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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.

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://clinicaltrials.gov/ct2/show/NCT02419495.

SUBMITTER: Thein KZ

PROVIDER: S-EPMC8542012 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundCarboplatin 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.MethodsThis 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.ResultsOf 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.ConclusionThe 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.Clinicaltrialsgov Identifier: NCT02419495. Sponsor(s): Karyopharm Therapeutics. (Trial registration: NCT02419495. Registered 14 April 2015, https://clinicaltrials.gov/ct2/show/NCT02419495 ).

Project description:Purpose Our preclinical work identified depletion of ATR as a top candidate for topoisomerase 1 (TOP1) inhibitor synthetic lethality and showed that ATR inhibition sensitizes tumors to TOP1 inhibitors. We hypothesized that a combination of selective ATR inhibitor M6620 (previously VX-970) and topotecan, a selective TOP1 inhibitor, would be tolerable and active, particularly in tumors with high replicative stress. Patients and Methods This phase I study tested the combination of M6620 and topotecan in 3-week cycles using 3 + 3 dose escalation. The primary end point was the identification of the maximum tolerated dose of the combination. Efficacy and pharmacodynamics were secondary end points. Results Between September 2016 and February 2017, 21 patients enrolled. The combination was well tolerated, which allowed for dose escalation to the highest planned dose level (topotecan 1.25 mg/m2, days 1 to 5; M6620 210 mg/m2, days 2 and 5). One of six patients at this dose level experienced grade 4 thrombocytopenia that required transfusion, a dose-limiting toxicity. Most common treatment-related grade 3 or 4 toxicities were anemia, leukopenia, and neutropenia (19% each); lymphopenia (14%); and thrombocytopenia (10%). Two partial responses (≥ 18 months, ≥ 7 months) and seven stable disease responses ≥ 3 months (median, 9 months; range, 3 to 12 months) were seen. Three of five patients with small-cell lung cancer, all of whom had platinum-refractory disease, had a partial response or prolonged stable disease (10, ≥ 6, and ≥ 7 months). Pharmacodynamic studies showed preliminary evidence of ATR inhibition and enhanced DNA double-stranded breaks in response to the combination. Conclusion To our knowledge, this report is the first of an ATR inhibitor-chemotherapy combination. The maximum dose of topotecan plus M6620 is tolerable. The combination seems particularly active in platinum-refractory small-cell lung cancer, which tends not to respond to topotecan alone. Phase II studies with biomarker evaluation are ongoing.

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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.

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