A phase I open-label study of selinexor with paclitaxel and carboplatin in patients with advanced ovarian or endometrial cancers.

Abstract

PURPOSE:

Selinexor, a selective inhibitor of nuclear export, monotherapy causes nuclear accumulation of tumor-suppressor proteins and has anti-tumor activity in ovarian and endometrial cancers. The safety and tolerability of oral selinexor plus intravenous carboplatin and paclitaxel chemotherapy (selinexor + CP) was evaluated in this population.

PATIENTS AND METHODS:

This phase I, 3 + 3 dose-escalation study assessed 4 selinexor + CP regimens. Patients in cohorts of 3, regardless of disease type, were administered 1 of 4 alternating regimens (selinexor at 30 mg/m2 or 60 mg plus CP at AUC 5 and 175 mg/m2 or 80 mg/m2, respectively) for 6-10 cycles (1 cycle = 21 days), followed by selinexor maintenance. Enrolled patients with ovarian cancer had received 1 prior platinum-based therapy. Patients with endometrial cancer were chemotherapy-naive or had received 1 prior platinum-based therapy. Response was evaluated every 9 weeks.

RESULTS:

Twenty-three patients were treated (5 serous ovarian cancer; 18 endometrial cancer, including 6 carcinosarcomas). The most common treatment-related adverse events (TRAEs) were thrombocytopenia (100%), leukopenia (91%), and hyperglycemia (87%). The most common grade 3/4 TRAEs were leukopenia (70%), neutropenia (70%), lymphopenia (61%), anemia (57%), and alanine transaminase increase (43%). One treatment-related dose-limiting toxicity (grade 3 syncope) occurred. Twelve patients achieved a partial response and 1 achieved a complete response. Responses to all four regimens were observed in ovarian and endometrial cancers.

CONCLUSIONS:

Combination selinexor + CP was safe and tolerated in advanced ovarian and endometrial cancers.

• Authors: Maria M Rubinstein, Rachel N Grisham, Karen Cadoo, Chrisann Kyi, William P Tew, Claire F Friedman, Roisin E O'Cearbhaill, Dmitriy Zamarin, Qin Zhou, Alexia Iasonos, Ines Nikolovski, Hongmei Xu, Krysten N Soldan, Imogen Caird, Madhuri Martin, Joyce Guillen, Khalil T Eid, Carol Aghajanian, Vicky Makker
• Journal: Gynecologic oncology (Gynecol Oncol) Vol. 160 Issue 1 Pg. 71-76 (01 2021) ISSN: 1095-6859 [Electronic] United States
• PMID: 33139041 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2020 Elsevier Inc. All rights reserved.

Chemical References

• Hydrazines
• Karyopherins
• Receptors, Cytoplasmic and Nuclear
• Triazoles
• selinexor
• Carboplatin
• Paclitaxel

Topics

• Adult
• Aged
• Antineoplastic Combined Chemotherapy Protocols (administration & dosage, adverse effects)
• Carboplatin (administration & dosage, adverse effects)
• Dose-Response Relationship, Drug
• Endometrial Neoplasms (drug therapy, metabolism, pathology)
• Female
• Humans
• Hydrazines (administration & dosage, adverse effects, pharmacokinetics)
• Karyopherins (antagonists & inhibitors, metabolism)
• Middle Aged
• Ovarian Neoplasms (drug therapy, metabolism, pathology)
• Paclitaxel (administration & dosage, adverse effects, pharmacokinetics)
• Receptors, Cytoplasmic and Nuclear (antagonists & inhibitors, metabolism)
• Triazoles (administration & dosage, adverse effects, pharmacokinetics)
• Exportin 1 Protein