Journal Article

Phase I study of JAK1/2 inhibitor ruxolitinib with weekly paclitaxel for the treatment of HER2-negative metastatic breast cancer

Tolaney, Sara M, Chen, Wendy Y, Regan, Meredith M, Williams, James T, Overmoyer Beth, Partridge, Ann H, Mayer, Erica L, Lynce Filipa, Freedman, Rachel A, Winer, Eric P, Bunnell, Craig A

2021

Overview

PurposePreclinical studies support the JAK2–STAT3 signaling pathway as a key driver in CD44+ CD24− “stem-cell-like” breast cancer cells. Ruxolitinib is an orally bioavailable JAK1/2 inhibitor. We aimed to identify the recommended phase 2 dose (RP2D) of ruxolitinib in combination with paclitaxel in patients with HER2-negative metastatic breast cancer (MBC).MethodsEligible patients had HER2-negative MBC and had received ≤ 3 chemotherapy regimens for advanced disease. Patients received oral ruxolitinib (10–25 mg bid) in a 3 + 3 dose escalation design in combination with weekly paclitaxel 80 mg/m2 in a 3-week cycle. The primary objective was to determine the maximum tolerated dose (MTD) and the RP2D.ResultsNineteen patients received protocol therapy (mean age 52 years). Eight (42%) had triple-negative breast cancer and 11 (58%) had hormone receptor-positive disease; 12 (63%) had visceral disease. Ten (53%) patients had not received prior treatment for advanced disease. Patients received a median number of 5 cycles of combination therapy (range 1–12) and five patients continued single-agent ruxolitinib. The MTD of ruxolitinib was 25 mg bid when combined with paclitaxel, and the RP2D for the combination was 15 mg bid. Thirteen (68%) patients required dose reductions or holds. Most frequent toxicities reported of any grade were neutropenia (50%) and anemia (33%). There were no grade 4/5 toxicities attributed to study drug. Four (21%) patients had PR, 12 (63%) had SD and three (16%) had PD as their best response.ConclusionThe combination of ruxolitinib and weekly paclitaxel was well tolerated with evidence of clinical activity. Further analysis of this combination is ongoing (NCT02041429).Trial registrationNCT02041429. Date of registration: January 22, 2014.

• Publisher: Springer Nature B.V
• Subject: Breast cancer / Cancer therapies / CD44 antigen / Chemotherapy / Dosage / ErbB-2 protein / Inhibitor drugs / Janus kinase / Janus kinase 2 / Metastases / Metastasis / Neutropenia / Paclitaxel / Patients / Signal transduction / Stat3 protein / Stem cells / Targeted cancer therapy