Chemotherapy +/− Ganitumab for Ewing Sarcoma

Not currently recruiting at 370 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether adding ganitumab to standard chemotherapy more effectively treats newly diagnosed Ewing sarcoma that has metastasized. Researchers aim to determine if ganitumab, which blocks the IGF-1R pathway and may halt tumor growth, can improve outcomes when combined with drugs like vincristine and doxorubicin. The trial includes two groups: one receiving only the usual chemotherapy and the other receiving chemotherapy plus ganitumab. Ideal participants are those diagnosed with Ewing sarcoma that has spread to the lungs, bones, or other distant sites and have not yet received chemotherapy or radiation therapy. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants a chance to contribute to potentially groundbreaking treatment advancements.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that ganitumab, when combined with other treatments, is generally well-tolerated. One study found that doses of ganitumab up to 12 mg/kg were safe when used with other cancer drugs. Although some patients experienced unexpected side effects, the treatment was deemed safe enough for further testing.

In other studies, ganitumab did not significantly benefit patients with Ewing sarcoma, but it remained safe. This indicates that while ganitumab may not greatly aid in combating the cancer, it did not cause serious harm to patients.

The chemotherapy drugs used, such as vincristine, doxorubicin, and cyclophosphamide, are standard treatments for Ewing sarcoma. These drugs are known to have side effects, but doctors are familiar with them and know how to manage them.

In summary, ganitumab and the chemotherapy drugs have been studied for safety, and while side effects can occur, they are generally manageable. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the treatment for Ewing Sarcoma because it introduces ganitumab, a monoclonal antibody, into the mix. Unlike standard chemotherapy options like vincristine, doxorubicin, and cyclophosphamide, ganitumab targets the insulin-like growth factor 1 receptor (IGF-1R), which may be crucial in tumor growth. This targeted approach could enhance the effectiveness of traditional chemotherapy by specifically attacking cancer cell pathways. Additionally, the inclusion of ganitumab in maintenance therapy offers a novel strategy to potentially prevent cancer recurrence.

What evidence suggests that this trial's treatments could be effective for Ewing sarcoma?

This trial will compare two treatment regimens for Ewing sarcoma. Regimen A involves chemotherapy with drugs like vincristine and doxorubicin, which commonly kill or stop the spread of cancer cells. Regimen B adds ganitumab to the chemotherapy regimen. Research has shown that adding ganitumab to chemotherapy has not significantly improved results for patients with newly diagnosed metastatic Ewing sarcoma. Specifically, in one study, 39.1% of patients who received ganitumab with chemotherapy lived for three years without their cancer worsening. This indicates that while ganitumab targets a pathway believed to help stop tumor growth, it hasn't yet made a significant difference in survival rates. Overall, while ganitumab offers a new approach, current results suggest it has limited success in improving patient outcomes when added to standard chemotherapy. ^{1 6 7 8 9}

Who Is on the Research Team?

Steven G DuBois

Principal Investigator

Children's Oncology Group

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10082251/

Randomized Phase III Trial of Ganitumab With Interval ... INTRODUCTION. Patients with newly diagnosed, metastatic Ewing sarcoma have poor outcomes, with most studies reporting 3-year event-free survival ...

2. ascopubs.org ascopubs.org/doi/abs/10.1200/JCO.22.01815

Randomized Phase III Trial of Ganitumab With Interval- ... Ganitumab added to interval-compressed chemotherapy did not significantly reduce the risk of EFS event in patients with newly diagnosed metastatic Ewing ...

3. onclive.com onclive.com/view/ganitumab-plus-interval-compressed-chemotherapy-fails-to-improve-efs-in-metastatic-ewing-sarcoma

Ganitumab Plus Interval-Compressed Chemotherapy Fails ... Findings showed that among patients treated with ganitumab plus chemotherapy (n = 150), the 3-year EFS rate was 39.1% (95% CI, 31.3%-46.7%,), ...

4. clinicaltrials.gov clinicaltrials.gov/study/NCT03029481

Single Patient Expanded Access to Ganitumab for ... Despite improvements in outcomes for patients with localized Ewing sarcoma, patients with relapsed metastatic Ewing sarcoma continue to have poor outcomes with ...

5. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0022356524463842

Efficacy of Ganitumab (AMG 479), Alone and in ... Our results support studying ganitumab in combination with mTORC1 inhibitors for the treatment of sarcomas and suggest that INSR signaling is an important ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT03029481

Single Patient Expanded Access to Ganitumab for ... A large body of preclinical data supports a role for IGF-1R inhibition in the treatment of Ewing sarcoma. More recently, clinical trials of IGF-1R monoclonal ...

7. aacrjournals.org aacrjournals.org/clincancerres/article/18/12/3414/178659/Safety-and-Pharmacokinetics-of-Ganitumab-AMG-479

Safety and Pharmacokinetics of Ganitumab (AMG 479 ... Results: Ganitumab up to 12 mg/kg appeared well tolerated combined with sorafenib, panitumumab, erlotinib, or gemcitabine. Treatment-emergent adverse events ...

8. clinicaltrials.gov clinicaltrials.gov/study/NCT04129151

NCT04129151 | Palbociclib + Ganitumab In Ewing Sarcoma This research study is: Testing whether palbociclib and ganitumab are safe when given together and effective in treating Ewing sarcoma.

9. ascopost.com ascopost.com/news/february-2023/addition-of-anti-igf-1r-antibody-ganitumab-to-interval-compressed-chemotherapy-in-newly-diagnosed-patients-with-metastatic-ewing-sarcoma/

Addition of Anti–IGF-1R Antibody Ganitumab to Interval- ... The investigators concluded, “Ganitumab added to interval-compressed chemotherapy did not significantly reduce the risk of event-free survival ...