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A Multicenter Phase I Study Evaluating Dual PI3K and BRAF Inhibition with PX-866

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A Multicenter Phase I Study Evaluating Dual PI3K and BRAF Inhibition with PX-866 Author Manuscript Published OnlineFirst on October 19, 2017; DOI: 10.1158/1078-0432.CCR-17-1807 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 1 1 A multicenter phase I study evaluating dual PI3K and BRAF inhibition with PX-866 2 and vemurafenib in patients with advanced BRAF V600 mutant solid tumors 3 4 Authors: Clinton Yam1,2, Xiaowei Xu1, Michael A. Davies2, Phyllis A. Gimotty3, Jennifer 5 J.D. Morrissette4, Michael T. Tetzlaff2, Khalida M. Wani2, Shujing Liu1, Wanleng Deng2, 6 Meghan Buckley3, Jianhua Zhao4, Ravi K. Amaravadi1, Naomi B. Haas1, Ragini R. 7 Kudchadkar5, Anna C. Pavlick6, Jeffrey A. Sosman7, Hussein Tawbi2,8, Luke Walker9, Lynn 8 M. Schuchter1, Giorgos C. Karakousis1 & Tara C. Gangadhar1 9 10 1) Abramson Cancer Center and the Division of Hematology & Oncology, Perelman School 11 of Medicine, University of Pennsylvania, Philadelphia, PA 12 2) The University of Texas MD Anderson Cancer Center, Houston, TX 13 3) Department of Biostatistics and Epidemiology, Perelman School of Medicine, University 14 of Pennsylvania, Philadelphia, PA 15 4) Center for Personalized Diagnostics, Department of Pathology and Laboratory Medicine, 16 Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 17 5) H. Lee Moffitt Cancer Center, Tampa, FL 18 6) New York University Medical Center, New York. NY 19 7) Vanderbilt-Ingram Cancer Center, Nashville, TN 20 8) The University of Pittsburgh, Pittsburgh, PA 21 9) Cascadian Therapeutics (formerly Oncothyreon) Inc., Seattle, WA 22 23 Running Title: Phase I study of PI3K/BRAF inhibition in BRAF V600 mutant tumors 24 Keywords: PX-866, phase I study, BRAF V600 mutant cancers, PI3K inhibition, melanoma 25 26 Financial support: This work was supported in part by grants from the Melanoma Research 27 Alliance (Young Investigator Award to T.C.G.), the Young Friends of the Abramson Cancer Downloaded from clincancerres.aacrjournals.org on September 27, 2021. © 2017 American Association for Cancer Research. Author Manuscript Published OnlineFirst on October 19, 2017; DOI: 10.1158/1078-0432.CCR-17-1807 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 2 1 Center (Young Investigator Award to T.C.G.), the Melanoma Research Foundation 2 Breakthrough Consortium, the PENN/Wistar Melanoma SPORE (P50 CA174523), the 3 Departments of Medicine at the University of Pennsylvania and the Corporal Michael J. 4 Crescenz VA Medical Center (Frederick F. Samaha Award for Resident Scholarship to C.Y.), 5 the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (M.A.D.) and 6 Cascadian Therapeutics (formerly Oncothyreon), Inc. The MDACC Functional Proteomics 7 Core is supported by NCI CA16672. 8 9 Corresponding author: Tara C. Gangadhar, Abramson Cancer Center and the Division of 10 Hematology & Oncology, Perelman School of Medicine, University of Pennsylvania. Phone: 11 215-662-7908 Fax: 215-662-4646 Email: [email protected] 12 13 Conflicts of interest: M.A.D. has served on the advisory boards for GlaxoSmithKline, 14 Norvatis, Roche/Genentech, Bristol-Myers Squibb, Sanofi-Aventis and Vaccines. M.A.D. has 15 been the principal investigator of grants to MD Anderson Cancer Center from Oncothyreon, 16 GlaxoSmithKline, Roche/Genentech, Merck, Myriad and Sanofi-Aventis. 17 18 Translational relevance word count: 140 words 19 20 Abstract word count: 250 21 22 Text word count: 5678 23 24 Number of tables/figures: 6 25 26 Number of figures: 2 Downloaded from clincancerres.aacrjournals.org on September 27, 2021. © 2017 American Association for Cancer Research. Author Manuscript Published OnlineFirst on October 19, 2017; DOI: 10.1158/1078-0432.CCR-17-1807 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 3 1 STATEMENT OF TRANSLATIONAL RELEVANCE 2 The phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR pathway has been implicated in a 3 variety of solid tumors and has been proposed to be a mechanism of resistance to BRAF 4 inhibition. Combining PI3K inhibitors with BRAF inhibitors therefore represents a rational 5 therapeutic option in patients with BRAF V600 mutated cancers. This article reports data 6 from a phase I study evaluating the novel combination of PX-866, an oral pan-isoform 7 inhibitor of PI3K and vemurafenib, a BRAF inhibitor, demonstrating the safety and feasibility 8 of this combinatorial treatment approach. Furthermore, this study is the first clinical study to 9 demonstrate intra-tumoral changes in pAKT expression and the immune microenvironment in 10 response to PI3K inhibition. In addition, our data also suggests that PTEN loss-of-function at 11 baseline may be associated with improved responses, potentially identifying a subset of 12 patients who would derive greater benefit from dual PI3K and BRAF inhibition. 13 14 ABSTRACT 15 Purpose: The objectives of the study were to evaluate the safety of daily oral PX-866 in 16 combination with twice daily vemurafenib and to identify potential predictive biomarkers for 17 this novel combination. 18 Experimental Design: We conducted a phase I, open-label, dose escalation study in patients 19 with advanced BRAF V600 mutant solid tumors. PX-866 was administered on a continuous 20 schedule in combination with vemurafenib. Patients underwent a baseline and on-treatment 21 biopsy after 1-week of PX-866 monotherapy for biomarker assessment. 22 Results: 24 patients were enrolled. The most common treatment-related adverse events were 23 gastrointestinal side effects. One dose limiting toxicity (DLT) of grade 3 rash and one DLT of 24 grade 3 pancreatitis were observed in cohort 2 (PX-866 6mg daily; vemurafenib 960mg twice 25 daily) and cohort 3 (PX-866 8mg daily; vemurafenib 960mg twice daily), respectively. Of 23 26 response evaluable patients, 7 had confirmed partial responses (PRs), 10 had stable disease 27 and 6 had disease progression. Decreases in intra-tumoral pAKT expression were observed Downloaded from clincancerres.aacrjournals.org on September 27, 2021. © 2017 American Association for Cancer Research. Author Manuscript Published OnlineFirst on October 19, 2017; DOI: 10.1158/1078-0432.CCR-17-1807 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 4 1 following treatment with PX-866. Patients who achieved PRs had higher rates of PTEN loss 2 by immunohistochemistry (80% vs 58%) and pathogenic PTEN mutations and/or deletions 3 (57% vs 25%). Two patients with durable PRs had an increase in intra-tumoral CD8 T-cell 4 infiltration following treatment with PX-866. 5 Conclusion: PX-866 was well tolerated at its maximal tolerated single-agent dose when given 6 in combination with a modified dose of vemurafenib (720mg twice daily). Response to 7 treatment appeared to be associated with PTEN loss and treatment with PX-866 seemed to 8 increase CD8 T-cell infiltration in some patients. 9 10 INTRODUCTION 11 The phosphatidylinositol-3-kinase (PI3K) and AKT signaling pathway has been found to be 12 aberrantly activated in multiple human cancers including melanoma, glioma, colon, non-small 13 cell lung, breast, prostate and head and neck cancers (1-3). Deregulation of the PI3K/AKT 14 pathway, which can cause resistance to BRAF inhibition, may be mediated by several 15 mechanisms in melanoma, including loss of function of the phosphatase and tensin homolog 16 (PTEN) tumor suppressor, upstream growth factor receptor activation or PIK3CA gene 17 mutation and/or amplification (4-10). Dual inhibition of both PI3K and BRAF is a possible 18 strategy to improve the efficacy of targeted therapy for BRAF V600 mutant melanoma. 19 Identification of specific subsets of patients who will benefit from such combinations may 20 help further individualize therapy and improve outcomes in melanoma. 21 22 PX-866 (Cascadian Therapeutics [formerly Oncothyreon], Inc.) is a synthetic wortmannin 23 derivative and a potent, orally available, irreversible pan-isoform PI3K inhibitor (11), with 24 half maximal inhibitory concentration (IC50) values for the PI3K-α, PI3K-β, PI3K-γ and 25 PI3K-δ isoforms being 39 nM, 88nM, 124 nM and 183 nM, respectively (PX-866 26 Investigator’s Brochure V5.0, Cascadian Therapeutics, Inc.). The maximum tolerated dose 27 (MTD) in a single agent phase I dose escalation study on a continuous schedule was 8mg Downloaded from clincancerres.aacrjournals.org on September 27, 2021. © 2017 American Association for Cancer Research. Author Manuscript Published OnlineFirst on October 19, 2017; DOI: 10.1158/1078-0432.CCR-17-1807 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 5 1 daily with pharmacodynamic inhibition of pAKT observed at the MTD and a dose limiting 2 toxicity (DLT) of diarrhea (12) . Other common grade 1 and 2 gastrointestinal adverse events 3 included nausea, vomiting and reversible asparatate aminotransferase (AST) and alanine 4 aminotransferase (ALT) elevation. Subsequent studies further demonstrated the safety and 5 tolerability of PX-866 in combination with other agents including docetaxel (13) and 6 cetuximab (14) in patients with advanced solid tumors. 7 8 The combination of PX-866 and BRAF inhibition demonstrated synergistic inhibition of cell 9 proliferation in melanoma cell lines (15,16). Furthermore, combined targeting of PI3K and 10 mitogen-activated protein kinase (MAPK) pathways in PTEN null melanoma cell lines has 11 been shown to result in enhanced cell killing (17). In addition, synergistic anti-tumor effects 12 have also been observed in pre-clinical xenograft mouse models of melanoma (15). These 13 data suggest that the combination of PI3K inhibition and vemurafenib may improve outcomes 14 in patients with melanoma harboring PTEN deletions or other changes that increase PI3K 15 pathway activation. In addition, tumor profiling of baseline patient biopsies along with 16 comparative analysis of pre-treatment and on-treatment biopsies may help to increase our 17 knowledge of resistance mechanisms to BRAF inhibition and facilitate the interpretation of 18 the clinical effects of PI3K inhibition in combination with BRAF inhibitor therapy.
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