Selinexor in combination with weekly paclitaxel in patients with advanced or metastatic solid tumors: Results of an open label, single-center, multiarm phase 1b study.
Authors: Westin Shannon Neville , Fu Siqing , Tsimberidou Apostolia Maria , Piha-Paul Sarina Anne Anne , Akhmedzhanov Fechukwu , Yilmaz Bulent , McQuinn Lacey , Brink Amanda L. , Gong Jing , Leung Cheuk Hong , Lin Heather Y. , Hong David S. , Pant Shubham , Jazaeri Amir A. , Gershenson David Marc , Sood Anil K. , Coleman Robert L. , Shah Jatin J. , Meric-Bernstam Funda , Naing Aung 
Published: June 2021

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Background: Selinexor is a first-in-class novel, oral potent selective inhibitor of nuclear export (SINE) which blocks Exportin-1 (XPO1) leading to nuclear accumulation and activation of tumor suppressor proteins and prevention of translation of proto-oncogenes. Weekly paclitaxel is a standard chemotherapy regimen used in various tumor types. Preclinical models show that selinexor with paclitaxel exerts antitumor activity against multiple solid tumors. Our objective was to determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of selinexor and weekly paclitaxel. Methods: This was an open label, single-center, multi-arm phase 1b study utilizing a “3 + 3” design and a “basket type” expansion. Selinexor (twice weekly orally) and weekly paclitaxel (80mg IV 2 week on, 1 week off) was employed as one of 13 parallel arms. Two dose levels (DL) of selinexor were explored: DL1 selinexor 60mg; DL2 selinexor 80mg. Patients (pts) with advanced or metastatic solid tumors were eligible if they had adequate bone marrow and organ function. There was no limit on prior lines of therapy. Efficacy was evaluated using RECIST 1.1. Progression free survival (PFS) was defined as time from treatment until disease progression or death. Results: Of 35 pts treated, all were evaluable for toxicity, and 31 (88%) were evaluable for response. Pt diagnoses included ovarian (n = 28), breast (n = 4), prostate (n = 2), and cervical (n = 1) cancer. Pts had a median of four prior therapies (range 1-10), and 47% had a prior taxane. All pts with ovarian cancer had platinum resistant/refractory disease; high grade serous histology was most common. There were no DLTs and DL1 was chosen as the RP2D given its long term tolerability. 97% of pts had at least one treatment-emergent adverse event (TEAE) and the most common TEAEs were anemia (74%), nausea (57%), fatigue (51%), leukopenia (51%), neutropenia (49%), thrombocytopenia (46%), and vomiting (31%). The most prevalent grade ≥ 3 TEAE were neutropenia (46%), anemia (31%), leukopenia (17%), and fatigue (9 %). Partial responses (PR) were noted in 4 pts (13%); 10 pts (32%) achieved stable disease for > 4 months for a clinical benefit rate (CBR) of 45%. 16 pts (47%) had prior exposure to a taxane, including 1 pt who achieved PR. Among 24 evaluable pts with ovarian cancer, response rate was 17%, CBR was 58%, and PFS was 6.83 months (95% CI 3.73, not reached (NR)). Median duration of clinical benefit in ovarian cancer was 7.57 months (95% CI: 4.43, NR). Conclusions: Oral selinexor in combination with weekly paclitaxel demonstrated promising clinical activity with manageable toxicity, and further evaluation with once weekly selinexor is warranted. This combination should be considered for further exploration in a randomized study, especially in ovarian malignancies. Clinical trial information: NCT02419495.