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

Autor:	Landen CN; Department of Obstetrics and Gynecology, University of Virginia, Charlottesville, VA., Buckanovich RJ; UPMC Hillman Cancer Center and Magee-Womens Research Institute and Foundation, Pittsburgh, PA., Sill MW; Clinical Trials Development Division, NRG Oncology Statistical and Data Center, Roswell Park Comprehensive Cancer Center, Buffalo, NY., Mannel RS; University of Oklahoma Health Sciences, Stephenson Cancer Center, Oklahoma City, OK., Walker JL; University of Oklahoma Health Sciences, Stephenson Cancer Center, Oklahoma City, OK., DiSilvestro PA; Women & Infants Program in Women's Oncology, Providence, RI., Mathews CA; Women & Infants Program in Women's Oncology, Providence, RI., Mutch DG; Gynecologic Oncology, Washington University, St Louis, MO., Hernandez ML; Mercy Clinic Women's Oncology-Whiteside, Springfield, MO., Martin LP; Hospital of the University of Pennsylvania, Abramson Cancer Center, Philadelphia, PA., Bishop E; Froedtert & Medical College of Wisconsin, Milwaukee, WI., Gill SE; Gynecologic Oncology, SJC Oncology Services-Georgia, LLC, Savannah, GA., Gordinier ME; Norton Children's Hospital, Louisville, KY., Burger RA; Hospital of the University of Pennsylvania, Abramson Cancer Center, Philadelphia, PA.; Mersana Therapeutics, Cambridge, MA., Aghajanian C; Department of Medicine, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York, NY., Liu JF; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA., Moore KN; University of Oklahoma Health Sciences, Stephenson Cancer Center, Oklahoma City, OK., Bookman MA; Department of Medical Oncology, Kaiser-Permanente Northern California, San Francisco, CA.
Jazyk:	angličtina
Zdroj:	Journal of clinical oncology : official journal of the American Society of Clinical Oncology [J Clin Oncol] 2024 Jul 20; Vol. 42 (21), pp. 2537-2545. Date of Electronic Publication: 2024 May 22.
DOI:	10.1200/JCO.23.02076
Abstrakt:	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/m 2 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.
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu