Selinexor in combination with weekly paclitaxel in patients with metastatic solid tumors: Results of an open label, single-center, multi-arm phase 1b study with expansion phase in ovarian cancer.

Selinexor is a first-in-class, oral selective inhibitor of nuclear export (SINE) compound which blocks Exportin-1 (XPO1). Our objective was to determine maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of selinexor and weekly paclitaxel. This was an open label, single-center, multi-arm phase 1b study utilizing a "3 + 3" design and a "basket-type" expansion in recurrent solid tumors. Selinexor (60 mg or 80 mg twice weekly orally) and weekly paclitaxel (80 mg IV 2 week on, 1 week off) were one of 13 parallel arms. Efficacy was evaluated using RECIST version 1.1. All 35 patients treated were evaluable for toxicity and 31 (88%) were evaluable for response. Patient diagnoses included platinum-resistant/refractory ovarian (n = 28), breast (n = 4), prostate (n = 2), and cervical (n = 1) cancer. Patients had a median of four prior therapies (range 1-10), and 47% had a prior taxane in the recurrent setting. There were no DLTs and 60 mg was chosen as the RP2D due to long-term tolerability. Ninety-seven percent of patients had at least one treatment-emergent adverse event (TEAE), and the most common grade ≥ 3 TEAE were neutropenia (46%), anemia (31%), and nausea (21%). Among 24 evaluable patients with ovarian cancer, response rate was 17%, CBR was 58%, and median PFS was 6.8 months (95% CI 3.7, not reached (NR)). Oral selinexor in combination with weekly paclitaxel demonstrated promising clinical activity with manageable toxicity. This combination should be considered for further exploration in a randomized study, especially in ovarian malignancies.

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Declaration of Competing Interest Shannon N. Westin receives research support to institution from AstraZeneca, Bayer, Clovis Oncology, Cotinga Pharmaceuticals, GSK, Mereo, Novartis, OncXerna, Roche/Genentech, Zentalis and consulting fees from Agenus, AstraZeneca, Caris, Clovis Oncology, Eisai, EQRX, GSK, ImmunoGen, Lilly, Merck, Mereo, Mersana, Roche/Genentech, Vincerx, and Zentalis; Siqing Fu receives research support to the institution from Abbisko, BeiGene, BioAtla, LLC. Boehringer Ingelheim, Eli Lilly & Co., Exelisis, Green2Bio, Inc., Hookipa Biotech, IMV, Inc., Innovent Biologics, Co., Ltd., K-Group Beta, Lyvgen Biopharm, MacroGenics, Millennium Pharmaceuticals, Nerviano Medical Sciences, NeuPharma, NextCure, Ningbo NewBay Technology Development, Novartis, NovoCure, Parexel International, LLC, PureTech Health, LLC, Sellas Life Sciences Group, Soricimed Biopharma, Inc., SQZ Biotechnologies, Sumitomo Dainippon, Taiho Oncology and NCCN, Treadwell Therapeutics, Turnstone Biologics, Tyligand Bioscience, Ltd., and Vaccibody AS. Apostolia Tsimberidou receives research support to the institution from BI Pharma, IMMATICS, Parker Institute for Cancer Immunotherapy, Agenus, Tempus, Tvardi, Boston Biomedical, Karus Therapeutics, Novacure, Ltd., and consulting fees from Vincerx and Diaccurate; Sarina Piha-Paul receives research support to the institution from AbbVie, Inc., ABM Therapeutics, Inc., Acepodia, Inc., Alkermes, Aminex Therapeutics, Amphivena Therapeutics, Inc., BioMarin Pharmaceutical, Inc., Boehringer Ingelheim, Bristol Myers Squib, Cerulean Pharma, Inc., Chugai Pharmaceutical Co., Ltd., Curis, Inc., Cyclacel Pharmaceuticals, Daiichi Sankyo, Eli Lilly, ENB Therapeutics, Five Prime Therapeutics, F-Star Beta Limited, F-Star Therapeutics, Gene Quantum, Genmab A/S, Gilead Sciences, Inc., GlaxoSmithKline, Helix BioPharma Corp., HiberCell, Inc., Immunomedics, Inc., Incyte Corp., Jacobio Pharmaceuticals Co., Ltd., Lytix Biopharma AS, Medimmune, LLC., Medivation, Inc., Merck Sharp and Dohme Corp., Novartis Pharmaceuticals, Pieris Pharmaceuticals, Inc., Pfizer, Phanes Therapeutics, Principia Biopharma, Inc., Puma Biotechnology, Inc., Purinomia Biotech, Inc., Rapt Therapeutics, Inc., Seattle Genetics, Silverback Therapeutics, Synlogic Therapeutics, Taiho Oncology, Tesaro, Inc., TransThera Bio, ZielBio, Inc., and consulting fees from CRC Oncology; David S. Hong receives research support to the institution from AbbVie, Adaptimmune, Adlai-Nortye, Amgen, Astra-Zeneca, Bayer, Bristol-Myers Squibb, Daiichi-Sankyo, Deciphera, Eisai, Endeavor, Erasca, F. Hoffmann-La Roche, Fate Therapeutics, Genentech, Genmab, Ignyta, Infinity, Kite, Kyowa Kirin, Lilly, LOXO, Merck, Medimmune, Mirati, Mologen, Navier, NCI-CTEP, Novartis, Numab, Pfizer, Pyramid Bio, SeaGen, Takeda,TCR2, Teckro, Turning Point Therapeutics, Verstatem, VM Oncology, travel accommodations/expenses from Bayer, Genmab, AACR, ASCO, SITC, Telperian, consulting fees from Adaptimmune, Alpha Insights, Acuta, Alkermes, Amgen, Aumbiosciences, Axiom, Baxter, Bayer, Boxer Capital, BridgeBio, COR2ed, COG, Ecor1, Genentech, Gilead, GLG, Group H, Guidepoint, HCW Precision, Immunogen, Infinity, Janssen, Liberium, Medscape, Numab, Oncologia Brasil, Pfizer, Pharma Intelligence, POET Congress, Prime Oncology, Seattle Genetics, ST Cube, Takeda, Tavistock, Trieza Therapeutics, Turning Point, WebMD, Ziopharm and other ownership interests with Molecular Match (Advisor), OncoResponse (Founder, Advisor), Telperian (Founder,Advisor); Shubham Pant receives consulting fees from Merck, GSK, Kiyatec, and has stocks in Bio-Path; Amir Jazaeri receives research support to the institution from Iovance, BMS, Eli Lilly, Pfizer, Ziopharm, AstraZeneca, Aravivie, Merck, Immatics USA, consulting fees from Aravive, Agenus, Macrogenics, BMS, Alkermes, Instill Bio, Immune-Onc, GSK, Obsedian, AvengeBio, NuProbe, EMD-Serono, Guidepoint, Gherson Lehrman Group, participation in a DSMB for Roche, and stock/stock options from AvengeBio. David Gershenson receives research support to the institution from NRG Oncology, Novartis, royalties/licenses from Elsevier, UpToDate, consulting fees from Genentech, payment for lectures from CFS PER Conference, participation in DSMB/advisory board for Onconova, Springworks, leadership role in International Consortium for Low-Grade Serous Cancer, and stock or stock options from Johnson & Johnson, Bristol Myers Squibb, and Procter and Gamble; Anil K. Sood receives research support to institution from M-Trap, royalties/licensure from BioPath, consulting fees from AstraZeneca, Merck, GSK, Kiyatec, and; Robert L. Coleman receives research support to institution from AstraZeneca, Clovis, Genelux, Genmab, Merck, Immunogen Janssen, Roche/Genentech, consulting fees from Agenus, Alkermes, AstraZeneca, Clovis, Deciphera, Genelux, Genmab, GSK, Immunogen Janssen, OncoQuest, Onxeo, Onxerna, Regeneron, Roche/Genentech, and participates in DSMB for VBL Therapeutics; Jatin Shah is employed and receives stock/stock options from Karyopharm; Funda Meric-Bernstam receives research support to the institution from Aileron Therapeutics, Inc. AstraZeneca, Bayer Healthcare Pharmaceutical, Calithera Biosciences Inc., Curis Inc., CytomX Therapeutics Inc., Daiichi Sankyo Co. Ltd., Debiopharm International, eFFECTOR Therapeutics, Genentech Inc., Guardant Health Inc., Klus Pharma, Takeda Pharmaceutical, Novartis, Puma Biotechnology Inc., Taiho Pharmaceutical Co., consulting fees from AbbVie, Aduro BioTech Inc., Alkermes, AstraZeneca, DebioPharm, eFFECTOR Therapeutics, F. Hoffman-La Roche Ltd., Genentech Inc., IBM Watson, Infinity Pharmaceuticals, Jackson Laboratory, Kolon Life Science, Lengo Therapeutics, OrigiMed, PACT Pharma, Parexel International, Pfizer Inc., Samsung Bioepis, Seattle Genetics Inc., Tallac Therapeutics, Tyra Biosciences, Xencor, Zymeworks, payment for lecture from Chugai Biopharmaceuticals, and participation on DSMB/Advisory Board with Black Diamond, Biovica, Eisai, Immunomedics, Inflection Biosciences, Karyopharm Therapeutics, Loxo Oncology, Mersana Therapeutics, OnCusp Therapeutics, Puma Biotechnology Inc., Seattle Genetics, Silverback Therapeutics, Spectrum Pharmaceuticals, and Zentalis; Aung Naing receives research support to institution from NCI, EMD Serono, MedImmune, Healios Onc. Nutrition, Atterocor/Millendo, Amplimmune, ARMO BioSciences, Karyopharm Therapeutics, Incyte, Novartis, Regeneron, Merck, Bristol- Myers Squibb, Pfizer, CytomX Therapeutics, Neon Therapeutics, Calithera Biosciences, TopAlliance Biosciences, Eli Lilly, Kymab, PsiOxus, Arcus Biosciences, NeoImmuneTech, ImmuneOncia, Surface Oncology, Monopteros Therapeutics, BioNTech SE, Seven & Eight Biopharma, SOTIO Biotech AG, Immune Deficiency Foundation, Jeffery Modell Foundation and Chao physician-scientist, Baxalta, consulting fees from ARMO BioSciences, CytomX Therapeutics, Novartis, Genome & Company, OncoSec KEYNOTE-695, Kymab, STCube Pharmaceuticals, Deka Biosciences, Takeda, CSL, Behring, Horizon, and Pharming. All other authors note no relevant conflict of interest.