Selinexor, an orally bioavailable selective inhibitor of nuclear exporter Exportin-1 (XPO1), was shown to not only lessen DNA damage repair proteins but also potentiate cancer cells to DNA damaged-based therapies in in vivo studies.
This was an open label, single-center, multi-arm phase Ib study utilizing a “3 + 3” design and a “basket type” expansion. Selinexor with carboplatin, irinotecan, doxorubicin and cyclophosphamide (DC), irinotecan with fluorouracil and folinic acid (FOLFIRI), and capecitabine and oxaliplatin (XELOX), were employed as separate parallel arms. Selinexor was dosed at either 40mg QW with XELOX and FOLFIRI, or 60mg QW with irinotecan, and DC. Selinexor was dosed at 60 mg QW or BIW with carboplatin. Patients with advanced solid tumors whose disease was refractory or relapsed following prior systemic therapy or where the addition of selinexor to standard chemotherapy deemed appropriate, were eligible.
Of 19 patients treated in 5 arms, 14 patients were evaluable for response. The most common cancers were breast (n=3), colorectal (n=3) cancers, and 2 each with neuroendocrine, ovarian and pancreas cancers. All patients had at least one treatment emergent adverse events (TEAE) and the most prevalent were thrombocytopenia (84%), leukopenia (84%), nausea (73%), neutropenia (63%), anemia (63%), fatigue (58%), and vomiting (52%). The commonest grade (G) ≥ 3 TEAE were neutropenia (42%), leukopenia (31%), hyponatremia (29%), anemia (26%), thrombocytopenia (25%), and hyponatremia (25%). Three patients had DLT; a patient dosed at selinexor 60mg BIW with DC reported G3 leukopenia and G4 neutropenia whereas others dosed at selinexor 40mg QW with XELOX or FOLFIRI had G3 diarrhea and febrile neutropenia, respectively. No patients achieved partial or complete response (PR/CR) while 7 patients (50%) obtained stable disease (SD). Clinical benefit rate (CR+PR+SD ≥4 months) was 35.7%. Treatment time to progression ranged from 2 to 30 weeks.
Oral selinexor in combination with standard chemotherapies was practical and showed some clinical activity. The RP2D of selinexor was 40 mg once weekly in combination with XELOX or FOLFIRI.
NCT02419495.
The authors.
Karyopharm.
All authors have declared no conflicts of interest.