Although upfront treatment for ovarian cancer (OC) achieves complete remission in over 70% of women, the majority of patients (pts, 80%) relapse and die from disease. Thus, there is great interest in improving standard of care and exploring maintenance strategies. Immune evasion and suppression is a central feature of the OC microenvironment. Immune abrogation has also been linked to primary and adaptive chemoresistance and angiogenesis. Prolongation of immunocompetence represents a promising intervention to achieve lasting tumor suppression promoting survival. Further, chemotherapy may increase immunogenicity by releasing tumor-specific antigens providing an environment for long-term tumor control. Governance of T cell regulation with immune therapy has been explored in advanced solid tumors. Clinical experience with agents targeting PD-1/PD-L1 in OC is limited but responses have been observed. Durvalumab is a novel PD-L1 inhibitor with activity across a number of different solid tumors in in vitro and in vivo models. As yet, it is unknown which pts stand to benefit the most from this agent.
A total of 30 evaluable pts with untreated, advanced stage OC undergoing neoadjuvant chemotherapy will be treated with paclitaxel, carboplatin and durvalumab, followed by durvalumab maintenance. Pretreatment biopsies will be obtained at laparoscopy or by interventional radiology from up to 4 sites. Interval tumor reductive surgery (TRS) will be performed after 3 cycles. Matched biopsies will be obtained at TRS. The study incorporates a phase I safety lead in (n = 6) to ensure the combination has acceptable toxicity and pts undergo TRS in a timely fashion. Dose-limiting toxicities (DLTs) will be assessed. This will be followed by open enrollment on the phase II portion. The primary objective is to explore basal levels and effects of durvalumab in combination with chemotherapy on molecular markers in immune-related pathways and lymphoid populations including DNA copy number, mutation, RNA/protein expression, PD-L1 expression and T-cell infiltration, before and after treatment. Secondary objectives are progression free survival, overall survival, and patient reported outcomes.
Clinical trial identification
NCT02726997 March 24, 2016
Legal entity responsible for the study
The University of Texas MD Anderson Cancer Center
AstraZeneca, Ovarian Cancer Moonshot, Sabin Family Foundation
S. Westin: Research Support: AstraZeneca, Novartis, Critical Outcomes Technologies, Inc Advisory Board/Consulting: AstraZeneca, Clovis, Roche/Genentech, Ovation, Medivation, Vermillion, Casdin Capital. A. Jazaeri: Research Support: AstraZeneca, Lion Biotech, Pfizer Advisory Board/Consulting: EMD-Serono, Genentech. M. Frumovitz: Research Support: Novadaq; Consulting: Novadaq. P. Soliman: Research support: Novartis. G. Mills: Research Support: Abbvie, Adelson Medical Research Foundation, AstraZeneca, Nanostring, Pfizer, Tesaro Consulting: AstraZeneca, Medimmune, Pfizer Licensed technology HRD assay to Myriad Genetics. A. Vergara-Silva: Employee of AstraZeneca/MedImmune. R. Coleman: Research Support: AstraZeneca, Clovis, Janssen, Abbvie, Merck, Roche/Genentech, Millennium; Advisory Board/Consulting: AstraZeneca, Clovis, Janssen, Abbvie, Merck, Roche/Genentech, Millennium, Tesaro, Novartis, Pfizer, Bayer, Array, Millennium. All other authors have declared no conflicts of interest.