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.

Potential drug repurposing of ruxolitinib to inhibit the JAK/STAT pathway for the treatment of patients with epithelial ovarian cancer

“…A phase I/II randomized clinical trial (NCT02713386) recently investigated combination therapy of ruxolitinib phosphate with paclitaxel and carboplatin in patients with epithelial ovarian, fallopian tube, or primary peritoneal cancers 134 . This trial demonstrated that ruxolitinib was well tolerated and that prolongation of PFS was achieved, hence, further study is warranted 135 …”

“…134 This trial demonstrated that ruxolitinib was well tolerated and that prolongation of PFS was achieved, hence, further study is warranted. 135 All these preclinical and clinical data have provided justification for repurposing ruxolitinib in the OC setting. Thus, other clinical studies and further research to confirm or contradict the potentials of ruxolitinib treatment in patients with EOC are eagerly awaited.…”

The Role of Cancer Stem Cell Markers in Ovarian Cancer

“…The NCT01579812 clinical trial assessed the impact of metformin as an anticancer agent [114]. The obtained results indicated a reduction in ALDH+ CD133+ CSCs and increased sensitivity to cisplatin ex vivo, which translated into a better-than-expected overall survival of patients receiving metformin, confirming the efficacy of the drug in various treatment combinations [115].…”

Enhanced amphiregulin exposure promotes modulation of the high grade serous ovarian cancer tumor immune microenvironment

“…Moreover, there has been vested clinical interest in targeting the STAT3 pathway with small molecule inhibitors ( Song et al, 2023 ). Intriguingly, ruxolitinib, a JAK/STAT inhibitor, which is known to inhibit pSTAT3 in ovarian cancer cells ( Han et al, 2018 ), was recently evaluated in a phase I/II clinical trial in combination with frontline carboplatin and paclitaxel chemotherapy (NRG-GY007, NCT02713386) ( Landen et al, 2022 ). Despite the fact that the addition of ruxolitinib was narrowly insignificant, this study demonstrated feasibility and acceptable toxicity and has opened the door for additional combination approaches including ruxolitinib in ovarian cancer in the frontline setting.…”