TY - JOUR
T1 - Phase i and Randomized Phase II Study of Ruxolitinib with Frontline Neoadjuvant Therapy in Advanced Ovarian Cancer
T2 - An NRG Oncology Group Study
AU - Landen, Charles N.
AU - Buckanovich, Ronald J.
AU - Sill, Michael W.
AU - Mannel, Robert S.
AU - Walker, Joan L.
AU - Disilvestro, Paul A.
AU - Mathews, Cara A.
AU - Mutch, David G.
AU - Hernandez, Marcia L.
AU - Martin, Lainie P.
AU - Bishop, Erin
AU - Gill, Sarah E.
AU - Gordinier, Mary E.
AU - Burger, Robert A.
AU - Aghajanian, Carol
AU - Liu, Joyce F.
AU - Moore, Kathleen N.
AU - Bookman, Michael A.
N1 - Publisher Copyright:
© American Society of Clinical Oncology.
PY - 2024/7/20
Y1 - 2024/7/20
N2 - PURPOSEThe 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 METHODSPatients 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.RESULTSSeventeen 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).CONCLUSIONRuxolitinib 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.
AB - PURPOSEThe 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 METHODSPatients 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.RESULTSSeventeen 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).CONCLUSIONRuxolitinib 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.
UR - http://www.scopus.com/inward/record.url?scp=85199223815&partnerID=8YFLogxK
U2 - 10.1200/JCO.23.02076
DO - 10.1200/JCO.23.02076
M3 - Article
C2 - 38776484
AN - SCOPUS:85199223815
SN - 0732-183X
VL - 42
SP - 2537
EP - 2545
JO - Journal of Clinical Oncology
JF - Journal of Clinical Oncology
IS - 21
ER -