Irinotecan + Temozolomide for Ewing Sarcoma

Recruiting at 8 trial locations

Overseen By Emily Slotkin, MD

Age: < 65

Sex: Any

Trial Phase: Phase 2

Sponsor: Memorial Sloan Kettering Cancer Center

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

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

Duration: Approximately 12-18 months

83 Participants Needed

Trial Summary

What is the purpose of this trial?

The purpose of this study is to find out what effects, good and/or bad, the combination of irinotecan and temozolomide has on Ewing sarcoma. Irinotecan and temozolomide are chemotherapy drugs that are used very often to treat pediatric patients at MSKCC. The investigators have used these two drugs for many years to treat patients with Ewing sarcoma whose cancer has relapsed. For patients with newly diagnosed Ewing sarcoma the current standard of care at MSKCC is a five drug chemotherapy regimen in combination with surgery and/or radiation therapy. This standard regimen is called the EFT regimen. . Some patients with Ewing sarcoma do not have their cancer cured by the chemotherapy and surgery/radiation therapy. This study adds the chemotherapy drugs called irinotecan and temozolomide to the standard EFT regimen. The investigators are trying to improve the success of standard therapy by adding these drugs. The use of irinotecan and temozolomide in this study is experimental because they have not been used before in patients with newly diagnosed Ewing sarcoma. However the investigators have found these drugs to be effective in patients with relapsed Ewing sarcoma. It is not known if adding these two drugs will improve the outcomes of patients treated for Ewing sarcoma.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. However, since prior chemotherapy or radiotherapy is not allowed, you may need to discuss your current treatments with the trial team.

What data supports the effectiveness of the drug combination Irinotecan and Temozolomide for Ewing Sarcoma?

Research shows that the combination of Irinotecan and Temozolomide has been used in both children and adults with relapsed Ewing Sarcoma, demonstrating some effectiveness. Preclinical models and a Phase I trial indicated that this drug combination is active and tolerable, with responses observed in patients with Ewing Sarcoma. ^{1 2 3 4 5}

Is the combination of irinotecan and temozolomide safe for humans?

Research shows that the combination of irinotecan and temozolomide has been found to be generally safe and tolerable in both children and adults with relapsed Ewing sarcoma, based on several clinical trials. ^{1 2 3 4 6}

How is the drug combination of irinotecan and temozolomide unique for treating Ewing sarcoma?

The combination of irinotecan and temozolomide is unique for treating Ewing sarcoma because it shows a sequence-dependent synergy, meaning the drugs work better together in a specific order, and has been found to be effective and tolerable in patients with relapsed Ewing sarcoma, especially when other treatments have failed. ^{1 2 3 4 7}

Research Team

Emily Slotkin, MD

Principal Investigator

Memorial Sloan Kettering Cancer Center

Eligibility Criteria

This trial is for patients aged 1 to 40 years with newly diagnosed, untreated Ewing sarcoma. They must have normal heart and kidney function, adequate liver function even if the tumor involves the liver, and sufficient blood cell counts. Participants need a central venous catheter and must agree to use contraception if of reproductive potential.

Inclusion Criteria

I was diagnosed with my condition between the ages of 1 and 40.

I have been newly diagnosed with Ewing sarcoma and have not received any treatment.

My kidney function tests are normal.

Exclusion Criteria

Pregnant or breastfeeding females

I have not had chemotherapy or radiotherapy, except for emergency treatment.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive a combination of irinotecan and temozolomide with the standard EFT regimen

Approximately 12-18 months

Multiple cycles with frequent visits

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 years

Long-term follow-up

Monitoring of event-free survival and adverse events

4 years

Treatment Details

Interventions

• Irinotecan
• Temozolomide

Trial Overview The study tests adding irinotecan and temozolomide (chemotherapy drugs) to the existing high-dose alkylator-based chemotherapy regimen (EFT), along with surgery/radiation as needed. This combination aims to improve outcomes in patients who are newly diagnosed with Ewing sarcoma.

Participant Groups

Group I: Patients with metastatic disease Experimental Treatment 12 Interventions

Patients will get 10 cycles of the combination intercalated between the final 4 cycles of standard chemotherapy. * Cycles 4, 5, 7, 8, 10, 11, 13, 14, 16, and 17 will include: * Irinotecan will be given on 10 days over weeks 1 and 2 of a cycle at a dose of 20 mg/m2/day intravenously * Temozolomide will be given daily on the first 5 days of irinotecan administration at a dose of 100 mg/m2/day orally or intravenously * Cycles 6, 9, and 12 will include: * Ifosfamide 2,800 mg/m2/day on days 1-5 * Etoposide 100 mg/m2/day on days 1-5 * Cycle 15 will include: * Cyclophosphamide will be given on days 1 and 2 at a dose of 2,100 mg/m2/day, or for patients \< 10 years of age at a dose of 70 mg/kg/day * Doxorubicin will be given on days 1 and 2 at a dose of 37.5 mg/m2/day * Vincristine will be given on day 1 at a dose of 2 mg/m2 or 0.067 mg/kg (whichever is lower, to a max dose of 2 mg)

Group II: Patients with localized disease Experimental Treatment 12 Interventions

Patients with localized disease will receive six cycles of the combination as "maintenance" therapy following standard chemotherapy. * Cycles 4-6 will include: * Ifosfamide 2,800 mg/m2/day on days 1-5 * Etoposide 100 mg/m2/day on days 1-5 * Cycle 7 will include : * Cyclophosphamide will be given on days 1 and 2 at a dose of 2,100 mg/m2/day, or for patients \< 10 years of age at a dose of 70 mg/kg/day * Doxorubicin will be given on days 1 and 2 at a dose of 37.5 mg/m2/day * Vincristine will be given on day 1 at a dose of 2 mg/m2 or 0.067 mg/kg (whichever is lower, to a max dose of 2 mg) * Cycles 8-13 will include: * Irinotecan will be given on 10 days over weeks 1 and 2 of a cycle at a dose of 20 mg/m2/day intravenously * Temozolomide will be given daily on the first 5 days of irinotecan administration at a dose of 100 mg/m2/day orally or intravenously

Who Is Running the Clinical Trial?

Memorial Sloan Kettering Cancer Center

Lead Sponsor

Trials

1,998

Recruited

602,000+

Findings from Research

In a study of 51 patients with recurrent Ewing sarcoma, the combination of temozolomide and irinotecan (TEMIRI) demonstrated a disease control rate of 71%, indicating significant efficacy in managing this cancer.

Factors such as the Eastern Cooperative Oncology Group (ECOG) performance status and lactate dehydrogenase (LDH) levels were found to significantly influence progression-free survival, highlighting their potential as predictive markers for treatment response.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Irinotecan and temozolomide in recurrent Ewing sarcoma: an analysis in 51 adult and pediatric patients. Palmerini, E., Jones, RL., Setola, E., et al.[2018]

Irinotecan and temozolomide (IT) chemotherapy is effective for treating relapsed Ewing sarcoma, showing similar objective response rates (28% in both pediatric and adult patients) and manageable toxicity levels across age groups.

However, pediatric patients experienced significantly longer progression-free survival (7.4 months) compared to adults (2.2 months), suggesting that age may influence treatment outcomes and warrant further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Irinotecan and temozolomide chemotherapy in paediatric and adult populations with relapsed Ewing Sarcoma. Salah, S., To, YH., Khozouz, O., et al.[2021]

A combination of temozolomide and irinotecan was found to be tolerable and active in treating advanced Ewing sarcoma, with 1 complete response and 3 partial responses observed among 14 evaluable patients.

The treatment regimen was manageable, with minimal myelosuppression and only 11% of courses experiencing grade 3-4 diarrhea, suggesting that home administration of irinotecan is safe and feasible for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Temozolomide and intravenous irinotecan for treatment of advanced Ewing sarcoma. Wagner, LM., McAllister, N., Goldsby, RE., et al.[2018]

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]

References

1. England pubmed.ncbi.nlm.nih.gov

Irinotecan and temozolomide in recurrent Ewing sarcoma: an analysis in 51 adult and pediatric patients. [2018]

2. Italy pubmed.ncbi.nlm.nih.gov

Irinotecan and temozolomide chemotherapy in paediatric and adult populations with relapsed Ewing Sarcoma. [2021]

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

Temozolomide and intravenous irinotecan for treatment of advanced Ewing sarcoma. [2018]

4. England pubmed.ncbi.nlm.nih.gov

Irinotecan plus temozolomide in relapsed Ewing sarcoma: an integrated analysis of retrospective studies. [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

Irinotecan and temozolomide for Ewing sarcoma: the Memorial Sloan-Kettering experience. [2022]

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

Vincristine, irinotecan, and temozolomide in patients with relapsed and refractory Ewing sarcoma. [2022]