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 language | English (US) |
|---|---|
| Pages (from-to) | 5398-5407 |
| Number of pages | 10 |
| Journal | Cancer Research |
| Volume | 78 |
| Issue number | 18 |
| DOIs | |
| State | Published - Sep 15 2018 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Oncology
- Cancer Research
Cite this
Phase IB results of the rational combination of selumetinib and cyclosporin A in advanced solid tumors with an expansion cohort in metastatic colorectal cancer. / Krishnamurthy, Anuradha; Dasari, Arvind; Noonan, Anne M.; Mehnert, Janice M.; Lockhart, Albert; Leong, Stephen; Capasso, Anna; Stein, Mark N.; Sanoff, Hanna K.; Lee, James J.; Hansen, Aaron; Malhotra, Usha; Rippke, Sarah; Gustafson, Daniel L.; Pitts, Todd M.; Ellison, Kim; Davis, S. Lindsey; Messersmith, Wells A.; Eckhardt, S. Gail; Lieu, Christopher H.
In: Cancer Research, Vol. 78, No. 18, 15.09.2018, p. 5398-5407.Research output: Contribution to journal › Article
}
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
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.
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.
UR - http://www.scopus.com/inward/record.url?scp=85053200715&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85053200715&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-18-0316
DO - 10.1158/0008-5472.CAN-18-0316
M3 - Article
VL - 78
SP - 5398
EP - 5407
JO - Journal of Cancer Research
JF - Journal of Cancer Research
SN - 0099-7013
IS - 18
ER -