Onivyde + Talazoparib/Temozolomide for Ewing Sarcoma

Recruiting at 9 trial locations

Overseen By Sara Federico, MD

Age: < 65

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: St. Jude Children's Research Hospital

Disqualifiers: Pregnant, Breastfeeding, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 2

46 Participants Needed

Trial Summary

What is the purpose of this trial?

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.

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, there are specific requirements about the time that must pass after certain treatments before joining the study, such as chemotherapy or radiotherapy. It's best to discuss your current medications with the trial team to get a clear answer.

What data supports the effectiveness of the drug combination Onivyde, Talazoparib, and Temozolomide for Ewing Sarcoma?

Research shows that combining talazoparib with temozolomide has been effective in treating Ewing sarcoma in preclinical models, achieving complete responses with minimal toxicity. Additionally, a phase I trial demonstrated the efficacy of talazoparib and irinotecan with or without temozolomide in pediatric patients with recurrent or refractory solid tumors, including Ewing sarcoma. ^{1 2 3 4 5}

Is the combination of Onivyde, Talazoparib, and Temozolomide safe for humans?

Research shows that combining talazoparib with temozolomide can be toxic, but using a special formulation like NanoTLZ can reduce this toxicity. In studies, this combination has been tested in children and young adults with solid tumors, showing some safety when doses are carefully managed. ^{1 2 3 4 6}

What makes the drug combination of Onivyde, Talazoparib, and Temozolomide unique for treating Ewing Sarcoma?

This drug combination is unique because it uses Talazoparib, a PARP inhibitor, with Temozolomide, a DNA-alkylating agent, to potentially overcome drug resistance in Ewing Sarcoma. The use of PEGylated or nanoformulated Talazoparib enhances the therapeutic window, reducing toxicity and allowing higher doses, which is not possible with traditional formulations. ^{1 2 3 4 5}

Research Team

Sara M Federico, MD

Principal Investigator

St. Jude Children's Research Hospital

Eligibility Criteria

This trial is for children and young adults aged between 1 and 30 with recurrent or refractory solid tumors, including Ewing sarcoma. Participants must have measurable disease, be in a certain health condition (Karnofsky >50% or Lansky >50%), have adequate organ function, not be pregnant or breastfeeding, agree to use contraception, and have recovered from previous treatments.

Inclusion Criteria

My cancer can be measured or seen on tests.

My organs and bone marrow are functioning well.

My cancer came back or didn't respond after my first treatment.

Exclusion Criteria

I am using two forms of birth control.

I agree not to donate sperm or eggs for a specified period after taking the study drug.

Pregnant or breastfeeding

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase I Treatment

Participants receive Onivyde plus talazoparib or Onivyde plus temozolomide to determine the recommended phase 2 doses (RP2Ds)

Up to 24 months

Intravenous Onivyde on Days 1 and 8, oral talazoparib or temozolomide on specified days

Phase II Treatment

Participants with Ewing sarcoma receive Onivyde plus talazoparib or Onivyde plus temozolomide to evaluate progression-free survival

Up to 24 months

Intravenous Onivyde on Days 1 and 8, oral talazoparib or temozolomide on specified days

Follow-up

Participants are monitored for safety and effectiveness after treatment

5 years

Treatment Details

Interventions

• Onivyde
• Talazoparib
• Temozolomide

Trial Overview The study tests Onivyde combined with either talazoparib or temozolomide in two separate arms (A & B) to find the highest tolerable doses against solid tumors. It includes expansion arms for different tumor types at these doses. Phase II focuses on Ewing sarcoma patients testing the same combinations.

Participant Groups

Group I: (Arm A) ONI plus TAL Active Control 2 Interventions

The phase I/II study will evaluate a treatment regimen; nanoliposomal irinotecan (nal-IRN, Onivyde) plus talazoparib (TAL)

Group II: (Arm B) ONI plus TMZ Active Control 2 Interventions

The phase I/II study will evaluate a treatment regimen; Onivyde (ONI) plus temozolomide (TMZ)

Who Is Running the Clinical Trial?

St. Jude Children's Research Hospital

Lead Sponsor

Trials

451

Recruited

5,326,000+

Pfizer

Industry Sponsor

Trials

4,712

Recruited

50,980,000+

Known For

Vaccine Innovations

Top Products

Viagra, Zoloft, Lipitor, Prevnar 13

Albert Bourla

Pfizer

Chief Executive Officer since 2019

PhD in Biotechnology of Reproduction, Aristotle University of Thessaloniki

Patrizia Cavazzoni

Pfizer

Chief Medical Officer

MD from McGill University

Ipsen

Industry Sponsor

Trials

358

Recruited

74,600+

David Loew

Ipsen

Chief Executive Officer since 2020

BA in Business Administration and MBA from the University of St. Gallen, Switzerland

Sandra Silvestri

Ipsen

Chief Medical Officer since 2023

MD, PhD

Findings from Research

A phase I trial involving 41 pediatric patients with recurrent or refractory solid tumors showed that the combination of talazoparib and irinotecan, with or without temozolomide, is feasible and has demonstrated activity, particularly in Ewing sarcoma, with objective response rates of 10.3% for arm A and 25% for arm B.

The most common severe side effects included neutropenia and thrombocytopenia, indicating that while the treatment is active, it also carries significant hematologic risks that need to be managed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase I trial of talazoparib and irinotecan with and without temozolomide in children and young adults with recurrent or refractory solid malignancies. Federico, SM., Pappo, AS., Sahr, N., et al.[2021]

The nanoparticle formulation of talazoparib (NanoTLZ) significantly reduced toxicity compared to the oral form of talazoparib when combined with temozolomide (TMZ), allowing for a higher maximum tolerated dose.

Using NanoTLZ with TMZ did not require a dose reduction of TMZ, which was necessary when using oral talazoparib, suggesting that this delivery method may enhance the safety and efficacy of the treatment for Ewing sarcoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nanoformulation of Talazoparib Increases Maximum Tolerated Doses in Combination With Temozolomide for Treatment of Ewing Sarcoma. Baldwin, P., Likhotvorik, R., Baig, N., et al.[2020]

The protracted d × 5×2 schedule of vincristine, irinotecan, and temozolomide (VIT) demonstrated a significantly higher objective response rate (54.5%) compared to the shorter d × 5 schedule (20.8%) in patients with relapsed or refractory Ewing sarcoma, based on a study of 46 patients.

Patients on the d × 5 schedule experienced more severe adverse events, indicating that the d × 5×2 schedule not only provided better efficacy but also had a more favorable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Longer versus Shorter Schedules of Vincristine, Irinotecan, and Temozolomide (VIT) for Relapsed or Refractory Ewing Sarcoma: A Randomized Controlled Phase 2 Trial. Xu, J., Xie, L., Sun, X., et al.[2023]

In a phase II trial involving 38 patients with recurrent oligodendroglial tumors, temozolomide (TMZ) demonstrated a high response rate, with 52.6% of patients showing a complete or partial response, indicating its efficacy as a first-line chemotherapy.

TMZ was generally well tolerated, with hematologic side effects being the most common, and only one patient discontinuing treatment due to toxicity, suggesting a favorable safety profile for chemotherapy-naive patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II study of first-line chemotherapy with temozolomide in recurrent oligodendroglial tumors: the European Organization for Research and Treatment of Cancer Brain Tumor Group Study 26971. van den Bent, MJ., Taphoorn, MJ., Brandes, AA., et al.[2022]

References

1. United States pubmed.ncbi.nlm.nih.gov

PEGylated talazoparib enhances therapeutic window of its combination with temozolomide in Ewing sarcoma. [2022]

2. England pubmed.ncbi.nlm.nih.gov

A phase I trial of talazoparib and irinotecan with and without temozolomide in children and young adults with recurrent or refractory solid malignancies. [2021]

3. Switzerland pubmed.ncbi.nlm.nih.gov

Nanoformulation of Talazoparib Increases Maximum Tolerated Doses in Combination With Temozolomide for Treatment of Ewing Sarcoma. [2020]

4. United States pubmed.ncbi.nlm.nih.gov

Phase 1/2 trial of talazoparib in combination with temozolomide in children and adolescents with refractory/recurrent solid tumors including Ewing sarcoma: A Children's Oncology Group Phase 1 Consortium study (ADVL1411). [2022]

5. United States pubmed.ncbi.nlm.nih.gov

Longer versus Shorter Schedules of Vincristine, Irinotecan, and Temozolomide (VIT) for Relapsed or Refractory Ewing Sarcoma: A Randomized Controlled Phase 2 Trial. [2023]

6. United States pubmed.ncbi.nlm.nih.gov

Phase II study of first-line chemotherapy with temozolomide in recurrent oligodendroglial tumors: the European Organization for Research and Treatment of Cancer Brain Tumor Group Study 26971. [2022]