Chemotherapy +/− Ganitumab for Ewing Sarcoma

Recruiting at 351 trial locations

Age: < 65

Sex: Any

Trial Phase: Phase 3

Sponsor: National Cancer Institute (NCI)

Must not be taking: Corticosteroids

Disqualifiers: Prior chemotherapy, Radiation therapy, Diabetes, 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

312 Participants Needed

Trial Summary

What is the purpose of this trial?

This randomized phase III trial studies how well combination chemotherapy with or without ganitumab works in treating patients with newly diagnosed Ewing sarcoma that has spread to other parts of the body. Treatment with drugs that block the IGF-1R pathway, such as ganitumab, may interfere with the ability of tumor cells to grow and spread. Drugs used in chemotherapy, such as vincristine, doxorubicin, cyclophosphamide, ifosfamide, and etoposide, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. It is not yet known whether adding ganitumab to combination chemotherapy is more effective in treating patients with newly diagnosed metastatic Ewing sarcoma.

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

The trial does not specify if you need to stop taking your current medications, but it does exclude patients who are on chronic corticosteroid therapy for more than 3 weeks. If you are on such medications, you may need to stop them to participate.

What data supports the effectiveness of the drug combination used in the treatment of Ewing Sarcoma?

Research shows that adding ifosfamide and etoposide to a drug combination including cyclophosphamide, doxorubicin, and vincristine improved 5-year overall survival to 70%-80% in children with localized Ewing sarcoma. Additionally, a study reported a 5-year overall survival rate of 72.2% for adult patients with localized disease using a similar drug regimen. ^{1 2 3 4 5}

Is the chemotherapy treatment for Ewing Sarcoma safe?

The chemotherapy treatment for Ewing Sarcoma, which includes drugs like vincristine, ifosfamide, doxorubicin, and etoposide, has been studied for safety. Some patients experience severe side effects, and there have been cases of treatment-related deaths, especially with high-dose chemotherapy. However, these treatments are generally considered safe enough to be used in clinical settings, with careful monitoring for adverse reactions. ^{4 6 7 8 9}

What makes the chemotherapy treatment with Ganitumab unique for Ewing Sarcoma?

This treatment is unique because it combines standard chemotherapy drugs like vincristine, ifosfamide, doxorubicin, and etoposide with Ganitumab, which is not typically used in standard Ewing Sarcoma treatments. Ganitumab is an experimental drug that may offer additional benefits by targeting specific pathways involved in cancer growth. ^{1 6 7 10 11}

Research Team

Steven G DuBois

Principal Investigator

Children's Oncology Group

Eligibility Criteria

This trial is for patients with newly diagnosed Ewing sarcoma that has spread, who haven't had prior chemotherapy or radiation. They must have a biopsy of the primary tumor and meet specific health criteria like normal kidney function, heart function, blood sugar levels, and liver enzymes. Pregnant or breastfeeding women are excluded, as well as those with diabetes or on long-term steroids.

Inclusion Criteria

My liver enzyme levels are within the normal range, except I have liver cancer.

My cancer has spread to my bones.

Submission of pre-treatment serum, tumor tissue, and whole blood required

Exclusion Criteria

My cancer started in the soft tissues within the brain's protective layers.

I have had chemotherapy or radiation therapy before.

Lactating females unless they agree not to breastfeed

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Induction Therapy

Patients receive vincristine sulfate, doxorubicin hydrochloride, cyclophosphamide, ifosfamide, and etoposide phosphate with or without ganitumab

12 weeks

Weekly visits for drug administration

Local Control Therapy

Patients undergo surgery and/or radiation therapy

5-6 weeks

Consolidation Therapy

Patients receive vincristine sulfate, doxorubicin hydrochloride, cyclophosphamide, ifosfamide, and etoposide phosphate with or without ganitumab

16 weeks

Bi-weekly visits for drug administration

Maintenance Therapy

Patients receive ganitumab every 3 weeks for 8 cycles

24 weeks

Every 3 weeks for drug administration

Follow-up

Participants are monitored for safety and effectiveness after treatment

10 years

Treatment Details

Interventions

• Cyclophosphamide
• Doxorubicin
• Doxorubicin Hydrochloride
• Etoposide
• Etoposide Phosphate
• External Beam Radiation Therapy
• Ganitumab
• Ifosfamide
• Quality-of-Life Assessment
• Stereotactic Radiosurgery
• Therapeutic Surgical Procedure
• Vincristine
• Vincristine Sulfate

Trial Overview The study is testing if adding ganitumab to standard combination chemotherapy (vincristine, doxorubicin, cyclophosphamide, ifosfamide, etoposide) improves outcomes in metastatic Ewing sarcoma. Ganitumab targets the IGF-1R pathway which may help stop cancer growth. Patients are randomly assigned to receive either just chemo or chemo plus ganitumab.

Participant Groups

Group I: Regimen B (VDC/IE + ganitumab) Experimental Treatment 12 Interventions

INDUCTION THERAPY: Patients receive Induction therapy as in Regimen A and receive ganitumab IV over 30-60 minutes or 60-120 minutes on day 1 of weeks 1, 3, 5, 7, 9, and 11. LOCAL CONTROL THERAPY: Between weeks 13-18, patients undergo surgery and/or radiation therapy. CONSOLIDATION THERAPY: Patients receive Consolidation therapy as in Regimen A and receive ganitumab IV over 30-60 minutes or 60-120 minutes on day 1 of weeks 7, 9, 11, 13, and 15. METASTATIC SITE IRRADIATION: Patients with lung metastases undergo whole lung radiation and patients with bone metastases undergo definitive SBRT or EBRT. MAINTENANCE: Patients receive ganitumab IV over 30-60 minutes or 60-120 minutes every 3 weeks for 8 cycles.

Group II: Regimen A (VDC/IE) Experimental Treatment 11 Interventions

See Design Details.

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?

National Cancer Institute (NCI)

Lead Sponsor

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]

In a study involving 851 patients with Ewing tumors receiving 4,746 courses of the VIDE chemotherapy regimen, the most common adverse reactions were myelosuppression and infections, but these were manageable with supportive therapy, allowing for the maintenance of targeted dose intensity.

Age and gender significantly influenced the severity of hematotoxicity, with younger patients and females experiencing more severe effects, while the use of G-CSF did not significantly reduce the rates of neutropenia-related fever and infections.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety assessment of intensive induction with vincristine, ifosfamide, doxorubicin, and etoposide (VIDE) in the treatment of Ewing tumors in the EURO-E.W.I.N.G. 99 clinical trial. Juergens, C., Weston, C., Lewis, I., et al.[2022]

In a study of 58 patients with relapsing/refractory Ewing sarcoma, low-dose oral etoposide (VP-16) demonstrated efficacy, with 11 out of 46 evaluable patients showing a response, including one complete remission and nine partial remissions, lasting an average of 8 months.

The treatment was associated with manageable toxicity, with 15% of cycles showing severe hematologic toxicity, and a noted risk of secondary leukemia, consistent with existing literature, suggesting that low-dose VP-16 could be a viable option in palliative care.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oral etoposide in relapsed or refractory Ewing sarcoma: a monoinstitutional experience in children and adolescents. Podda, MG., Luksch, R., Puma, N., et al.[2017]

References

1. 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]

2. 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]

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

In vitro chemosensitivity of two Ewing's sarcoma cell lines: implication for autologous bone marrow transplantation. [2019]

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. 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]

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

Safety assessment of intensive induction with vincristine, ifosfamide, doxorubicin, and etoposide (VIDE) in the treatment of Ewing tumors in the EURO-E.W.I.N.G. 99 clinical trial. [2022]

7. England pubmed.ncbi.nlm.nih.gov

Impact of gender on efficacy and acute toxicity of alkylating agent -based chemotherapy in Ewing sarcoma: secondary analysis of the Euro-Ewing99-R1 trial. [2022]

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

High-Dose Chemotherapy and Blood Autologous Stem-Cell Rescue Compared With Standard Chemotherapy in Localized High-Risk Ewing Sarcoma: Results of Euro-E.W.I.N.G.99 and Ewing-2008. [2019]

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

Oral etoposide in relapsed or refractory Ewing sarcoma: a monoinstitutional experience in children and adolescents. [2017]

10. England pubmed.ncbi.nlm.nih.gov

Treatment strategies for metastatic Ewing's sarcoma. [2019]

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

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