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 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

2 Citations (Scopus)

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
Externally publishedYes

Fingerprint

Cyclosporine
Colorectal Neoplasms
Wnt Signaling Pathway
Neoplasms
irinotecan
oxaliplatin
Mitogen-Activated Protein Kinase Kinases
Exanthema
Hypertension
AZD 6244
Heterografts
Edema
Creatinine
Up-Regulation
Biomarkers
Clinical Trials
Cell Line
Pharmaceutical Preparations

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 journalArticle

Krishnamurthy, A, Dasari, A, Noonan, AM, Mehnert, JM, Lockhart, A, Leong, S, Capasso, A, Stein, MN, Sanoff, HK, Lee, JJ, Hansen, A, Malhotra, U, Rippke, S, Gustafson, DL, Pitts, TM, Ellison, K, Davis, SL, Messersmith, WA, Eckhardt, SG & Lieu, CH 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, vol. 78, no. 18, pp. 5398-5407. https://doi.org/10.1158/0008-5472.CAN-18-0316
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. / Phase IB results of the rational combination of selumetinib and cyclosporin A in advanced solid tumors with an expansion cohort in metastatic colorectal cancer. In: Cancer Research. 2018 ; Vol. 78, No. 18. pp. 5398-5407.
@article{06f017b2495841bfbb08374362e30541,
title = "Phase IB results of the rational combination of selumetinib and cyclosporin A in advanced solid tumors with an expansion cohort in metastatic colorectal cancer",
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.",
author = "Anuradha Krishnamurthy and Arvind Dasari and Noonan, {Anne M.} and Mehnert, {Janice M.} and Albert Lockhart and Stephen Leong and Anna Capasso and Stein, {Mark N.} and Sanoff, {Hanna K.} and Lee, {James J.} and Aaron Hansen and Usha Malhotra and Sarah Rippke and Gustafson, {Daniel L.} and Pitts, {Todd M.} and Kim Ellison and Davis, {S. Lindsey} and Messersmith, {Wells A.} and Eckhardt, {S. Gail} and Lieu, {Christopher H.}",
year = "2018",
month = "9",
day = "15",
doi = "10.1158/0008-5472.CAN-18-0316",
language = "English (US)",
volume = "78",
pages = "5398--5407",
journal = "Journal of Cancer Research",
issn = "0099-7013",
publisher = "American Association for Cancer Research Inc.",
number = "18",

}

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 -