopsy samples. Three patients with biliary cancer had objective responses (one complete and two partial).Conclusions:Binimetinib demonstrated a manageable safety profile, target inhibition, and dose-proportional exposure. The 45 mg twice daily dose was identified as the recommended phase 2 dose. The three objective responses in biliary cancer patients are encouraging and support further evaluation in this population.

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