Phase IB results of the rational combination of selumetinib and cyclosporin A in advanced solid tumors with an expansion cohort in metastatic colorectal cancer

Anuradha Krishnamurthy, Arvind Dasari, Anne M. Noonan, Janice M. Mehnert, Albert C. Lockhart, Stephen Leong, Anna Capasso, Mark N. Stein, Hanna K. Sanoff, James J. Lee, Aaron Hansen, Usha Malhotra, Sarah Rippke, Daniel L. Gustafson, Todd M. Pitts, Kim Ellison, S. Lindsey Davis, Wells A. Messersmith, S. Gail Eckhardt, Christopher H. Lieu

Research output: Contribution to journalArticle

3 Scopus citations

Abstract

MEK inhibition is of interest in cancer drug development, but clinical activity in metastatic colorectal cancer (mCRC) has been limited. Preclinical studies demonstrated Wnt pathway overexpression in KRAS-mutant cell lines resistant to the MEK inhibitor, selumetinib. The combination of selumetinib and cyclosporin A, a noncanonical Wnt pathway modulator, demonstrated antitumor activity in mCRC patient-derived xenografts. To translate these results, we conducted a NCI Cancer Therapy Evaluation Program–approved multicenter phase I/IB trial (NCT02188264) of the combination of selumetinib and cyclosporin A. Patients with advanced solid malignancies were treated with the combination of oral selumetinib and cyclosporin A in the dose escalation phase, followed by an expansion cohort of irinotecan and oxaliplatin-refractory mCRC. The expansion cohort utilized a single-agent selumetinib "run-in" to evaluate FZD2 biomarker upregulation and KRAS-WT and KRAS-MT stratification to identify any potential predictors of efficacy. Twenty and 19 patients were enrolled in dose escalation and expan-

sion phases, respectively. The most common adverse events and grade 3/4 toxicities were rash, hypertension, and edema. Three dose-limiting toxicities (grade 3 hypertension, rash, and increased creatinine) were reported. The MTD was selumetinib 75 mg twice daily and cyclosporin A 2 mg/kg twice daily on a 28-day cycle. KRAS stratification did not identify any differences in response between KRAS-WT and KRAS-MT cancers. Two partial responses, 18 stable disease, and 10 progressive disease responses were observed. Combination selumetinib and cyclosporin A is well tolerated, with evidence of activity in mCRC. Future strategies for concept development include identifying better predictors of efficacy and improved Wnt pathway modulation. Significance: These findings translate preclinical studies combining selumetinib and cyclosporin into a phase I first-in-human clinical trial of such a combination in patients with advanced solid malignancies.

Original languageEnglish (US)
Pages (from-to)5398-5407
Number of pages10
JournalCancer Research
Volume78
Issue number18
DOIs
StatePublished - Sep 15 2018

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Krishnamurthy, A., Dasari, A., Noonan, A. M., Mehnert, J. M., Lockhart, A. C., Leong, S., Capasso, A., Stein, M. N., Sanoff, H. K., Lee, J. J., Hansen, A., Malhotra, U., Rippke, S., Gustafson, D. L., Pitts, T. M., Ellison, K., Davis, S. L., Messersmith, W. A., Eckhardt, S. G., & Lieu, C. H. (2018). Phase IB results of the rational combination of selumetinib and cyclosporin A in advanced solid tumors with an expansion cohort in metastatic colorectal cancer. Cancer Research, 78(18), 5398-5407. https://doi.org/10.1158/0008-5472.CAN-18-0316