Abstract OT2-6-05: Phase I/II trial of ruxolitinib in combination with trastuzumab in metastatic HER2 positive breast cancer

Abstract

Abstract Background Integrated analysis of whole genome RNAi screening with computationally reverse engineered interactome models identified IL6/JAK/STAT as a master regulator pathway essential for growth of ErbB2/HER2 positive breast cancer. Ruxolitinib (R), FDA-approved treatment for myelofibrosis, inhibits JAK1 and JAK2. The combination of R plus Trastuzumab (T) is synergistic in tumor growth inhibition in mouse xenografts of HER2 amplified breast cancer cell lines. These data provide a strong rationale for studying the efficacy of combination R and T in a clinical trial. Trial Design A multi-center, open-label, phase I/II (P1/2) trial of R plus T in HER2+ metastatic breast cancer (MBC) who have progressed on T-based therapy. P1 will be a dose-escalation study with a 3 + 3 design to determine maximum tolerable dose (MTD) for the combination. The recommended P2 dose (RP2D) will be used in a non-randomized, open-label P2 trial with 30 evaluable patients (pts). Given the anticipated limited overlapping toxicities, 33 pts are expected for the P1/2 (range: 33-42 pts). The duration of a treatment cycle will be 21 days. R will be taken orally twice a day continuously. The P1 dosing range will be 10-25 mg BID (dose level 0: 20 mg BID). T will be administered on Day 1 of each cycle at standard dosing. Objective Response Rate (ORR) will be assessed by imaging every 9 weeks. Blood samples will be obtained for biomarker analysis, pre-treatment, on-treatment on C1D8, and then every 9 weeks. Pre-treatment biopsies from archival tissue or new biopsy, on treatment biopsy after C1, and upon progression of disease will be discussed with pts with accessible disease. Main Eligibility Criteria: 1. HER2 positive MBC 2. Progression on at least one T-containing regimen in the metastatic setting 3. Measurable or un-measurable disease 4. LVEF >50% 5. No history of prior JAK2 inhibitor 6. No HIV-positive or active infection 7. No concurrent medications that are potent CYP3A4 inhibitor or inducer Specific Aims 1. Primary: P1: MTD of combined R + T. P2: Progression Free Survival (PFS) 2. Secondary: a) Clinical: ORR, clinical benefit rate (CBR), and tolerability. Pts will be stratified by hormone receptor (HR) status to explore differences in efficacy between HR+ and HR-. b) Explore potential predictive tumor and blood-based predictive biomarkers at baseline, on treatment, and progression: (tumor: pSTAT3 expression); serum: IL-6, IL-8, C-reactive protein; circulating tumor cell pSTAT3 expression; and tumor gene expression. Statistical Methods Assuming a historical PFS of 8 weeks with single-agent agent HER2-targeted therapy in HER2+ MBC after progressing on T-based therapy, we predict that pts receiving the combination of R plus T will have a PFS of at least 13 weeks. With a 2-sided alpha of 0.05, we have 80% power to detect a difference with 30 pts. Target Accrual Sample Size: 33-42 pts; projected over 2 years at 4 sites: Columbia, Einstein, Mount Sinai, and Cornell. Contact Kevin Kalinsky/ Matt Maurer kk2693@columbia.edu/mm2058@columbia.edu. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT2-6-05.