The purpose of this study is to define the dose-limiting toxicities and maximum tolerated dose of the poly ADP-ribose polymerase inhibitor niraparib and escalating doses of temozolomide and/or irinotecan in patients with pre-treated incurable Ewing sarcoma.

Inclusion Criteria:

• Histologically confirmed Ewing sarcoma
• Evidence of Ewing sarcoma translocation by FISH or RT-PCR.
• Must be willing to undergo tumor biopsy at study entry for biologic correlates.
• If patient > 18 years, must be willing to undergo on-treatment tumor biopsy unless medically contra-indicated
• Recurrent or refractory tumors with no known curative treatment options according to the judgment of the investigator.
• Age ≥ 13 years.
• Life expectancy of ≥ 3 months.
• ECOG performance status 0-2.
• Measurable disease on CT or MRI by RECIST 1.1.
• Adequate organ function
• Patients must have received as a minimum a first line chemotherapy regimen consisting of at least 2 of the following agents: doxorubicin, cyclophosphamide, ifosfamide, etoposide.
• Time elapsed from previous therapy must be ≥ 3 weeks for systemic therapy, ≥ 2 weeks for radiation therapy or major surgery.
• Patients who have undergone autologous hematopoietic stem cell transplantation are eligible once they have recovered from all toxicities from therapy
• Patients who have received allogeneic hematopoietic stem cell transplantation will be eligible 6 months after the procedure provided there is no evidence of active graft-versus-host disease and immunosuppressive treatment has been discontinued for at least 30 days.
• Patients with central nervous system disease are eligible for enrollment if they have received prior radiotherapy or surgery to sites of central nervous system metastatic disease, have been off glucocorticoids for at least 4 weeks, have no overt evidence of neurological deficit and are ≥ 6 weeks from completion of brain irradiation.
• Patients or their legal representative (if the patient is < 18 years old) must be able to read, understand and provide written informed consent to participate in the trial.
• Females of childbearing potential as well as males and their partners must agree to use an effective form of contraception during the study and for 6 months following the last dose of study medication.

Exclusion Criteria:

• Clinically significant unrelated illness which would, in the judgment of the treating physician, compromise the patient's ability to tolerate the investigational agent or be likely to interfere with the study procedures or results.
• Patients with baseline QTc > 480 msec.
• Inability to swallow capsules.
• Known hypersensitivity to any of the components of niraparib or prior hypersensitivity reactions to that class of drugs.
• Known hypersensitivity reaction to temozolomide or any of its components, or dacarbazine (DTIC) if enrolled on ARM 1 or irinotecan or any of its components if enrolled on ARM 2
• Concomitant use of any other investigational or anticancer agent(s).
• Pregnant patients or patients who are breast feeding. Subjects capable of pregnancy (post menarche and not post-menopausal, defined as over 12 months since final menstrual period) must have a negative pregnancy test within 7 days prior to first dose.
• Other clinically significant malignant disease diagnosed within the previous 5 years, excluding intra-epithelial cervical neoplasia or non-melanoma skin cancer.
• Active central nervous system disease.
• Known history of MDS or AML
• Known persistent (> 4 weeks) ≥ Grade 2 neutropenia, ≥ Grade 2 thrombocytopenia or > Grade 3 anemia from prior cancer therapy