Abstract P4-21-37: Phase I trial of ruxolitinib in combination with trastuzumab in metastatic HER2 positive breast cancer
Authors: Mundi PS , Lee S , Chi D , Bhardwaj A , Makower D , Cigler T , Crew KD , Hershman DL , Califano A , Silva J , Kalinsky KM 
Published: May 2019

Abstract
Background
Preclinical and clinical studies suggest that trastuzumab resistance in HER2 amplified breast cancer (HER2+ BC) is mediated by cross-activation of alternative signaling pathways. Computational analysis and pooled whole-genome RNAi screens in HER2 transformed BC cell lines identified the IL6/JAK2/STAT3 axis as a master regulator pathway. The combination of trastuzumab plus ruxolitinib, a JAK1/JAK2 inhibitor, demonstrated synergistic tumor growth inhibition in mouse xenografts of HER2 transformed BC cell lines. These data provide the rationale for studying the efficacy of ruxolitinib and trastuzumab in a clinical trial.
Design
This is a multi-center, open-label, phase I/II trial of ruxolitinib plus trastuzumab in patients (pts) with HER2+ metastatic BC (MBC) who have progressed on &gt;2 HER2-directed therapies in the metastatic setting (including trastuzumab, pertuzumab and T-DM1). The phase I is an adaptive design with 10 pts, using the time-to-event continual reassessment method to determine the recommended phase II dose. Phase II will be a non-randomized, open-label trial with 30 evaluable pts. The duration of a treatment cycle is 21 days, with trastuzumab given on Day 1 and ruxolitinib taken orally twice daily continuously. The primary endpoint of phase I is to determine the maximum tolerated dose of the drug combination. The phase I dose range for ruxolitinib is 10-25 mg BID (dose level 0: 20 mg BID). Response is assessed by imaging every 9 weeks. Blood samples and optional tissue biopsies are obtained for biomarker analysis at the following time points: pre-treatment, on-treatment C2D1, and at progression.
Results
Phase I started accrual in the fall of 2014. The trial has accrued 12 patients, with 9 evaluable and 3 non-evaluable patients. Of the evaluable patients, the mean age was 55.9 (range 32-69). Of these, 7 were postmenopausal (78%) 5/9 (56%) were estrogen receptor positive, and all had measurable disease. The mean number of prior lines of therapy in the metastatic setting was 5.6 (range: 3-8), including a mean of 3.2 (range: 2-5) prior regimens containing HER2 targeted therapies. As of 6/12/16, 2 patients remain on therapy. As this is an adaptive design, efficacy and drug tolerability will not be mentioned in this abstract to not bias the ongoing analysis. However, we anticipate that by SABCS 2016, 10 evaluable patients will have completed the DLT period – at which point, complete data will be presented.
Conclusion
Ruxolitinib plus trastuzumab is a novel, non-chemotherapy containing regimen. The phase I analysis is ongoing. We plan on reporting full safety/tolerability and efficacy data once 10 evaluable patients have completed the phase I (9/10 have currently completed DLT period). Given an early signal in HER2+ breast cancer, in this heavily pretreated population we will proceed directly to a phase II trial with the combination.
Citation Format: Mundi PS, Lee S, Chi D, Bhardwaj A, Makower D, Cigler T, Crew KD, Hershman DL, Califano A, Silva J, Kalinsky KM. Phase I trial of ruxolitinib in combination with trastuzumab in metastatic HER2 positive breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-21-37.