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Phase Ib Results of the Rational Combination Of Published OnlineFirst July 24, 2018; DOI: 10.1158/0008-5472.CAN-18-0316 Cancer Translational Science Research 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 Krishnamurthy1, Arvind Dasari2, Anne M. Noonan3, Janice M. Mehnert4, Albert C. Lockhart5, Stephen Leong1, Anna Capasso1, Mark N. Stein4, Hanna K. Sanoff6, James J. Lee7, Aaron Hansen8, Usha Malhotra4, Sarah Rippke1, Daniel L. Gustafson9, Todd M. Pitts1, Kim Ellison1, S. Lindsey Davis1, Wells A. Messersmith1, S. Gail Eckhardt1,10, and Christopher H. Lieu1 Abstract MEK inhibition is of interest in cancer drug development, sion phases, respectively. The most common adverse events but clinical activity in metastatic colorectal cancer (mCRC) has and grade 3/4 toxicities were rash, hypertension, and edema. been limited. Preclinical studies demonstrated Wnt pathway Three dose-limiting toxicities (grade 3 hypertension, rash, overexpression in KRAS-mutant cell lines resistant to the MEK and increased creatinine) were reported. The MTD was inhibitor, selumetinib. The combination of selumetinib selumetinib 75 mg twice daily and cyclosporin A 2 mg/kg and cyclosporin A, a noncanonical Wnt pathway modulator, twice daily on a 28-day cycle. KRAS stratification did not demonstrated antitumor activity in mCRC patient-derived identify any differences in response between KRAS-WT xenografts. To translate these results, we conducted a NCI and KRAS-MT cancers. Two partial responses, 18 stable Cancer Therapy Evaluation Program–approved multicenter disease, and 10 progressive disease responses were observed. phase I/IB trial (NCT02188264) of the combination Combination selumetinib and cyclosporin A is well toler- of selumetinib and cyclosporin A. Patients with advanced ated, with evidence of activity in mCRC. Future strategies solid malignancies were treated with the combination of oral for concept development include identifying better predic- selumetinib and cyclosporinAinthedoseescalation tors of efficacy and improved Wnt pathway modulation. phase, followed by an expansion cohort of irinotecan and oxaliplatin-refractory mCRC. The expansion cohort utilized Significance: These findings translate preclinical studies a single-agent selumetinib "run-in"toevaluateFZD2bio- combining selumetinib and cyclosporin into a phase I first- marker upregulation and KRAS-WT and KRAS-MT stratifica- in-human clinical trial of such a combination in patients with tion to identify any potential predictors of efficacy. Twenty advanced solid malignancies. Cancer Res; 78(18); 5398–407. and 19 patients were enrolled in dose escalation and expan- Ó2018 AACR. Introduction cancer will be diagnosed (2). Approximately, 20% of patients have metastatic or stage IV disease and only 13.9% of patients are Colorectal cancer is the third leading cause of malignancy and alive at 5 years (2). Current treatment options include initial the fourth common cause of cancer-related death worldwide (1). treatment with a 5-flurouracil (5-FU) and leucovorin backbone In the United States, colorectal cancer is the fourth most common accompanied by oxaliplatin or irinotecan. Bevacizumab, a VEGF cancer, and this year, an estimated 140,250 new cases of colorectal inhibitor, is administered along with 5-FU–based therapy and is commonly continued beyond progression. Rat sarcoma (RAS) gene wild-type patients with metastatic colorectal cancer (mCRC) 1University of Colorado, Denver, Colorado. 2MD Anderson Cancer Center, Hous- fi 3 4 have been shown to bene t from mAbs directed against EGFR. ton, Texas. Ohio State University, Columbus, Ohio. Rutgers Cancer Institute of Other agents used in later lines of therapy include regorafenib, a New Jersey, New Brunswick, New Jersey. 5Washington University School of Medicine, St. Louis, Missouri. 6University of North Carolina, Chapel Hill, North multi-kinase inhibitor, and TAS-102, a combination of a thymi- Carolina. 7University of Pittsburgh, Pittsburgh, Pennsylvania. 8Princess Margaret dine-based nucleic acid analogue and a potent thymidine phos- Hospital, Toronto, Canada. 9Colorado State University, Denver, Colorado. phorylase inhibitor. 10University of Texas at Austin Dell Medical School, LIVESTRONG Cancer Despite these therapeutic advances, mCRC is often incurable Institutes, Austin, Texas. with a sobering median survival of 28–30 months (3). There is an Corresponding Author: Christopher H. Lieu, Division of Medical Oncology, unmet need for research and development of new and more University of Colorado Cancer Center, MS 8117, 12801 E 17th Avenue, Room effective therapies. A better understanding of the resistance 8126, Aurora, CO 80045. Phone: 303-724-6390; Fax: 303-724-3889; E-mail: mechanisms to targeted therapy has led to rational combination [email protected] strategies (4). One of the distinctive fundamental capabilities of doi: 10.1158/0008-5472.CAN-18-0316 cancer is the ability to sustain proliferative signaling. The MAPK Ó2018 American Association for Cancer Research. pathway (RAS/RAF/MEK/ERK) is one such proliferation pathway 5398 Cancer Res; 78(18) September 15, 2018 Downloaded from cancerres.aacrjournals.org on October 2, 2021. © 2018 American Association for Cancer Research. Published OnlineFirst July 24, 2018; DOI: 10.1158/0008-5472.CAN-18-0316 MEK and Wnt Inhibition in Metastatic Colorectal Cancer that is frequently dysregulated in cancer through gain-of-function function mutation of adenomatous polyposis coli (APC)isan mutations in the RAS and RAF (rapidly accelerated fibro- early event in the development of colorectal cancer (20). The two sarcoma) proteins. RAS mutations are found in roughly 55% well-known noncanonical or b-catenin–independent pathways þ of colorectal cancers and its downstream effector pathways are the Wnt/Ca2 pathway (Fig. 1B) and the planar cell polarity þ include the MAPK/ERK, the PI3K, and the Ral-GDS pathways. pathway (Fig. 1C). The Wnt/Ca2 pathway also acts through Wnt- MEK is a critical MAPK enzyme in the downstream pathway FZD activation of Dsh. Dsh through PLC activates IP3, which þ þ from RAS and RAF that phosphorylates and activates ERK/ leads to release of intracellular Ca2 , and the Ca2 in turn p-ERK, its only known substrate, which in turn translocates activates CamK11 and a serine/threonine phosphatase, calci- to the nucleus where it activates many transcription factors, neurin. Calcineurin-induced dephosphorylation of NFAT results resulting in growth and proliferation (4–6). Unfortunately, in the translocation of NFAT to the nucleus where it regulates activation of this downstream signaling pathway is associated transcription of genes (Fig. 1B). Preclinical studies of selumetinib- with lack of beneficial responses to EGFR antibody blockade resistant KRAS-MT colorectal cancer cell lines show overexpres- in patients with mutations in these proteins (7, 8). sion of several members of the Wnt pathway including Frizzled Therefore, MEK inhibition has been an attractive therapeutic (FZD). Both gene set enrichment analysis and a synthetic lethal target for cancer treatment and has been tested in clinical trials screen demonstrated that many of the genes involved in the since 2000. The safety, tolerability, and efficacy of MEK inhibition canonical and noncanonical Wnt pathways were upregulated in has been established from numerous studies investigating selu- selumetinib-resistant colorectal cancer cell lines (22). metinib, as well as other MEK inhibitors such as trametinib and Recent studies have shown that cyclosporin A, a calcineurin cobimetinib (9–13). Single-agent activity has been somewhat inhibitor, traditionally used for its immunosuppressive effects, þþ modest except for trametinib, which demonstrated improved inhibits the activity of the noncanonical Wnt/Ca /NFAT sig- median progression-free survival (4.8 vs. 1.5 months, P < naling pathway (23–25). DeGregori and colleagues identified þ 0.001) and 6-month survival rates (81% vs. 67%) in patients the Wnt/Ca2 pathway genes as being synthetically lethal in with advanced BRAF V600E- or V600K-mutated melanoma combination with imatinib in RNAi-based screens and NFAT (10, 14). This lack of convincing clinical activity of single-agent inhibition by cyclosporin A resulted in the sensitization of MEK inhibition could be due to simultaneous dysregulation of leukemia cells to Bcr-Abl inhibition (23). Synergistic antitumor multiple signaling pathways and/or compensatory pathways that effects with the combination of cyclosporin A and selumetinib overcome the effect of MEK inhibitors (5, 6, 15–17). The com- were observed in KRAS-MT colorectal cancer xenografts that bination of MEK inhibitors with other targeted agents or chemo- were known to be resistant to selumetinib monotherapy. These therapy may overcome resistance and thus improve efficacy. xenografts were noted to have increased expression of FZD2 by Selumetinib (AZD6244; ARRY-142886) is an orally active qRT-PCR when treated with selumetinib monotherapy. Given small-molecule MEK inhibitor that has been studied in many the predilection of cyclosporin A to inhibit P-glycoprotein drug clinical trial settings. In the initial phase I study, selumetinib was efflux pumps, the abovementioned preclinical study also mea- found to be well tolerated with a recommended phase II dose sured selumetinib concentrations in plasma, tumor, and liver (RP2D) of 100 mg twice daily (16). Bennouna and colleagues when treated with selumetinib alone and in combination with
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