A Phase II Study of the PARP Inhibitor Olaparib in Combination with the DNA Damaging Agent Temozolomide for the Treatment of Advanced Uterine Leiomyosarcoma
Uterine leiomyosarcoma (uLMS) is a clinically aggressive subtype of soft tissue sarcoma. Advanced uLMS is treated with chemotherapy; however, clinical outcomes remain poor. Recent whole exome and RNA sequencing studies suggest uLMS harbors characteristic defects in the homologous recombination (HR) DNA damage repair pathway (features of “BRCAness”) which may imply susceptibility to novel targeted treatment approaches. Accordingly, preclinical studies from our laboratory demonstrated marked efficacy for combination treatment with the alkylating agent temozolomide (T) and the PARP inhibitor olaparib (O) which potentiates DNA damage and apoptosis, and markedly suppresses proliferation, in uLMS models. We successfully proposed a 22 patient open-label single-arm study of T + O in uLMS to the NCI’s Cancer Therapy Evaluation Program (PI: Matthew Ingham, NCI Protocol #10250) which is currently in development with plans for activation in mid-2019. Patients with advanced uLMS and progression on at least one prior line of systemic therapy will receive T (75 mg/m2 once daily) + O (200 mg twice daily) for days 1-7 of a 21 day cycle. The primary endpoint is the objective response rate (ORR) and the study design yields 93% power with type 1 error of 6% to detect an improvement in ORR from 10% (null hypothesis; clinically inactive) to 35% (alternative hypothesis; worthy of further study). All patients undergo pre-treatment and on-treatment tumor biopsies. Tissue will be evaluated with several candidate assays for defective HR, including (a) next generation sequencing for alterations in HR genes, (b) expression of Schlafen family member 11 (SLFN11) and (c) RAD51 foci formation. Relationship between defective HR as measured by each assay and clinical benefit from T+O will be evaluated. We will also evaluate specimens for MGMT promoter methylation, a known predictive biomarker for sensitivity to T, and effect of MGMT methylation on clinical benefit from T+O. We will also measure densities of immune cell subsets in the immune microenvironment (iME) in pre- and on-treatment biopsy specimens using quantitative multiplex immunohistochemistry and evaluate whether defects in HR repair and the study treatment are associated with changes in this iME.