Multicenter phase i trial of the mitogen-activated protein kinase 1/2 inhibitor bay 86-9766 in patients with advanced cancer

Colin D. Weekes, Daniel D. Von Hoff, Alex Adjei, Diane P. Leffingwell, S. Gail Eckhardt, Lia Gore, Karl D. Lewis, Glen J. Weiss, Ramesk K Ramanathan, Grace K. Dy, Wen Wee Ma, Beth Sheedy, Cory Iverson, Jeffrey N. Miner, Zancong Shen, Li Tain Yeh, Ronald L. Dubowy, Michael Jeffers, Prabhu Rajagopalan, Neil J. Clendeninn

Research output: Contribution to journalArticle

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Abstract

Purpose: To evaluate the safety, pharmacokinetics, and pharmacodynamics of BAY 86-9766, a selective, potent, orally available, small-molecule allosteric inhibitor of mitogen-activated protein kinase 1/2 in patients with advanced solid tumors. Experimental Design: BAY 86-9766 was administered orally daily in 28-day courses, with doses escalated to establish the maximum-tolerated dose (MTD). An expanded cohort was evaluated at the MTD. Pharmacokinetic and pharmacodynamic parameters were assessed, with extracellular signal-regulated kinase (ERK) phosphorylation evaluated in paired biopsies from a subset of the expanded MTD cohort. Tumor specimens were evaluated for mutations in select genes. Results: Sixty-nine patients were enrolled, including 20 patients at the MTD. The MTD was 100 mg given once-daily or in two divided doses. BAY 86-9766 was well-tolerated. The most common treatment-related toxicities were acneiform rash and gastrointestinal toxicity. BAY 86-9766 was well-absorbed after oral administration (plasma half-life ~12 hours), and displayed dose proportional pharmacokinetics throughout the tested dose range. Continuous daily dosing resulted in moderate accumulation at most dose levels. BAY 86-9766 suppressed ERK phosphorylation in biopsied tissue and tetradecanoylphorbol acetate- stimulated peripheral blood leukocytes. Of 53 evaluable patients, one patient with colorectal cancer achieved a partial response and 11 patients had stable disease for 4 or more courses. An ocular melanoma specimen harbored a GNAQ-activating mutation and exhibited reduced ERK phosphorylation in response to therapy. Conclusion: This phase I study showed that BAY 86-9766 was well-tolerated, with good oral absorption, dose proportional pharmacokinetics, target inhibition at the MTD, and some evidence of clinical benefit across a range of tumor types.

Original languageEnglish (US)
Pages (from-to)1232-1243
Number of pages12
JournalClinical Cancer Research
Volume19
Issue number5
DOIs
StatePublished - Mar 1 2013
Externally publishedYes

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Maximum Tolerated Dose
Mitogen-Activated Protein Kinase 1
Extracellular Signal-Regulated MAP Kinases
Pharmacokinetics
Neoplasms
Phosphorylation
Mutation
Tetradecanoylphorbol Acetate
Exanthema
Oral Administration
Half-Life
Colorectal Neoplasms
Melanoma
Leukocytes
Research Design
Biopsy
Safety
Therapeutics
Genes

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Multicenter phase i trial of the mitogen-activated protein kinase 1/2 inhibitor bay 86-9766 in patients with advanced cancer. / Weekes, Colin D.; Von Hoff, Daniel D.; Adjei, Alex; Leffingwell, Diane P.; Eckhardt, S. Gail; Gore, Lia; Lewis, Karl D.; Weiss, Glen J.; Ramanathan, Ramesk K; Dy, Grace K.; Ma, Wen Wee; Sheedy, Beth; Iverson, Cory; Miner, Jeffrey N.; Shen, Zancong; Yeh, Li Tain; Dubowy, Ronald L.; Jeffers, Michael; Rajagopalan, Prabhu; Clendeninn, Neil J.

In: Clinical Cancer Research, Vol. 19, No. 5, 01.03.2013, p. 1232-1243.

Research output: Contribution to journalArticle

Weekes, CD, Von Hoff, DD, Adjei, A, Leffingwell, DP, Eckhardt, SG, Gore, L, Lewis, KD, Weiss, GJ, Ramanathan, RK, Dy, GK, Ma, WW, Sheedy, B, Iverson, C, Miner, JN, Shen, Z, Yeh, LT, Dubowy, RL, Jeffers, M, Rajagopalan, P & Clendeninn, NJ 2013, 'Multicenter phase i trial of the mitogen-activated protein kinase 1/2 inhibitor bay 86-9766 in patients with advanced cancer', Clinical Cancer Research, vol. 19, no. 5, pp. 1232-1243. https://doi.org/10.1158/1078-0432.CCR-12-3529
Weekes, Colin D. ; Von Hoff, Daniel D. ; Adjei, Alex ; Leffingwell, Diane P. ; Eckhardt, S. Gail ; Gore, Lia ; Lewis, Karl D. ; Weiss, Glen J. ; Ramanathan, Ramesk K ; Dy, Grace K. ; Ma, Wen Wee ; Sheedy, Beth ; Iverson, Cory ; Miner, Jeffrey N. ; Shen, Zancong ; Yeh, Li Tain ; Dubowy, Ronald L. ; Jeffers, Michael ; Rajagopalan, Prabhu ; Clendeninn, Neil J. / Multicenter phase i trial of the mitogen-activated protein kinase 1/2 inhibitor bay 86-9766 in patients with advanced cancer. In: Clinical Cancer Research. 2013 ; Vol. 19, No. 5. pp. 1232-1243.
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T1 - Multicenter phase i trial of the mitogen-activated protein kinase 1/2 inhibitor bay 86-9766 in patients with advanced cancer

AU - Weekes, Colin D.

AU - Von Hoff, Daniel D.

AU - Adjei, Alex

AU - Leffingwell, Diane P.

AU - Eckhardt, S. Gail

AU - Gore, Lia

AU - Lewis, Karl D.

AU - Weiss, Glen J.

AU - Ramanathan, Ramesk K

AU - Dy, Grace K.

AU - Ma, Wen Wee

AU - Sheedy, Beth

AU - Iverson, Cory

AU - Miner, Jeffrey N.

AU - Shen, Zancong

AU - Yeh, Li Tain

AU - Dubowy, Ronald L.

AU - Jeffers, Michael

AU - Rajagopalan, Prabhu

AU - Clendeninn, Neil J.

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N2 - Purpose: To evaluate the safety, pharmacokinetics, and pharmacodynamics of BAY 86-9766, a selective, potent, orally available, small-molecule allosteric inhibitor of mitogen-activated protein kinase 1/2 in patients with advanced solid tumors. Experimental Design: BAY 86-9766 was administered orally daily in 28-day courses, with doses escalated to establish the maximum-tolerated dose (MTD). An expanded cohort was evaluated at the MTD. Pharmacokinetic and pharmacodynamic parameters were assessed, with extracellular signal-regulated kinase (ERK) phosphorylation evaluated in paired biopsies from a subset of the expanded MTD cohort. Tumor specimens were evaluated for mutations in select genes. Results: Sixty-nine patients were enrolled, including 20 patients at the MTD. The MTD was 100 mg given once-daily or in two divided doses. BAY 86-9766 was well-tolerated. The most common treatment-related toxicities were acneiform rash and gastrointestinal toxicity. BAY 86-9766 was well-absorbed after oral administration (plasma half-life ~12 hours), and displayed dose proportional pharmacokinetics throughout the tested dose range. Continuous daily dosing resulted in moderate accumulation at most dose levels. BAY 86-9766 suppressed ERK phosphorylation in biopsied tissue and tetradecanoylphorbol acetate- stimulated peripheral blood leukocytes. Of 53 evaluable patients, one patient with colorectal cancer achieved a partial response and 11 patients had stable disease for 4 or more courses. An ocular melanoma specimen harbored a GNAQ-activating mutation and exhibited reduced ERK phosphorylation in response to therapy. Conclusion: This phase I study showed that BAY 86-9766 was well-tolerated, with good oral absorption, dose proportional pharmacokinetics, target inhibition at the MTD, and some evidence of clinical benefit across a range of tumor types.

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