Abstract OT3-01-06: Phase I/II trial of ruxolitinib in combination with trastuzumab in metastatic HER2 positive breast cancer
Authors: Kalinsky K , Chi D-C , Lee S , Bhardwaj A , Makower D , Cigler T , Crew KD , Hershman DL , Califano A , Silva J , Maurer M 
Published: May 2016

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 an adaptive design with 10 patients, using the time-to-event continual reassessment method. 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, approximately 36 pts (range: 32-40) are expected for the P1/2. 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 C2D1, and then at progression. Pre-treatment biopsies from archival tissue or new biopsy, on treatment biopsy on C2D1, and upon progression of disease will be discussed with pts with accessible disease.
Main Eligibility Criteria:
1. HER2 positive MBC
2. Progression on HER2-directed therapy in metastatic setting, including Pertuzumab and T-DM1
3. Measurable or non-measurable disease
4. LVEF great than 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: 32-40 pts; projected over 2 years at 4 sites: Columbia, Einstein, Mount Sinai, and Cornell. Trial accruing since Fall 2014.
Citation Format: Kalinsky K, Chi D-C, Lee S, Bhardwaj A, Makower D, Cigler T, Crew KD, Hershman DL, Califano A, Silva J, Maurer M. Phase I/II trial of ruxolitinib in combination with trastuzumab in metastatic HER2 positive breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr OT3-01-06.