Olaparib and Temozolomide with or without Irinotecan Hydrochloride in Treating Patients with Recurrent or Metastatic Ewing Sarcoma or Rhabdomyosarcoma Previously Treated with Chemotherapy

Inclusion Criteria

• Participant must have histologically confirmed metastatic Ewing sarcoma for Arms 1 and 2, and rhabdomyosarcoma for Arm 3
• The sarcoma must have progressed following at least one standard prior chemotherapy regimen
• Hemoglobin >= 10.0 g/dL (measured within 28 days prior to administration of study treatment)
• Absolute neutrophil count (ANC) >= 1.5 x 10^9/L (measured within 28 days prior to administration of study treatment)
• Platelet count >= 100 x 10^9/L (measured within 28 days prior to administration of study treatment)
• Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) (measured within 28 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 upper limit of normal (unless liver metastases are present in which case it must be =< 5 x ULN) (measured within 28 days prior to administration of study treatment)
• Serum creatinine =< 1.5 x institutional upper limit of normal (ULN) (measured within 28 days prior to administration of study treatment)
• Eastern Cooperative Oncology Group (ECOG) performance status 0-1
• Participant must have a life expectancy >= 16 weeks
• Women of childbearing potential must have a negative urine or serum pregnancy test within 28 days of initial dose of olaparib and temozolomide, and again within 7 days prior to treatment on day 1; if screening occurs within 7 days of day 1, only one pregnancy test is required; postmenopausal is defined as: * Amenorrheic for 1 year or more 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, or surgical sterilization (bilateral oophorectomy or hysterectomy)
• Participant is willing to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up
• Presence of measurable disease: at least one lesion, not previously irradiated, that can be accurately measured at baseline as >= 10 mm in the longest diameter (except lymph nodes which must have short axis >= 15 mm) with computed tomography (CT) or magnetic resonance imaging (MRI) and which is suitable for accurate repeated measurements
• Any participant must obtain prior approval from insurance to reimburse for oral temozolomide for the duration of the study or agree to self-pay for oral temozolomide or obtain institutional commitment from the study site to provide temozolomide
• Participant must have adequate venous or central access for irinotecan administration

Exclusion Criteria

• Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site)
• Participants who have previously enrolled and received study drugs on arm 1 of this study cannot re-enroll onto arm 1 after being removed from this study, but if they were removed from arm 1 for disease progression, they are eligible to re-register onto this study in order to enroll onto arm 2 of this study if they otherwise meet all of the eligibility criteria for this study; all participants who received an investigational product on a clinical trial, including arm 1 of this study, must wait 21 days prior to course 1 day 1 (C1D1) of this study
• Participants receiving any systemic chemotherapy, radiotherapy, or targeted anti-cancer therapy within 2 weeks or 3 half-lives from the last dose prior to study treatment (or a longer period depending on the half-life of the agents used); the patient can receive bisphosphonates or steroids
• Participants are to discontinue the use of the following classes of inhibitors of cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4); patients who are on these drugs are eligible if a washout period of a minimum of 7 days occurs before start of olaparib and temozolomide * Azole antifungals * Macrolide antibiotics * Protease inhibitors
• Persistent clinically significant grade >= 2 toxicities (as per >= CTCAE v4) related to prior cancer therapy
• Participants with a previously documented diagnosis of myelodysplastic syndrome (or any dysplastic leukocyte morphology suggestive of myelodysplastic syndromes [MDS]) or acute myeloid leukemia
• Participants with symptomatic uncontrolled brain metastases; a scan to confirm the absence of brain metastases is not required
• Major surgery within 14 days of starting study treatment and patients must have recovered from any effects of any major surgery
• Participants considered a poor medical risk due to a serious, uncontrolled medical disorder, non-malignant systemic disease or active, uncontrolled infection; examples include, but are not limited to, corrected QT interval (QTc) prolongation > 470 msec, uncontrolled ventricular arrhythmia, recent (within 3 months) myocardial infarction, unstable spinal cord compression (untreated and unstable for at least 28 days prior to study entry), superior vena cava syndrome, extensive bilateral lung disease with less than 20% predicted lung function by diffusion capacity of the lungs for carbon monoxide (DLCO) (lung diffusion capacity testing), or any psychiatric disorder that prohibits obtaining informed consent
• Participants unable to swallow orally administered medication and patients with gastrointestinal disorders likely to interfere with absorption of the study medication
• Pregnant or breast feeding women are excluded; all patients (male and female) must agree to practice a medically acceptable method of contraception; should a woman become pregnant or suspect that she is pregnant while participating in this study, she should inform her treating physician immediately
• Patients who are known to be serologically positive for human immunodeficiency virus (HIV) and are receiving antiviral therapy
• Patients with known active hepatitis B or C
• Patients with a known hypersensitivity to olaparib or any of the excipients of the product
• Patients with uncontrolled seizures
• Patients who need to continue treatment with any prohibited medications
• Patients who have not completed the appropriate washout period for the prohibited medications