Overview

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

Status:
Recruiting
Trial end date:
2025-12-31
Target enrollment:
0
Participant gender:
All
Summary
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.
Phase:
Phase 1/Phase 2
Accepts Healthy Volunteers?
No
Details
Lead Sponsor:
St. Jude Children's Research Hospital
Collaborators:
Ipsen
Pfizer
Treatments:
Irinotecan
Talazoparib
Temozolomide
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).