A phase I/II study of ruxolitinib with frontline neoadjuvant and post-surgical therapy in patients with advanced epithelial ovarian, Fallopian tube, or primary peritoneal cancer.

Abstract

5501 Background: The Interleukin-6/JAK/STAT3 axis, via an increase in cancer stem-like cell (CSC) survival, is a reported driver of chemotherapy resistance. We hypothesized that addition of the JAK1/2 inhibitor ruxolitinib to standard chemotherapy would be tolerable and, by targeting therapy-resistant cells, improve the progression-free survival (PFS) of ovarian/fallopian tube/primary peritoneal carcinoma (OV/FT/PPC) patients treated in the up-front setting. Methods: Patients with OV/FT/PPC dispositioned to neoadjuvant chemotherapy were eligible for NRG-GY007 (NCT #02713386). In phase I, treatment was with dose-dense paclitaxel (P) 70 or 80 mg/m2 days 1, 8, and 15; carboplatin (C) AUC 5 or 6 day 1; and ruxolitinib (R) 15mg PO BID, every 21 days. In the absence of tumor progression or an inability to tolerate surgery, interval tumor reductive surgery (TRS) was required after cycle 3. After TRS, 3 additional cycles were administered, followed by maintenance ruxolitinib until progression, unacceptable toxicity, or voluntary withdrawal. In phase II, patients were randomized to dose-dense PC (arm 1) or dose-dense PC plus ruxolitinib (arm 2) at the phase I-defined dose of 15mg PO BID. After 3 cycles, TRS was performed, followed by another 3 cycles of the randomized regimen, without maintenance ruxolitinib. The primary phase II endpoint was progression-free survival (PFS). Results: 17 patients were enrolled in phase I. The MTD was P at 70, C at 5, and R at 15, which was chosen as the phase II dose. 130 patients were enrolled in phase II with a median follow-up of 24 months. There were five Grade 5 events in phase II, 2 in arm 1 and 3 in arm 2, with all except one being unrelated to therapy; a G5 febrile neutropenia in arm 2 was considered possibly related. In arm 2 there was potential trend towards higher grade 3-4 anemia (64% v 27% control), grade 3-4 neutropenia (53% v 37%), thromboembolic events (12.6% v 2.4%), and febrile neutropenia (6% v 0%). The HR for PFS was 0.702 (90% 1-sided CI = 0-0.89, log-rank p = 0.059). The median PFS in arm 1 was 11.6 versus 14.6 in arm 2. The overall survival HR = 0.785 (90% CI = 0.44 to 1.39, p = 0.70). There were no differences between rates of total gross resection. Conclusions: Ruxolitinib 15mg PO BID was well-tolerated with acceptable toxicity in combination with dose-dense PC. The primary endpoint of prolongation of PFS was achieved in the experimental arm. Further study of this combination can be considered. This trial also demonstrates the feasibility of early-phase randomized studies with novel agents and biospecimen collection in front line neoadjuvant treatment of ovarian cancer. Clinical trial information: 02713386.