A Phase II Clinical Trial Evaluating the Combination of Olaparib and Temozolomide for the Treatment of Advanced Uterine Leiomyosarcoma

This phase II trial studies olaparib and temozolomide in treating patients with uterine leiomyosarcoma (LMS) that may have spread from where it first started to nearby tissue, lymph nodes, or distant parts of the body (advanced), that has spread from where it first started to other places in the body (metastatic) or cannot be removed by surgery (unresectable). PARPs are proteins that help repair DNA mutations. PARP inhibitors, such as olaparib, can keep PARP from working, so tumor cells can't repair themselves, and they may stop growing. Chemotherapy drugs, such as temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving olaparib and temozolomide may work better than giving either drug alone in treating patients with LMS.

PRIMARY OBJECTIVE: I. To evaluate whether combination treatment with temozolomide (TMZ) + olaparib shows preliminary evidence of clinical activity among patients with advanced uterine leiomyosarcoma (LMS) as measured by the confirmed objective response rate (ORR). SECONDARY OBJECTIVES: I. To evaluate the toxicity profile associated with the combination treatment. II. To evaluate the progression free survival (PFS) associated with the combination treatment. III. To evaluate what proportion of uterine LMS tumors exhibit homologous recombination (HR) deficiency as measured by (1) genomic alterations in HR components at baseline and (2) deoxyribonucleic acid (DNA) repair protein RAD51 homolog (RAD51) foci formation at baseline and while on study treatment. IV. To evaluate the feasibility of these assays in human tissue, and to preliminarily evaluate for any association between presence of HR deficiency as measured by each assay and increased clinical benefit from the study treatment. EXPLORATORY OBJECTIVES: I. To evaluate what proportion of uterine LMS tumors exhibit HR deficiency as measured by Schlafen family member number 11(SLFN11) protein expression at baseline. II. To evaluate the feasibility of this assay in human tissue, and to preliminarily evaluate for any association between presence of HR deficiency as measured by this assay and increased clinical benefit from the study treatment. III. To evaluate MGMT protein expression in uterine LMS tumors, and to preliminarily evaluate for any association between MGMT expression and increased clinical benefit from the study treatment. IV. To perform an optional third tissue biopsy in patients who initially benefit from study treatment but later show early evidence of disease progression to evaluate for changes in the status of the RAD51 foci, MGMT, and SLFN11 assays at that time. OUTLINE: Patients receive olaparib orally (PO) twice per day (BID) and temozolomide PO once daily (QD) on days 1-7 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients undergo computed tomography (CT) or magnetic resonance imaging (MRI) throughout the trial and undergo tumor biopsy at screening and on study. After completion of study treatment, patients are followed up every 3 months for 2 years, and then every 6 months until death or withdrawal of consent.