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

Inclusion Criteria:

   - Patients must have histologically documented LMS of uterine origin. Pathology review
   and confirmation of diagnosis will occur at the site enrolling the patient on this
   study.

   - Patients must have locally advanced and unresectable or metastatic disease.

   - Patients must have disease which is measurable at study entry according to Response
   Evaluation Criteria in Solid Tumors (RECIST) version 1.1 criteria. Additionally,
   patients must have a site of disease deemed accessible for biopsy at no or minimal
   risk to the patient (including through the use of image-guidance). If there are
   questions regarding the feasibility of biopsy, the case should be reviewed with
   interventional radiology or the appropriate department at the study site prior to
   registration.

   - Patients must have had prior progression on, or intolerance to, at least one line of
   systemic therapy for advanced LMS. Adjuvant therapy administered after curative
   resection will not qualify as prior treatment. There is no upper limit on the number
   of prior therapies received.

   - Patients must be >= 18 years of age. Uterine LMS affects older adults and is rarely
   encountered in children and adolescents.

   - Patients must demonstrate an Eastern Cooperative Oncology Group (ECOG) performance
   status (PS) of =< 2 (Karnofsky >= 50%).

   - Absolute neutrophil count >= 1,500/mcL (measured within 14 days prior to
   administration of study treatment).

   - Hemoglobin >= 9 g/dL (without transfusion of packed red blood cells within the past 28
   days) (measured within 14 days prior to administration of study treatment).

   - Platelets >= 100,000/mcL (measured within 14 days prior to administration of study
   treatment).

   - Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) (measured within 14
   days prior to administration of study treatment).

   - Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase
   [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
   =< 2.5 x institutional ULN (measured within 14 days prior to administration of study
   treatment).

   - Glomerular filtration rate (GFR) >= 51 mL/min, based on a 24-hour urine test for
   creatinine clearance or estimated using the Cockcroft-Gault equation (measured within
   14 days prior to administration of study treatment).

   - If patients have evidence of chronic hepatitis B virus (HBV) infection, HBV viral load
   must be undetectable on suppressive therapy if indicated. Patients with a past or
   resolved HBV infection (defined as the presence of hepatitis B core antibody and
   absence of hepatitis B surface antigen [HBsAg]) are eligible.

   - If patients have a history of hepatitis C virus (HCV) infection, they must be treated
   with undetectable HCV viral load (polymerase chain reaction is negative for HCV
   ribonucleic acid [RNA]).

   - Patients must be postmenopausal or have evidence of non-childbearing status, OR, for
   women of childbearing potential, must have a negative urine or serum pregnancy test
   within 28 days of study treatment and confirmed again on day 1 prior to study
   treatment.

      - Postmenopausal is defined as:

         - Amenorrheic for >= 1 year following cessation of exogenous hormonal
         treatments

         - Luteinizing hormone (LH) and follicle stimulating hormone (FSH) levels in
         the postmenopausal range for women under 50

         - Radiation-induced oophorectomy with last menses > 1 year ago

         - Chemotherapy-induced menopause with > 1 year interval since last menses

         - Surgical sterilization (bilateral oophorectomy or hysterectomy).

   - Patients and their partners, if sexually active and of childbearing potential, must
   agree to the use of two highly effective forms of contraception in combination
   throughout the period of taking study treatment and for 3 months after the last dose
   of study drug(s) to prevent pregnancy in the study patient or partner.

   - Patients must be able to swallow orally administered medication.

   - Patients must have a life expectancy >= 16 weeks.

   - Patients must be able to understand and be willing to sign a written informed consent
   document. Patients with impaired decision-making capacity (IDMC) will be eligible if
   they have a close caregiver or legally authorized representative (LAR) available to
   assist them.

   - Patients must be willing and able to comply with the protocol for the duration of the
   study, including undergoing treatment and attending scheduled visits and examinations.

   - Patients with human immunodeficiency virus (HIV) infection may be enrolled on this
   study provided: (a) they are on a stable regimen of highly active anti-retroviral
   therapy (HAART) with no medications otherwise prohibited by this protocol (e.g.
   drug-drug interactions) and (b) require no concurrent antibiotics or antifungals for
   the prevention of opportunistic infections and (c) have a CD4 count above 250 cell/mcL
   and an undetectable viral load on standard polymerase chain reaction (PCR)-based tests
   within 1 month of initiation of study treatment. Other patients with clinically
   significant immunosuppression, e.g. organ transplant patients, are not eligible. If
   clarification is needed, this may be discussed with the medical monitor.

   - Patients must be able to have temozolomide provided as a standard of care medication.

Exclusion Criteria:

   - Patients must not have had any previous treatment with any poly(adenosine
   diphosphate[ADP]-ribose) polymerase (PARP) inhibitors, including olaparib, or prior
   treatment with dacarbazine and/or temozolomide.

   - Patients must have recovered from adverse events due to prior anti-cancer therapy
   (i.e., may not have residual toxicities > grade 1 or above baseline), excluding
   alopecia. Patients who have endocrinopathies associated with prior immunotherapy
   treatment but which are controlled with replacement therapy are eligible.

   - Prior to initiating study treatment, at least 28 days must have elapsed from the last
   dose of systemic anti-cancer treatment (cytotoxic, biologic or immunotherapeutic) or
   radiation therapy (except for palliative radiation, in which case a 14-day washout
   applies).

   - Patients must not have had major surgery within 2 weeks of starting study treatment
   and must have recovered from any effects of any major surgery that occurred > 2 weeks
   before starting study treatment.

   - Patients must not be receiving any other investigational agent.

   - Patients must not have been diagnosed with another malignancy unless curatively
   treated with no evidence of disease for >= 5 years except: adequately treated
   non-melanoma skin cancer, curatively treated in situ cancer of the cervix, ductal
   carcinoma in situ (DCIS), or any other malignant condition considered indolent and
   unlikely to require active therapy.

   - Patients must not have myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) or
   bone marrow biopsy findings consistent with MDS and/or AML.

   - Patients must not have active central nervous system (CNS) or leptomeningeal disease
   at the time of enrollment. Patients with a history of such disease previously treated
   with curative intent (such as with surgery or radiation) that have not progressed on
   subsequent imaging, have been clinically asymptomatic, and have not received systemic
   corticosteroids for at least 28 days, are eligible.

   - Patients must not have a history of allergic reactions attributed to compounds of
   similar chemical or biologic composition to olaparib or TMZ or any of the excipients
   of any study product.

   - Patients must refrain from concomitant use of known strong CYP3A inhibitors (e.g.,
   itraconazole, telithromycin, clarithromycin, protease inhibitors boosted with
   ritonavir or cobicistat, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) or
   moderate CYP3A inhibitors (e.g., ciprofloxacin, erythromycin, diltiazem, fluconazole,
   verapamil). The required washout period for strong or moderate CYP3A inhibitors prior
   to starting olaparib is 2 weeks. Because the lists of these agents are constantly
   changing, it is important to regularly consult a frequently-updated medical reference.
   As part of the enrollment/informed consent procedures, the patient will be counseled
   on the risk of interactions with other agents, and what to do if new medications need
   to be prescribed or if the patient is considering a new over-the-counter medicine or
   herbal product.

   - Patients must refrain from concomitant use of known strong CYP3A inducers (e.g.,
   phenobarbital, enzalutamide, phenytoin, rifampicin, rifabutin, rifapentine,
   carbamazepine, nevirapine and St John's wort) or moderate CYP3A inducers (e.g.,
   bosentan, efavirenz, modafinil). The required washout period for strong or moderate
   CYP3A inducers prior to starting olaparib is 5 weeks for enzalutamide or phenobarbital
   and 3 weeks for other agents.

   - Patients must not have an uncontrolled intercurrent illness including, but not limited
   to, ongoing or active infection, uncontrolled ventricular arrhythmia, recent (within 3
   months) myocardial infarction, uncontrolled major seizure disorder, unstable spinal
   cord compression, superior vena cava syndrome, extensive interstitial bilateral lung
   disease on high resolution computed tomography (HRCT) scan, or psychiatric illness
   that would limit compliance with study requirements.

   - Pregnant women are excluded from this study because olaparib is a PARP inhibitor with
   the potential for teratogenic or abortifacient effects. Because there is an unknown
   but potential risk for adverse events in nursing infants secondary to treatment of the
   mother with olaparib, breastfeeding should be discontinued if the mother is treated
   with olaparib. These potential risks may also apply to other agents used in this
   study.

   - Patients must not have gastrointestinal disorders likely to interfere with absorption
   of the study medication.

   - Patients must not have had involvement in the planning and/or conduct of the study.