Combination Chemotherapy for Ewing Sarcoma

Recruiting at 253 trial locations

Age: < 65

Sex: Any

Trial Phase: Phase 3

Sponsor: Children's Oncology Group

Disqualifiers: Metastatic disease, Non-Ewing diagnosis, Pregnancy, others

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

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

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

Compensation: Varies

Number of Visits: 3

642 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial examined the outcome benefit to patients of adding a new chemotherapy drug combination to the established treatment approach for patients with extracranial Ewing sarcoma, that had not spread from the primary site to other places in the body. The trial randomly assigned patients at the time of study entry to receive established standard treatment with the following 5-drugs: vincristine sulfate, doxorubicin hydrochloride, cyclophosphamide, ifosfamide and etoposide. The outcome for patients receiving the standard 5-drug combination was compared to the outcome for patients who received the same 5-drugs with an additional drug, topotecan hydrochloride delivered in a novel combination with vincristine sulfate and cyclophosphamide.

Do I need to stop my current medications to join the trial?

The trial does not specify whether you need to stop taking your current medications. However, since no prior chemotherapy or radiation therapy is allowed, you may need to discuss your current medications with the trial team to ensure they don't conflict with the study requirements.

What data supports the effectiveness of the drug combination used in the clinical trial for Ewing Sarcoma?

Research shows that adding ifosfamide and etoposide to a combination of vincristine, doxorubicin, and cyclophosphamide improved 5-year survival rates to 70%-80% in children with localized Ewing sarcoma. Additionally, a study found that a similar drug combination achieved a 72.2% 5-year survival rate in adults with localized Ewing sarcoma. ^{1 2 3 4 5}

Is the combination chemotherapy for Ewing Sarcoma generally safe for humans?

The combination chemotherapy for Ewing Sarcoma, which includes drugs like vincristine, doxorubicin, cyclophosphamide, ifosfamide, and etoposide, has been used in both children and adults with varying outcomes. While the treatment has shown effectiveness in improving survival rates, the safety data indicates that it is generally tolerated, but the level of evidence for safety in adults is limited due to the rarity of the disease. ^{1 3 4 5 6}

What makes this drug combination unique for treating Ewing Sarcoma?

This drug combination is unique because it includes a mix of six different chemotherapy drugs, which are used in an interval-compressed schedule to potentially enhance effectiveness. This approach is particularly novel as it combines drugs like topotecan and cyclophosphamide, which have shown activity in relapsed cases, with standard treatments, aiming to improve outcomes in newly diagnosed patients. ^{1 3 5 6 7}

Research Team

Patrick J Leavey

Principal Investigator

Children's Oncology Group

Eligibility Criteria

This trial is for patients with a new diagnosis of non-metastatic Ewing sarcoma or PNET located outside the brain, without prior treatment. Eligible participants must have proper kidney function, normal bilirubin levels, acceptable liver enzyme counts, and good heart function. Pregnant or breastfeeding women are excluded, as well as those who've had previous cancers treated with chemo or radiation.

Inclusion Criteria

I have been diagnosed with Ewing sarcoma or PNET.

I've only had a biopsy for my cancer, with no chemo or radiation.

My liver function tests are within normal limits.

Exclusion Criteria

I have Ewing Sarcoma as a second cancer and haven't had chemo or radiation for my first cancer.

My lung nodules are larger than specified sizes or biopsied positive for cancer.

All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Induction Therapy

Patients receive a combination of chemotherapy drugs including vincristine sulfate, doxorubicin hydrochloride, cyclophosphamide, ifosfamide, and etoposide, with additional topotecan hydrochloride in Arm B.

12 weeks

Weekly visits for drug administration

Consolidation Therapy

Continuation of chemotherapy with vincristine sulfate, doxorubicin hydrochloride, cyclophosphamide, ifosfamide, and etoposide, with additional topotecan hydrochloride in Arm B.

22 weeks

Weekly visits for drug administration

Follow-up

Participants are monitored for safety and effectiveness after treatment

5 years

Every 3 months for 3 years, then every 6 months for 2 years

Treatment Details

Interventions

• Cyclophosphamide
• Doxorubicin Hydrochloride
• Etoposide
• Ifosfamide
• Topotecan Hydrochloride
• Vincristine Sulfate

Trial Overview The study tests if adding topotecan hydrochloride to a standard chemotherapy regimen (vincristine sulfate, doxorubicin hydrochloride, cyclophosphamide, ifosfamide and etoposide) improves outcomes in Ewing sarcoma patients. Participants are randomly assigned to receive either the standard treatment alone or with the additional drug.

Participant Groups

Group I: Arm B (combination chemotherapy, topotecan hydrochloride) Experimental Treatment 8 Interventions

INDUCTION THERAPY: Patients receive vincristine sulfate IV on day 1 in weeks 1, 2, 5, 6, 9, 10, 11 and 12; topotecan hydrochloride IV over 30 minutes on days 1-5 in weeks 1 and 9; cyclophosphamide IV over 15-30 minutes on days 1-5 in weeks 1 and 9, and over 30-60 minutes on day 1 of weeks 5 and 11; ifosfamide and etoposide as in arm A; and doxorubicin hydrochloride IV on days 1 and 2 in weeks 5 and 11. CONSOLIDATION THERAPY: Patients receive vincristine sulfate IV on day 1 in weeks 1, 2, 7-10, 13-16, 19, and 20; topotecan hydrochloride IV over 30 minutes on days 1-5 in weeks 1, 7, and 15; cyclophosphamide IV over 15-60 minutes on days 1-5 in weeks 1, 7, and 15, and over 30-60 minutes on day 1 in weeks 9, 13, and 19; ifosfamide IV over 1 hour and etoposide IV over 1- 2 hours on days 1-5 in weeks 3, 5, 11, 17, and 21; and doxorubicin hydrochloride IV on days 1 and 2 in weeks 9,13, and 19. Patients received Dexrazoxane with doxorubicin hydrochloride in weeks 13 and 19.

Group II: Arm A (combination chemotherapy) Experimental Treatment 7 Interventions

INDUCTION THERAPY: Patients receive vincristine sulfate IV on day 1 in weeks 1, 2, 5, 6, 9, and 10; doxorubicin hydrochloride IV over 1-15 minutes (or as per institutional policies up to 60-minutes) on days 1 and 2 and cyclophosphamide IV over 30-60 minutes on day 1 in weeks 1, 5, and 9; and ifosfamide IV over 1 hour and etoposide IV over 1-2 hours on days 1-5 in weeks 3, 7, and 11. CONSOLIDATION THERAPY: Patients receive vincristine sulfate IV on day 1 in weeks 1, 2, 7, 8, 9, 10, 13, 14, 17, 18, 21, and 22; doxorubicin hydrochloride IV on days 1 and 2 in weeks 1 and 9; cyclophosphamide IV over 30-60 minutes on day 1 in weeks 1, 7, 9, 13, 17, and 21; and ifosfamide IV over 1 hour and etoposide IV over 1-2 hours on days 1-5 in weeks 3, 5, 11, 15, and 19. Patients received Dexrazoxane with doxorubicin hydrochloride in weeks 1 and 9.

Cyclophosphamide is already approved in United States, European Union, Canada, Japan for the following indications:

Approved in United States as Cytoxan for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma
• Rheumatoid arthritis

Approved in European Union as Endoxan for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma
• Rheumatoid arthritis

Approved in Canada as Neosar for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma
• Rheumatoid arthritis

Approved in Japan as Endoxan for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma

Who Is Running the Clinical Trial?

Children's Oncology Group

Lead Sponsor

Trials

467

Recruited

241,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Findings from Research

In a study of 110 patients with metastatic Ewing sarcoma or primitive neuroectodermal tumor (PNET), the combination of topotecan and cyclophosphamide showed promising activity, with 21 out of 37 patients achieving partial responses.

Amifostine, intended as a cytoprotective agent, did not provide myeloprotection, and overall survival rates remained unchanged compared to previous studies, indicating that while some treatments showed activity, the prognosis for these patients remains poor.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intensive therapy with growth factor support for patients with Ewing tumor metastatic at diagnosis: Pediatric Oncology Group/Children's Cancer Group Phase II Study 9457--a report from the Children's Oncology Group. Bernstein, ML., Devidas, M., Lafreniere, D., et al.[2013]

References

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

Pilot Study of Adding Vincristine, Topotecan, and Cyclophosphamide to Interval-Compressed Chemotherapy in Newly Diagnosed Patients With Localized Ewing Sarcoma: A Report From the Children's Oncology Group. [2018]

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

Intensive therapy with growth factor support for patients with Ewing tumor metastatic at diagnosis: Pediatric Oncology Group/Children's Cancer Group Phase II Study 9457--a report from the Children's Oncology Group. [2013]

3. England pubmed.ncbi.nlm.nih.gov

Localized Adult Ewing Sarcoma: Favorable Outcomes with Alternating Vincristine, Doxorubicin, Cyclophosphamide, and Ifosfamide, Etoposide (VDC/IE)-Based Multimodality Therapy. [2018]

4. Italy pubmed.ncbi.nlm.nih.gov

[Neoadjuvant treatment of Ewing's sarcoma: results obtained in 122 patients treated with a 6-drug chemotherapeutic protocol (vincristine, adriamycin, cyclophosphamide, dactinomycin, ifosfamide and etoposide)]. [2015]

5. Egypt pubmed.ncbi.nlm.nih.gov

Single-Centre Experience of Systemic Treatment with Vincristine, Ifosfamide, and Doxorubicin Alternating with Etoposide, Ifosfamide, and Cisplatin in Adult Patients with Ewing Sarcoma. [2020]

6. England pubmed.ncbi.nlm.nih.gov

Ifosfamide and actinomycin-D, added in the induction phase to vincristine, cyclophosphamide and doxorubicin, improve histologic response and prognosis in patients with non metastatic Ewing's sarcoma of the extremity. [2015]

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

Ewing Sarcoma: Current Management and Future Approaches Through Collaboration. [2022]