Abstract OT2-04-06: A phase I study of pembrolizumab combined with ruxolitinib in triple negative breast cancer (TNBC)
Authors: Almquist Daniel 
Published: March 2020

Abstract
Background: Recent data from the Impassion130 trial has shown the clinical benefit of PD-1/PD-L1 checkpoint blockade immunotherapy, in combination with chemotherapy, for the treatment of metastatic PD-L1 positive TNBC. The PD-1 inhibitor pembrolizumab has also been evaluated in multiple phase I and phase II clinical trials in advanced TNBC, and is associated with an improved rate of pathologic complete response with chemotherapy in the neoadjuvant I-SPY2 trial. A subset of TNBC cancers have high level amplification of chromosome 9p24.1, which encodes JAK2, PD-L1, and PD-L2 (the PDJ amplicon) which is associated with poor prognosis. The presence of the PDJ amplicon in TNBCand is associated with elevated RNA expression of JAK2 and of PD-L1 and sensitivity of PD-L1 expression to IFN-γ in vitro. It has been demonstrated that amplificationAmplification of PD-L1 showed larger tumors andis associated with higher incidence of lymph node metastasis and poor overall survival. These data suggest that there is a subset of patients with TNBC tumors that have coordinate overexpression of JAK2, PD-L1, and PD-L2, so that combination blockade of these pathways warrants evaluation in the clinical setting.
Trial Design: This is a single arm dose-escalation trial for stage IV TNBC patients who have progressed after at least one chemotherapy regimen in the metastatic setting. Monitoring of disease response is done with radiological imaging every 2 cycles as clinically indicated, per standard of care. Pembrolizumab is given IV on day 1 of each 21 day cycle. Ruxolitinib is given at the starting dose of 5 mg po BID daily, escalating to 20 mg po BID daily with subsequent dose levels.
Eligibility Criteria: Clinical stage IV ER-/PR- and HER2 negative patients (TNBC) who have progressed after at least one chemotherapy regimen in the metastatic setting. Patients must have a good performance status at the start of study. Patients also must have adequate hematologic and organ function, and have recovered from the acute effects from prior treatments. Tumor expression of PD-L1 by IHC and 9p24.1 gene amplification are measured but are not required for eligibility.
Specific Aims: The primary goal is to determine the maximum tolerated dose (MTD) of ruxolitinib in combination with fixed dosing of pembrolizumab in patients with advanced/metastatic TNBC. The secondary objectives are to describe the safety profile and clinical response of pembrolizumab in combination with ruxolitinib.
Statistical Methods: The phase I study with a target enrollment of up to 21 patients in a standard 3+3 design (3 for each of the first three dose levels and 6 for each of the final two dose levels) plus up to an additional 3 patients that were deemed cancels, ineligible, or replaced for purposes of DLT assessment.
Accrual: To date we have enrolled 8 patients since start of enrollment in January 2018, and the projected enrollment is 18 patients.
Contact information: For more information or to refer a patient, please contact study coordinator, Nicholas R. Schroeder. He can be reached at (480) 342-3089 or via email at schroeder.nicholas@mayo.edu
Citation Format: Daniel Almquist. A phase I study of pembrolizumab combined with ruxolitinib in triple negative breast cancer (TNBC) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr OT2-04-06.