Onivyde in Combination with Talazoparib or Temozolomide for the Treatment of Recurrent or Refractory Solid Tumors and Ewing Sarcoma

Inclusion Criteria

• Patients must be > 12 months and =< 30 years at the time of enrollment on study
• PHASE I: Patients with refractory or recurrent non-central nervous system (CNS) solid tumors not amenable to curative treatment are eligible. Patients must have had histologic verification of malignancy at original diagnosis or at the time of relapse. Patients eligible for the expansion cohort, A2, will include non-Ewing sarcoma (ES) patients with refractory or recurrent non-CNS solid tumors with a deleterious alteration in germline or somatic genes involved in hormone receptor (HR) repair and double strand breaks (DSBs) signaling, germline or somatic assessed by prior comprehensive sequencing performed in a Clinical Laboratory Improvement Act (CLIA)-approved (or equivalent) facility
• PHASE II: Patients with refractory or recurrent Ewing sarcoma (during or after completion of first-line therapy). Refractory disease is defined as progression during first line treatment or within 12 weeks of completion of first line treatment. Recurrent disease includes patients who received first line treatment and experienced disease progression at any time point > 12 weeks from the completion of first line therapy. Patients must have a histologic diagnosis of Ewing sarcoma with EWSR1- FLI1 translocation or other EWS rearrangement at the time of initial diagnosis. Repeat biopsy at the time of disease recurrence is strongly encouraged but it is not required/mandated for enrollment
• Patients must have either measurable or evaluable disease. Measurable disease includes soft tissue disease evaluable by cross-sectional imaging (Response Evaluation Criteria in Solid Tumors [RECIST]). Patients with bone disease without a measurable soft tissue component or bone marrow disease only are eligible for the phase 1 and phase 2 study but will not be included in the overall response (OR) endpoint
• Karnofsky >= 50% for patients >= 16 years of age and Lansky >= 50% for patients < 16 years of age. Note: 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
• PHASE I: Patients who have received prior therapy with an irinotecan-based or temozolomide-based regimen are eligible. Patients who have received prior therapy with a PARP inhibitor other than talazoparib are eligible
• PHASE II: Patients should have received first line therapy and developed either refractory or recurrent disease (first relapse)
• Patients with solid tumors not metastatic to bone marrow: Peripheral absolute neutrophil count (ANC) >= 1,000/mm^3 (1 x 10^9/L)
• Patients with solid tumors not metastatic to bone marrow: Platelet count >= 75,000/mm^3 (75 x 10^9/L) (no transfusion within 7 days of enrollment)
• Patients with solid tumors not metastatic to bone marrow: Hemoglobin >= 9 g/dL (with or without support)
• In the phase I study, patients with solid tumors metastatic to bone marrow or with bone marrow hypocellularity defined as < 30% cellularity in at least one bone marrow site will be eligible for study, but they will not be evaluable for hematologic toxicity. These patients must not be refractory to red cell or platelet transfusions. At least 2 of every cohort of 3 patients (in the phase I study) must be evaluable for hematologic toxicity. If dose limiting hematologic toxicity is observed at any dose level, all subsequent patients enrolled at that dose level must be evaluable for hematologic toxicity
• Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 60 ml/min/1.73m^2 or a serum creatinine based on age/sex as follows: * 1 month to < 6 months: 0.4 (male); 0.4 (female) * 6 months to < 1 year: 0.5 (male); 0.5 (female) * 1 to < 2 years: 0.6 (male); 0.6 (female) * 2 to < 6 years: 0.8 (male); 0.8 (female) * 6 to < 10 years: 1 (male); 1 (female) * 10 to < 13 years: 1.2 (male); 1.2 (female) * 13 to < 16 years: 1.5 (male); 1.4 (female) * >= 16 years: 1.7 (male); 1.4 (female)
• Serum glutamic pyruvic transaminase (SGPT) (alanine aminotransferase [ALT]) concentration =< 5 x the institutional upper limit of normal (ULN)
• Total bilirubin concentration =< 2 x the institutional ULN for age
• Serum albumin >= 2 g/dL
• No evidence of dyspnea at rest and a pulse oximetry > 94% if there is a clinical indication for determination. Pulmonary function tests are not required
• Patients must have fully recovered from the acute toxic effects of chemotherapy, immunotherapy, surgery, or radiotherapy prior to entering this study: * Myelosuppressive chemotherapy: Patient has not received myelosuppressive chemotherapy within 3 weeks of enrollment onto this study (8 weeks if received prior myeloablative therapy) * Hematopoietic growth factors: At least 7 days must have elapsed since the completion of therapy with a growth factor. At least 14 days must have elapsed after receiving pegfilgrastim * Biologic (anti-neoplastic agent): At least 7 days must have elapsed since completion of therapy with a biologic agent. For agents that have known adverse events occurring beyond 7 days after administration, this period prior to enrollment must be extended beyond the time during which adverse events are known to occur * Monoclonal antibodies: At least 3 half-lives must have elapsed since prior therapy that included a monoclonal antibody or 28 days have elapsed since last dose of the monoclonal antibody with complete resolution of symptoms related to treatment * Radiotherapy: At least 2 weeks must have elapsed since any irradiation; at least 6 weeks must have elapsed since craniospinal radiation therapy (RT), iobenguane I-131 (131I-mIBG) therapy or substantial bone marrow irradiation (e.g., > 50% pelvis irradiation)
• Female participant who is post-menarchal must have a negative urine or serum pregnancy test and must be willing to have additional serum and urine pregnancy tests during the study
• Female or male participant of reproductive potential must agree to use effective contraceptive methods at screening and throughout duration of study treatment
• Written informed consent/assent from the patient and/or parent/legal guardian

Exclusion Criteria

• Pregnant or breastfeeding. Pregnant or breast-feeding women will not be entered on this study. Pregnancy tests must be obtained in girls who are post-menarchal. Males or females of reproductive potential may not participate unless they have agreed to use two methods of birth control: a medically accepted barrier of contraceptive method (e.g., male or female condom) and a second method of birth control during protocol therapy. Two highly effective methods of contraception are required for female patients during treatment and for at least 7 months after completing therapy. Male patients with female partners of reproductive potential and/or pregnant partners are advised to use two highly effective methods of contraception during treatment and for at least 4 months after the final dose
• Male and female participants must agree not to donate sperm or eggs, respectively, after the first dose of study drug through 105 days and 45 days after the last dose of study drug. Females considered not of childbearing potential include those who are surgically sterile (bilateral salpingectomy, bilateral oophorectomy, or hysterectomy)
• Concomitant medications: * Corticosteroids: Patients receiving corticosteroids that have not been on a stable or decreasing dose for at least 7 days prior to enrollment are not eligible * Investigational drugs: Patients cannot receive other investigational drugs while on this study * Anti-graft versus host disease (GVHD) drugs post-transplant: Patients receiving cyclosporine, tacrolimus or other GVHD agents are not eligible * Patients treated within the last 7 days prior to enrollment with strong UGT1A1 inhibitors * Patients treated within the last 7 days prior to enrollment with food or drugs that are known to be strong CYP3A4 inhibitors (e.g., boceprevir, clarithromycin, conivaptan, delavirdine, indinavir, itraconazole, ketoconazole, lopinavir, mibefradil, miconazole, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, voriconazole, and grapefruit or grapefruit juice); * Patients treated within the last 7 days prior to enrollment with drugs that are known to be strong CYP3A4 inducers (i.e., carbamazepine, phenytoin, rifampin, rifapentine, rifabutin, phenobarbital, and St. John’s wort); * Patients treated within the last 7 days prior to enrollment with drugs that are known to be potent P-gp inhibitors (i.e., amiodarone, carvedilol, clarithromycin, cobicistat, dronedarone, erythromycin, glecaprevir/pibrentasvir, indinavir, itraconazole, ketoconazole, lapatinib, lopinavir, propafenone, quinidine, ranolazine, ritonavir, saquinavir, sofosbuvir/velpatasvir/voxilaprevir, telaprevir, tipranavir, valspodar, and verapamil)
• In the phase I study, patients who have previously received talazoparib or onivyde are NOT eligible. Additionally patients who have progressed on a PARP inhibitor plus irinotecan containing regimen are NOT eligible
• In the phase II study, patients who have previously received talazoparib, onivyde, or temozolomide are NOT eligible
• Active, uncontrolled infection
• Prior solid organ transplant
• Prior total body irradiation (TBI)
• Unwilling or unable to comply with the safety monitoring requirements of this protocol
• History of a severe hypersensitivity reaction to irinotecan
• Clinically significant gastrointestinal disorders including hepatic disorders, colitis, or diarrhea > grade 1 at baseline
• Ongoing or history of non-infectious interstitial lung disease requiring significant medical intervention