Phase I and Randomized Phase II Study of Ruxolitinib With Frontline Neoadjuvant Therapy in Advanced Ovarian Cancer: An NRG Oncology Group Study

Abstract

Purpose: The interleukin-6/Janus kinase (JAK)/signal transducers and activators of transcription 3 axis is a reported driver of chemotherapy resistance. We hypothesized that adding the JAK1/2 inhibitor ruxolitinib to standard chemotherapy would be tolerable and improve progression-free survival (PFS) in patients with ovarian cancer in the upfront setting.

Materials and methods: Patients with ovarian/fallopian tube/primary peritoneal carcinoma recommended for neoadjuvant chemotherapy were eligible. In phase I, treatment was initiated with dose-dense paclitaxel (P) 70 mg/m² once daily on days 1, 8, and 15; carboplatin AUC 5 intravenously day 1; and ruxolitinib 15 mg orally (PO) twice a day, every 21 days (dose level 1). Interval debulking surgery (IDS) was required after cycle 3. Patients then received three additional cycles of chemotherapy/ruxolitinib, followed by maintenance ruxolitinib. In the randomized phase II, patients were randomly assigned to paclitaxel/carboplatin with or without ruxolitinib at 15 mg PO twice a day for three cycles, IDS, followed by another three cycles of chemotherapy/ruxolitinib, without further maintenance ruxolitinib. The primary phase II end point was PFS.

Results: Seventeen patients were enrolled in phase I. The maximum tolerated dose and recommended phase II dose were established to be dose level 1. One hundred thirty patients were enrolled in phase II with a median follow-up of 24 months. The regimen was well tolerated, with a trend toward higher grade 3 to 4 anemia (64% v 27%), grade 3 to 4 neutropenia (53% v 37%), and thromboembolic events (12.6% v 2.4%) in the experimental arm. In the randomized phase II, the median PFS in the reference arm was 11.6 versus 14.6 in the experimental, hazard ratio (HR) for PFS was 0.702 (log-rank P = .059). The overall survival HR was 0.785 (P = .24).

Conclusion: Ruxolitinib 15 mg PO twice a day was well tolerated with acceptable toxicity in combination with paclitaxel/carboplatin chemotherapy. The primary end point of prolongation of PFS was achieved in the experimental arm, warranting further investigation.

Trial registration: ClinicalTrials.gov NCT02713386.

Figure 1.. Progression-Free Survival in Phase II

In the phase II trial, progression-Free survival of patients receiving paclitaxel/carboplatin/ruxolitinib (PCR, hashed line) compared to paclitaxel/carboplatin alone (PC, solid line) is shown. Tick marks represent the number of months after randomization. The number of patients at risk are presented immediately below. Red line represents the median progression-free survival. Analysis included all patients randomized (intent to treat analysis).

Figure 2.. Overall survival in phase II

In the phase II trial, overall survival of patients receiving paclitaxel/carboplatin/ruxolitinib (PCR, hashed line) compared to paclitaxel/carboplatin alone (PC, solid line) is shown. Tick marks represent the number of months after randomization. The number of patients at risk is presented immediately below. Red line represents the median overall survival. Analysis included all patients randomized. Median overall survival was not reached in the experimental arm.