Selinexor in combination with topotecan in patients with advanced or metastatic solid tumors: Results of an open-label, single-center, multi-arm phase Ib study

Kyaw Zin Thein, Sarina A Piha-Paul, Apostolia Tsimberidou, Daniel D Karp, Filip Janku, Abdulrazzak Zarifa, Jatin Shah, Denái R Milton, Stacie Bean, Lacey McQuinn, Jing Gong, Rivka Colen, Brett W Carter, Vivek Subbiah, Deby C Ogbonna, Shubham Pant, Funda Meric-Bernstam, Aung Naing, Kyaw Zin Thein, Sarina A Piha-Paul, Apostolia Tsimberidou, Daniel D Karp, Filip Janku, Abdulrazzak Zarifa, Jatin Shah, Denái R Milton, Stacie Bean, Lacey McQuinn, Jing Gong, Rivka Colen, Brett W Carter, Vivek Subbiah, Deby C Ogbonna, Shubham Pant, Funda Meric-Bernstam, Aung Naing

Abstract

Background Selinexor, a first-in-class, oral selective inhibitor of nuclear export (SINE) compound inhibits Exportin-1(XPO1), had demonstrated synergistic activity with many chemotherapies and conferred in vivo antitumor efficacy in hematologic as well as solid tumors. Methods This open-label, single-center, multi-arm phase 1b study used a standard 3 + 3 design and a "basket type" expansion. Selinexor with intravenous topotecan was given in one of the 13 parallel arms. Patients with advanced or metastatic relapsed/refractory solid tumors following prior systemic therapy, or in whom the addition of selinexor to standard chemotherapy deemed appropriate, were eligible. Results Fourteen patients with the median age of 61 years (range, 22-68years) were treated, and the most common cancer types were gynecological cancers; ovarian (n = 5), endometrial (n = 2), and 1 each with fallopian tube and vaginal cancers. Of the 14 patients treated, 12 (86 %) had at least one treatment-related adverse event (TRAE). The most common TRAEs were anemia (71 %), thrombocytopenia (57 %), hyponatremia (57 %), vomiting (57 %), fatigue (50 %), nausea (50 %), and neutropenia (36 %). Two patients had dose limiting toxicities. One patient dosed at selinexor 80 mg had grade 3 nausea and vomiting and one patient dosed at selinexor 60 mg experienced grade 4 neutropenia and thrombocytopenia. Of the 13 efficacy evaluable patients, one (8 %) with endometrial cancer achieved unconfirmed partial response (uPR) and the time-to-treatment failure (TTF) was 48 weeks, whereas 6 of the 13 (46 %) patients had stable disease (SD) contributing to the clinical benefit rate of 46 %. The median TTF for all patients was 9 weeks (range, 2-48weeks). Conclusions Once weekly selinexor in combination with topotecan was viable and showed some preliminary tumor efficacy. The recommend phase 2 dose of selinexor was 60 mg once weekly in combination with IV topotecan.Trial registration: NCT02419495. Registered 14 April 2015, https://ichgcp.net/clinical-trials-registry/NCT02419495.

Keywords: KPT 330; Metastatic solid tumors; Selective inhibitor of nuclear export (SINE); Selinexor; Topotecan.

Conflict of interest statement

Apostolia-Maria Tsimberidou has the following financial relationships to disclose: Research Funding (Institution): Immatics, Parker Institute for Cancer Immunotherapy, Tempus, OBI Pharma, EMD Serono, Baxalta, ONYX, Bayer, Boston Biomedical, Placon Therapeutics, Karus Therapeutics, and Tvardi Therapeutics. Consulting or Advisory Role: Covance, Genentech and Tempus.

Aung Naing reports research funding from NCI; EMD Serono; MedImmune; Healios Onc. Nutrition; Atterocor; Amplimmune; ARMO BioSciences; Eli Lilly; Karyopharm Therapeutics; Incyte; Novartis; Regeneron; Merck; BMS; Pfizer, CytomX Therapeutics; Neon Therapeutics; Calithera Biosciences; TopAlliance Biosciences; Kymab; PsiOxus; Arcus Biosciences; NeoimmuneTech; ImmuneOncia; Surface Oncology. On advisory board of CytomX Therapeutics; Novartis and Genome & Company; OncoSec KEYNOTE-695; STCube. Travel and accommodation expense from ARMO BioSciences. Spouse Research funding: Immune Deficiency Foundation, Jeffery Modell Foundation and chao physician-scientist, and Baxalta. Advisory board: Takeda, CSL, Behring, Horizon, and Pharming.

Filip Janku reports Grant/Research Funding (Institutional): Novartis, Genentech, BioMed Valley Discoveries, Plexxikon, Deciphera, Piqur, Symphogen, Bayer, FujiFilm Corporation and Upsher-Smith Laboratories, Astex, Asana, Astellas, Agios, Proximagen, Bristol-Myers Squibb. Scientific Advisory Board: Deciphera, IFM Therapeutics, Synlogic, Guardant Health, Ideaya, PureTech Health. Paid Consultant: Trovagene, Immunomet, Jazz Pharmaceuticals, Sotio. Ownership Interests: Trovagene.

Funda Meric-Bernstam reports Consulting: Aduro BioTech Inc., Alkermes, AstraZeneca, DebioPharm, eFFECTOR Therapeutics, F. Hoffman-La Roche Ltd., Genentech Inc., IBM Watson, Jackson Laboratory, Kolon Life Science, OrigiMed, PACT Pharma, Parexel International, Pfizer Inc., Samsung Bioepis, Seattle Genetics Inc., Tyra Biosciences, Xencor, Zymeworks. Advisory Committee:

Immunomedics, Inflection Biosciences, Mersana Therapeutics, Puma Biotechnology Inc., Seattle Genetics, Silverback Therapeutics, Spectrum Pharmaceuticals, Zentalis. Sponsored Research: 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., Millennium Pharmaceuticals Inc., Novartis, Puma Biotechnology Inc., Taiho Pharmaceutical Co. Honoraria: Chugai Biopharmaceuticals, Mayo Clinic, Rutgers Cancer Institute of New Jersey. Other (Travel Related): Beth Israel Deaconess Medical Center.

Sarian A. Piha-Paul receives Research/Grant Funding through the institution from the following sources: 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.; Daiichi Sankyo; Eli Lilly; ENB Therapeutics; Five Prime Therapeutics; Gene Quantum; Genmab A/S; GlaxoSmithKline; Helix BioPharma Corp.; Incyte Corp.; Jacobio Pharmaceuticals Co., Ltd.; Medimmune, LLC.; Medivation, Inc.; Merck Sharp and Dohme Corp.; Novartis Pharmaceuticals; Pieris Pharmaceuticals, Inc.; Pfizer; Principia Biopharma, Inc.; Puma Biotechnology, Inc.; Rapt Therapeutics, Inc.; Seattle Genetics; Silverback Therapeutics; Taiho Oncology; Tesaro, Inc.; TransThera Bio; NCI/NIH; P30CA016672 – Core Grant (CCSG Shared Resources).

Shubham Pant reports Research Funding: Mirati Therapeutics (Inst), Eli Lilly (Inst), RedHill Biopharma (Inst), Xencor (Inst), Five Prime Therapeutics (Inst), Novartis (Inst), Rgenix (Inst), Sanofi (Inst), ArQule (Inst), Bristol Myers Squibb (Inst), Onco Response (Inst), GlaxoSmithKline (Inst), Ipsen. Financial Relationship/ Consultant: Tyme Inc., 4D-Pharma, Xencor, Ipsen.

Vivek Subbiah reports research funding/ Grant support for clinical trials: Roche/ Genentech, Novartis, Bayer, GlaxoSmithKline, Nanocarrier, Vegenics, Celgene, Northwest Biotherapeutics, Berghealth, Incyte, Fujifilm, Pharmamar, D3, Pfizer, Multivir, Amgen, Abbvie, Alfa-sigma, Agensys, Boston Biomedical, Idera Pharma, Inhibrx, Exelixis, Blueprint medicines, Loxo oncology, Medimmune, Altum, Dragonfly. therapeutics, Takeda and, National Comprehensive Cancer Network, NCI-CTEP and UT MD Anderson Cancer Center, Turning point therapeutics, Boston Pharmaceuticals; Travel: Novartis, Pharmamar, ASCO, ESMO, Helsinn, Incyte; Consultancy/ Advisory board: Helsinn, LOXO Oncology/Eli Lilly, R-Pharma US, INCYTE, QED pharma, Medimmune, Novartis. Other: Medscape.

Jatin Shah is an employee of and stockholder of Karyopharm. All remaining authors have declared no conflicts of interest.

None of the authors have any conflict of interest relevant to the subject of this manuscript.

© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.

Figures

Fig. 1
Fig. 1
a Waterfall plot of maximum change in tumor measurements (per RECIST v1.1) for evaluable patients. b Kaplan-Meier plot showing progression free survival (PFS) and overall survival (OS) for all treated patients. Abbreviations: RECIST v1.1, response evaluation criteria in solid tumors version 1.1; PR, partial response; SD, stable disease; PD, progressive disease. *One PD patient had missing values for tumor change

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