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Phase II study of selumetinib (AZD6244, ARRY-142886) plus irinotecan as second-line therapy in patients with K-RAS mutated colorectal cancer

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An Erratum to this article was published on 02 December 2014

Abstract

Background

More than half of colorectal tumors harbor activating mutations in RAS/RAF proteins. Selumetinib (AZD6244, ARRY-142886) is a small molecule kinase inhibitor targeting MEK kinase, downstream of RAS. We examined the efficacy and safety of selumetinib with irinotecan in second-line therapy.

Methods

Patients with K-RAS mutated colorectal cancer, progressing on first-line oxaliplatin‐based chemotherapy with bevacizumab, were eligible for this multicenter open-label phase I/II trial. In part A, a dose was determined using a standard “3 + 3” design; in part B, efficacy was determined. The primary endpoint was RECIST response rate. Historical data for irinotecan were used as reference. Secondary endpoints included progression-free survival and overall survival.

Results

Thirty-two patients entered the study, and 31 were treated. All had K-RAS exon 2 mutated tumors. In phase I, the recommended oral dose of selumetinib was 75 mg twice per day with intravenous (IV) irinotecan, 180 mg/m2 every 2 weeks. Three patients (9.7 %) had partial response . Sixteen patients (51.6 %) had stable disease for ≥4 weeks, including three >1 year. The most common grade 3 adverse events included diarrhea, neutropenia, fatigue, anemia, nausea, and dehydration. The study was terminated before a pre-planned accrual of 45 subjects.

Conclusions

Despite termination before full accrual, the point estimates of RR and median PFS show promising results, suggesting that further investigations of MEK inhibition in the treatment of metastatic colorectal cancer are warranted. Studies combining MEK inhibitors with cytotoxics or other targeted agents may lead to improved clinical activity based on the emerging preclinical data.

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Acknowledgments

This study was supported in part by a Grant from Astra-Zeneca pharmaceuticals.

Conflict of interest

Dr. Hochster has a consultant or advisory role for Astra-Zeneca, with no relationship to study outcome. All remaining authors have declared no conflicts of interest.

Author information

Authors and Affiliations

  1. Yale Cancer Center, 333 Cedar Street, New Haven, CT, 06520, USA

    H. S. Hochster & N. Uboha

  2. University of Colorado, Aurora, CO, USA

    W. Messersmith

  3. Swedish Cancer Institute, Seattle, WA, USA

    P. J. Gold

  4. Indiana University, Indianapolis, IN, USA

    B. H. ONeil

  5. NYU Cancer Institute, New York, NY, USA

    D. Cohen, C. G. Leichman & L. Leichman

  6. Fox Chase Cancer Center, Philadelphia, PA, USA

    C. Denlinger & S. Cohen

Authors
  1. H. S. Hochster
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  2. N. Uboha
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  3. W. Messersmith
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  4. P. J. Gold
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  5. B. H. ONeil
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  6. D. Cohen
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  7. C. Denlinger
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  8. S. Cohen
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  9. C. G. Leichman
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  10. L. Leichman
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Corresponding author

Correspondence to H. S. Hochster.

Additional information

For the Academic GI Cancer Consortium (AGICC).

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Hochster, H.S., Uboha, N., Messersmith, W. et al. Phase II study of selumetinib (AZD6244, ARRY-142886) plus irinotecan as second-line therapy in patients with K-RAS mutated colorectal cancer. Cancer Chemother Pharmacol 75, 17–23 (2015). https://doi.org/10.1007/s00280-014-2609-3

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  • DOI: https://doi.org/10.1007/s00280-014-2609-3

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