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

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.

Phase 1b study of mirvetuximab soravtansine, a folate receptor alpha (FRα)-targeting antibody-drug conjugate, in combination with carboplatin and bevacizumab in patients with platinum-sensitive ovarian cancer.

OBJECTIVE: Evaluate the antitumor activity and safety profile of the triplet combination of mirvetuximab soravtansine (MIRV), carboplatin, and bevacizumab in recurrent, platinum-sensitive ovarian cancer. METHODS: Participants with recurrent, platinum-sensitive epithelial ovarian, fallopian tube, or primary peritoneal cancer (1-2 prior lines of therapy) received MIRV (6 mg/kg adjusted ideal body weight), carboplatin (AUC5), and bevacizumab (15 mg/kg) once every 3 weeks. Carboplatin could be discontinued after 6 cycles per investigator discretion; continuation of MIRV+bevacizumab as maintenance therapy was permitted. Eligibility included folate receptor alpha (FRα) expression by immunohistochemistry (≥50% of cells with ≥2+ intensity; PS2+ scoring); prior bevacizumab was allowed. Tumor response, duration of response (DOR), progression-free survival (PFS), and adverse events (AEs) were assessed. RESULTS: Forty-one participants received triplet therapy, with a median of 6, 12, and 13 cycles of carboplatin, MIRV, and bevacizumab, respectively. The confirmed objective response rate was 83% (9 complete and 25 partial responses). The median DOR was 10.9 months; median PFS was 13.5 months. AEs (any grade) occurred as expected, based on each agent's safety profile; most common were diarrhea (83%), nausea (76%), fatigue (73%), thrombocytopenia (71%), and blurred vision (68%). Most cases were mild to moderate (grade ≤2), except for thrombocytopenia, for which most drug-related discontinuations occurred, and neutropenia. CONCLUSIONS: This triplet regimen (MIRV+carboplatin+bevacizumab) was highly active, with a tolerable AE profile in participants with recurrent, platinum-sensitive, FRα-expressing ovarian cancer. Thrombocytopenia was the primary cause of dose modifications. These outcomes compare favorably to historical data reported for platinum-based chemotherapy plus bevacizumab regimens in similar patient populations.