Selinexor in combination with carboplatin and paclitaxel in patients with advanced solid tumors: Results of a single-center, multi-arm phase Ib study

Bettzy A Stephen,Funda Meric-Bernstam,Denái R Milton,Jatin Shah,Apostolia Tsimberidou,Aung Naing,Filip Janku,Rivka Colen,David S Hong,Kyaw Z Thein,Daniel D Karp,Siqing Fu,Brett W Carter,Timothy A Yap,Jing Gong,Sarina A Piha-Paul,Selma Sulovic,Lacey Mcquinn

doi:10.1007/s10637-021-01188-1

Abstract

SummaryBackground. Carboplatin and paclitaxel (CT) is one of the standard chemotherapy regimens used in various tumor types. Preclinical models have suggested that selinexor, a first-in-class oral potent selective inhibitor of nuclear export Exportin-1, and CT exerts antitumor activity in multiple malignancies. Methods. This was a single-center, multi-arm phase Ib study utilizing a “basket type” expansion. CT and selinexor was employed as one of the 13 parallel arms. Advanced relapsed/refractory solid tumors following standard therapy or where the addition of selinexor to standard regimens deemed appropriate, were eligible. Results. Of 13 patients treated, 12 patients were evaluable for response. The most common cancers were breast (n = 4), esophageal (n = 2), ovarian (n = 2) and non-small cell lung cancers (n = 2). All 13 patients had at least one treatment-related adverse events (TRAEs) and the most common were neutropenia (85%), leukopenia (85%), thrombocytopenia (85%), anemia (69%), nausea (54%), vomiting (46%), and fatigue (46%). One patient at 60 mg QW experienced DLT with grade 3 nausea and vomiting lasting 3 days. Unconfirmed partial response (uPR) was observed in 3 patients; one patient each with esophageal, breast, and ovarian cancer. One patient with esophageal adenocarcinoma had confirmed PR, however, was discontinued from the study due to clinical progression. Five patients achieved stable disease (SD). Disease control rate was 8%. Majority of patients (77%), including two patients who had uPR, had prior exposure to carboplatin and/or paclitaxel. Time-to-treatment failure (TTF) ranged from 1 to 153 weeks. Conclusion. The RP2D of selinexor was 60 mg QW in combination with CT. The combination conferred viable clinical activity with durable objective responses which should further be explored in tumor types for which CT is used as standard of care. Trial information. ClinicalTrials.gov Identifier: NCT02419495. Sponsor(s): Karyopharm Therapeutics. (Trial registration: NCT02419495. Registered 14 April 2015, https://clinicaltrials.gov/ct2/show/NCT02419495).

Highlights

IntroductionKnown as exportins, regulate the conveyance of bulky cargo molecules through the nuclear pore
Nuclear export proteins, known as exportins, regulate the conveyance of bulky cargo molecules through the nuclear pore
Emerging data has suggested that tumor cells overexpress Exportin-1 (XPO1), which is the major nuclear export protein in the cell mediating the efflux of tumor suppressor proteins and the methyl-guanine capped mRNA binding protein eIF4E [22, 23]

Summary

Introduction

Known as exportins, regulate the conveyance of bulky cargo molecules through the nuclear pore This is crucial in preserving cellular homeostasis and is paramount in developing as a therapeutic target in cancer drug development [1]. Selective inhibitors of nuclear export (SINE) were developed to modulate this synchrony by selectively blocking XPO1, resulting in intranuclear accumulation and functional activation of TSP. This restores cell cycle checkpoints and halts tumor growth, leading to the selective apoptosis of cancer cells [8,9,10,11,12]

Methods

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Discussion

Conclusion