Study of Onivyde With Talazoparib or Temozolomide in Children With Recurrent Solid Tumors and Ewing Sarcoma

The phase I portion of this study is designed for children or adolescents and young adults (AYA) with a diagnosis of a solid tumor that has recurred (come back after treatment) or is refractory (never completely went away). The trial will test 2 combinations of therapy and participants will be randomly assigned to either Arm A or Arm B. The purpose of the phase I study is to determine the highest tolerable doses of the combinations of treatment given in each Arm.

In Arm A, children and AYAs with recurrent or refractory solid tumors will receive 2 medications called Onivyde and talazoparib. Onivyde works by damaging the DNA of the cancer cell and talazoparib works by blocking the repair of the DNA once the cancer cell is damaged. By damaging the tumor DNA and blocking the repair, the cancer cells may die. In Arm B, children and AYAs with recurrent or refractory solid tumors will receive 2 medications called Onivyde and temozolomide. Both of these medications work by damaging the DNA of the cancer call which may cause the tumor(s) to die.

Once the highest doses are reached in Arm A and Arm B, then "expansion Arms" will open. An expansion arm treats more children and AYAs with recurrent or refractory solid tumors at the highest doses achieved in the phase I study. The goal of the expansion arms is to see if the tumors go away in children and AYAs with recurrent or refractory solid tumors. There will be 3 "expansion Arms". In Arm A1, children and AYAs with recurrent or refractory solid tumors (excluding Ewing sarcoma) will receive Onivyde and talazoparib. In Arm A2, children and AYAs with recurrent or refractory solid tumors, whose tumors have a problem with repairing DNA (identified by their doctor), will receive Onivyde and talazoparib. In Arm B1, children and AYAs with recurrent or refractory solid tumors (excluding Ewing sarcoma) will receive Onivyde and temozolomide.

Once the highest doses of medications used in Arm A and Arm B are determined, then a phase II study will open for children or young adults with Ewing sarcoma that has recurred or is refractory following treatment received after the initial diagnosis. The trial will test the same 2 combinations of therapy in Arm A and Arm B. In the phase II, a participant with Ewing sarcoma will be randomly assigned to receive the treatment given on either Arm A or Arm B.

ONITT (ONIvyde, Talazoparib, Temozolomide) is a phase I/II study which will evaluate two treatment regimens; nanoliposomal irinotecan (nal-IRN, Onivyde) plus talazoparib (TAL) and Onivyde (ONI) plus temozolomide (TMZ) for the treatment of recurrent or refractory (RR) Ewing sarcoma. A dose finding phase I study will be open to patients with recurrent or refractory solid tumors. Patients will be assigned to receive either ONI plus TAL (Arm A) or ONI plus TMZ (Arm B). Once the recommended phase II doses (RP2D) of Arm A and Arm B are determined, expansion cohorts (A1, B1) will open at the RP2Ds for enrollment of non-Ewing sarcoma solid tumor patients. There will be an additional Arm A expansion cohort (A2) for patients with homologous recombination repair defects. Concurrently, the phase II study will open to patients with RR Ewing sarcoma. In the phase II study, patients with RR Ewing sarcoma will be randomized to receive either ONI plus TAL or ONI plus TMZ. The primary endpoint will be progression-free survival (PFS). PFS of both treatment arms in the phase II study will be compared to one another by using a two-arm non-inferiority design when superiority is expected.

Phase I Primary Objective To determine the recommended phase 2 doses (RP2Ds) of Onivyde combined with talazoparib (Arm A) and Onivyde combined with temozolomide (Arm B) administered to children, adolescents and young adults with refractory or recurrent solid malignancies.

Phase I Secondary Objectives

* To characterize the safety profile of the drug regimens, Onivyde plus talazoparib (Arm A) and Onivyde plus temozolomide (Arm B).
* To characterize the plasma pharmacokinetics (PK) of Onivyde and talazoparib in children, adolescents and young adults with refractory or recurrent solid malignancies.
* To estimate the antitumor activity of Onivyde plus talazoparib and Onivyde plus temozolomide.

Phase I Exploratory Objectives

* To describe the relationship between UGT1A1 genotype status with toxicity and response.
* To describe the molecular profile of germline and tumors, including evaluation of mutations in homologous recombination genes and their possible association to therapy response in patients with recurrent or refractory solid tumors.
* To measure ctDNA at different time points and evaluate its relationship with response to therapy.
* To describe the safety profile of the combination Onivyde plus talazoparib and Onivyde plus temozolomide at the determined RP2D in children, adolescents and young adults treated in the expansion cohorts.
* To describe the palatability and ease of administration of talazoparib liquid suspension in children who are unable to swallow the capsules.

Phase II Primary Objectives

• To compare the progression-free survival (PFS) of Onivyde plus talazoparib and Onivyde plus temozolomide in patients with refractory or recurrent Ewing sarcoma.

Phase II Secondary Objectives

* To describe the toxicity of the treatment regimens.
* To describe the objective response rate (ORR), disease control rate (DCR) after cycle 4, duration of response (DoR), event free survival (EFS) and overall survival (OS) for patients receiving Onivyde plus talazoparib and Onivyde plus temozolomide.
* To characterize the plasma pharmacokinetics of Onivyde and talazoparib in children, adolescents and young adults with refractory or recurrent Ewing sarcoma.

Phase II Exploratory Objectives

* To describe the relationship between UGT1A1 genotype status with toxicity and response.
* To describe the molecular profile of germline and tumors, including evaluation of mutations in homologous recombination genes and their possible association to chemotherapy response in patients with recurrent or refractory Ewing sarcoma.
* To describe ctDNA at different time points and the relationship with response to therapy.
* To describe the palatability and ease of administration of talazoparib liquid suspension in children who are unable to swallow the capsules.

Phase I The phase I portion of the study will include 2 separate treatment arms, Arms A and B. Arm A will evaluate Onivyde plus talazoparib (ONI + TAL). Arm B will evaluate Onivyde plus temozolomide (ONI + TMZ). Both phase I studies will be open to patients with recurrent or refractory solid tumors who meet eligibility criteria. In Arm A, patients will receive intravenous Onivyde on Days 1 and 8. They will receive oral talazoparib twice on Day 1 and then daily on Days 2-6. In Arm B, patients will receive intravenous Onivyde on Days 1 and 8. They will receive oral temozolomide daily on Days 1-5. Pharmacokinetic testing will take place during Cycle 1. Therapy may continue for up to 24 months. Tumor assessments will be performed at baseline and repeated after cycles 2, 4, 6 and then every 4 cycles thereafter to assess disease status. If at any designated disease evaluation time point a patient develops a response that is better than the prior response (i.e. SD at Cycle 2 evaluation, then PR at Cycle 4 evaluation), an interim disease evaluation is recommended after 28 days to confirm response. Therapy will be discontinued if there is evidence of disease progression or drug-related dose limiting toxicities requiring removal from treatment. Safety and tolerability will be monitored continuously throughout study participation.

Phase II Following the completion of the phase I dose finding studies, patients with recurrent or refractory Ewing sarcoma that meet eligibility criteria will be eligible for randomization into the phase II study. Arm A will evaluate Onivyde plus talazoparib (ONI + TAL). Arm B will evaluate Onivyde plus temozolomide (ONI + TMZ). In Arm A, patients will receive intravenous Onivyde on Days 1 and 8. They will receive oral talazoparib twice on Day 1 and then daily on Days 2-6. In Arm B, patients will receive intravenous Onivyde on Days 1 and 8. They will receive oral temozolomide daily on Days 1-5. Pharmacokinetic testing will take place during Cycle 1. Therapy may continue for up to 24 months. Tumor assessments will be performed at baseline and repeated after Cycles 2, 4, 6 and then every 4 cycles thereafter to assess disease status. If at any designated disease evaluation time point a patient develops a response that is better than the prior response (i.e. SD at Cycle 2 evaluation, then PR at Cycle 4 evaluation), an interim disease evaluation is recommended after 28 days to confirm response. Therapy will be discontinued if there is evidence of disease progression and/or any other condition(s) occur that do not allow treatment continuation or similar toxicities requiring removal from the trial. Safety and tolerability will be monitored continuously throughout study participation.

Sample size: In the dose escalation phase I study, approximately 18 patients per arm will be enrolled for a total of 36 patients. The dose expansion phase I study will include 3 treatment cohorts. Arm A will have 2 dose expansion cohorts including 1) a non-ES solid tumor cohort (A1) and 2) a DNA repair defects/mutations cohort (A2). Arm B will have 1 dose expansion cohort including non-ES solid tumors (B1). Approximately 12 patients will enroll per expansion treatment cohort for a total of 36 patients. In the phase II study, 44 patients will be enrolled on each arm for a total of 88 patients.

Eligibility Criteria:
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-ES patients with refractory or recurrent non-CNS solid tumors with a deleterious alteration in germline or somatic genes involved in HR repair and DSBs signaling, germline or somatic assessed by prior comprehensive sequencing performed in a 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.

Disease status

* Patients must have either measurable or evaluable disease (see Section 7.0 for definitions). Measurable disease includes soft tissue disease evaluable by cross-sectional imaging (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 OR endpoint.
* Performance level: Karnofsky \> 50% for patients \> 16 years of age and Lansky \> 50% for patients \< 16 years of age. 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.

Prior therapy

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).
* Organ function: Must have adequate organ and bone marrow function as defined by the following parameters:
* Patients with solid tumors not metastatic to bone marrow:
* Peripheral absolute neutrophil count (ANC) \>1,000/mm3 (1x109/L)
* Platelet count \> 75,000/mm3 (75x109/L) (no transfusion within 7 days of enrollment)
* 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.

* Adequate renal function defined as: Creatinine clearance or radioisotope GFR \> 60ml/min/1.73m2 or a serum creatinine maximum based on age/sex: age 6months to \<1 year, creatinine 0.4; 1 to \< 2 years, creatinine 0.6; 2 \< 6 years, creatinine 0.8; 6 \< 10 years, creatinine 1; 10 to \<13 years, creatinine 1.2; 13 to \< 16 years creatinine 1.5 (males) or 1.4 (females); \> 16 years, creatinine 1.7 (males) 1.4 (females)
* Adequate liver function defined as: normal liver function as defined by SGPT (ALT) concentration \<5x the institutional ULN, a total bilirubin concentration \<2x the institutional ULN for age, and serum albumin \> 2g/dL.
* Adequate pulmonary function defined as 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 RT, 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.

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).