Radiosensitizer RRx-001 in Combination With Irinotecan and Temozolomide for the Treatment of Pediatric Patients with Recurrent or Progressive Solid and Central Nervous System Cancers

Inclusion Criteria

• Patients must be between >= 1 and < 22 years of age at the time of study enrollment
• Patients must have a body surface area (BSA) of >= 0.4 m^2 at the time of study enrollment
• Patients with recurrent or progressive malignant (World Health Organization [WHO] grade 3 or 4 tumors) primary brain or spinal cord tumors and solid tumors (excluding lymphomas) are eligible for enrollment. Patients must have developed recurrent or progressive disease after or while receiving standard-of-care up-front treatment and must have no available curative therapies. Patients with metastatic disease including leptomeningeal disease are eligible. Tumor pathology is required from either diagnosis or recurrence except in the setting of radiologically-diagnosed diffuse intrinsic pontine glioma (DIPG) or non-germinomatous germ cell tumors diagnosed by elevated serum or cerebral spinal fluid alpha-fetoprotein or beta-human chorionic gonadotropin (HCG) tumor markers. Given the potential chemotherapy re-sensitizing effects of RRx-001, patients previously treated with a regimen including irinotecan and/or temozolomide are eligible. Patients with secondary malignancies are eligible if the patient’s first malignancy has been in remission for at least 5 years from the end of treatment
• Patients may have either measurable or non-measurable disease but evaluable
• Patients must have a Karnofsky score of >= 50% if >16 years old or a Lansky score of >= 50 if =< 16 years old. Patients who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score
• Patients must have fully recovered from the acute treatment-related toxicities (defined as < grade 1) other than organ function of their most recent prior anti-neoplastic therapy prior to study enrollment
• Myelosuppressive chemotherapy * Patients must have received their last dose of known myelosuppressive anti- cancer therapy at least 3 weeks prior to study enrollment or at least 6 weeks prior if treated with a nitrosourea
• Non-myelosuppressive chemotherapy * Patients must have received their last dose of a non-myelosuppressive chemotherapy or targeted agent at least 7 days prior to study enrollment
• Biological agent/monoclonal antibody/immunotherapy * Patients must have received their last dose of a biologic agent >= 7 days prior to study enrollment * For agents that have known adverse event (AE) occurring beyond 7 days after administration, this period must be extended to a minimum of 7 days past the time during which AE are known to occur * Patients must have received their last dose of a monoclonal antibody >= 21 prior to study enrollment. * Patients must have completed immunotherapy (e.g. tumor vaccines or oncolytic viruses) at least 42 days prior to study enrollment
• Autologous stem cell transplant * At least 12 weeks must have elapsed since the last infusion of autologous bone marrow or stem cells prior to study enrollment
• Radiotherapy (XRT) * Patients must have had their last fraction of craniospinal XRT or XRT to >= 50% of the pelvis at least 3 months prior to study enrollment * Patients must have had their last fraction of focal or whole brain XRT or of radiopharmaceutical therapy (including 131I-MIBG and radiolabeled antibody) at least 6 weeks prior to study enrollment * Patients must have had their last fraction of focal non-brain XRT at least >= 14 days prior to study enrollment.
• Hematopoietic growth factors * Patients must wait at least 14 days after the last dose of a long-acting growth factor (e.g., pegfilgrastim) or 7 days for short-acting growth factor prior to study enrollment
• Cellular Therapy * Patients must wait >= 42 days after the completion of any type of cellular therapy (e.g., modified T cells, natural killer (NK) cells, dendritic cells, etc.) prior to study enrollment
• Patients must be at least 4 weeks from major surgery including craniotomy or tumor debulking/resection and at least 1 week from stereotactic biopsy prior to study enrollment. Patients must have fully recovered from all acute effects of prior surgical intervention excluding central line placement prior to study enrollment. Patients must have fully recovered from all acute effects of central line placement prior to initiation of study treatment
• Patients with neurological deficits should have deficits that are stable for a minimum of 7 days prior to study enrollment. Patients with seizure disorders may be enrolled if the seizures are well-controlled with a stable seizure frequency and duration for a minimum 7 days
• Patients on chronic systemic steroids must be on a stable or decreasing dose for at least 7 days prior to study enrollment. If used to modify immune adverse events related to prior therapy, >= 14 days must have elapsed since last dose of corticosteroid
• Platelet count >= 75,000/mm^3. Patient must be transfusion independent defined as not receiving platelet transfusions with a 7-day period prior to study enrollment
• Peripheral absolute neutrophil count >= 1000/mm^3
• Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 50 mL/min/1.73 m^2 or a serum creatinine based on age and sex * Age: 1 to < 2 years; Maximum serum creatinine (mg/dL): 0.6 (male); 0.6 (female) * Age: 2 to < 6 years; Maximum serum creatinine (mg/dL): 0.8 (male); 0.8 (female) * Age: 6 to < 10 years; Maximum serum creatinine (mg/dL): 1 (male); 1 (female) * Age: 10 to < 13 years; Maximum serum creatinine (mg/dL): 1.2 (male); 1.2 (female) * Age: 13 to < 16 years; Maximum serum creatinine (mg/dL): 1.5 (male); 1.4 (female) * Age: =< 16 years; Maximum serum creatinine (mg/dL): 1.7 (male); 1.4 (female)
• Conjugated bilirubin =< 1.5 times the institutional laboratory’s upper limit of normal
• Alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3 times the institutional laboratory’s upper limit of normal
• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) =< 3 times the institutional laboratory’s upper limit of normal
• Oxygen saturation as measured by pulse oximetry > 93% on room air
• No evidence of dyspnea at rest
• Left ventricular ejection fraction > 50%
• Patients of child-bearing potential of both genders must utilize contraception including but not limited to hormonal contraception, barrier method, or abstinence for the duration of the study and 28 days after completion of study
• Patients must have a central line in place prior to administration of the first dose of RRx-001. Patients must have fully recovered from all acute effects of central line placement prior to initiation of study treatment
• The patient or parent/legally authorized representative is able to understand the consent and is willing to sign a written informed consent document according to institutional guidelines. Assent, when appropriate, will be obtained according to institutional guidelines
• Patients must be able to safely take oral medications either as liquid or tablet

Exclusion Criteria

• Pregnant or breast feeding are excluded from study enrollment as there is no available clinical information regarding human fetal or teratogenic toxicities. Pregnancy tests must be obtained in girls and young women who are post-menarchal prior to study enrollment
• Patients with the following conditions will be excluded from study enrollment: cyanotic heart disease, intermediate or severe beta-thalassemia, known G6PD deficiency, active infections, concurrent malignancy, a known thrombophilia syndrome, or a personal history of venous thromboembolism including catheter-associated thrombi. Additionally, patients with clinically significant or poorly controlled cardiac, pulmonary, hepatic, or other organ dysfunction that, in the opinion of the investigator, would compromise the patient’s ability to tolerate protocol therapy, put them at additional risk for toxicity, or interfere with the study procedures or results are not eligible for study enrollment. Patients with a known coagulopathy or bleeding diathesis or who have undergone either a solid organ or allogeneic bone marrow/stem cell transplant are not eligible for study enrollment
• Patients taking concurrent anti-cancer or investigational drug therapies are not eligible for study enrollment
• Patients taking anti-oxidants including alpha lipoic acid, vitamin E, N- acetylcysteine, and omega 3 fatty acid supplements are not eligible for study enrollment. Patients must be off these drugs for a minimum of 7 days prior to study enrollment and must remain off anti-oxidant medications for the duration of study treatment
• While on study, concomitant use of clozapine, echinacea, leflunomide, natalizumab, and tofacitinib are prohibited due to potential for increased temozolomide toxicity
• Patients who have received drugs that are strong inducers of CYP3A4 within 14 days prior to study enrollment are not eligible. While on study, concomitant use of the following medications is prohibited due to potential for increased irinotecan toxicity * CYP3A4 inducers, including armodafinil, barbiturates, bosentan, carbamazepine, deferasirox, echinacea, efavirenz, etravirine, fosphenytoin, modafinil, nafcilin, nevirapine, oxcarbazepine, phenobarbital, phenytoin, pioglitazone, primidone, rifabutin, riframpin, rifapentin, ritonavir, St. John’s wort, and topiramate * Strong CYP3A4 inhibitors, including atazanavir, boceprevir, clarithromycin, cobicistat, carunavir, delavirdine, grapefruit and grapefruit juice, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, suboxone, telaprevir, telithromycin, and voriconazole * UGT1A1 inhibitors, including atazanavir, diclofenac, ketoconazole, nilotinib, probenecid, silibinin, and tacrolimus
• Patients who in the opinion of the investigator are unwilling or unable to return for required follow-up visits or obtain follow-up studies required to assess toxicity to therapy or to adhere to drug administration plan, other study procedures, and study restrictions are not eligible for study enrollment