TY - JOUR
T1 - Phase IB results of the rational combination of selumetinib and cyclosporin A in advanced solid tumors with an expansion cohort in metastatic colorectal cancer
AU - Krishnamurthy, Anuradha
AU - Dasari, Arvind
AU - Noonan, Anne M.
AU - Mehnert, Janice M.
AU - Lockhart, Albert C.
AU - Leong, Stephen
AU - Capasso, Anna
AU - Stein, Mark N.
AU - Sanoff, Hanna K.
AU - Lee, James J.
AU - Hansen, Aaron
AU - Malhotra, Usha
AU - Rippke, Sarah
AU - Gustafson, Daniel L.
AU - Pitts, Todd M.
AU - Ellison, Kim
AU - Davis, S. Lindsey
AU - Messersmith, Wells A.
AU - Eckhardt, S. Gail
AU - Lieu, Christopher H.
N1 - Funding Information:
This work was supported by grants NIH K23 CA190849-01A1 (to C.H. Lieu), NIH 1UM1CA186688 (to C.H. Lieu, W.A. Messersmith, and S.G. Eckhardt), Conquer Cancer Foundation Career Development Award (to C.H. Lieu), NCI P30 CA047904 for Early Phase Clinical Research Support (to J. J. Lee), and NCI UM1 CA099168 grant (to J. J. Lee).
Funding Information:
M.N Stein is a consultant/advisory board member for Merck Sharp & Dohme. H.K. Sanoff reports receiving a commercial research grant from Bayer and Merck. No potential conflicts of interest were disclosed by the other authors.
PY - 2018/9/15
Y1 - 2018/9/15
N2 - 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.
AB - 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.
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U2 - 10.1158/0008-5472.CAN-18-0316
DO - 10.1158/0008-5472.CAN-18-0316
M3 - Article
C2 - 30042150
AN - SCOPUS:85053200715
VL - 78
SP - 5398
EP - 5407
JO - Cancer Research
JF - Cancer Research
SN - 0008-5472
IS - 18
ER -