Chemotherapy + Targeted Therapy for Ewing Sarcoma

Age: < 65

Sex: Any

Trial Phase: Phase 2

Sponsor: St. Jude Children's Research Hospital

Must not be taking: CYP3A4 inducers/inhibitors

Disqualifiers: Pregnancy, Prior malignancy, others

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

24 Participants Needed

Trial Summary

What is the purpose of this trial?

This protocol will study treatment for Ewing sarcoma family of tumors (ESFT) and desmoplastic small round cell tumor (DSRCT). Participants with ESFT will be divided into two treatment groups, A or B, based on tumor characteristics. Group A (standard risk) participants have tumor that is not in the pelvis, has not spread to other parts of the body, and are less than 14 years of age. Because previous clinical trials have shown that standard treatment is very effective for children whose tumors have these characteristics, these participants will receive standard treatment. Group B (high risk) participants are 14 years of age or older or have tumor in the pelvis, or the tumor has spread to other parts of the body. Participants with DSRCT in the abdomen and/or pelvis or with tumor that cannot be removed by surgery alone or has spread to other parts of the body will be included in Group B. Participants in this group are considered high risk because there is a greater chance of tumor recurring following standard treatments currently in use. All participants will be followed and evaluated for 10 years following completion of therapy.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications, but if you are in Group B and will receive upfront window therapy, you must not take certain medications like azole antifungals, rifampin, phenytoin, phenobarbitol, carbamazepine, grapefruit juice, and St. John's wort within 1 week before starting the study.

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 combination of cyclophosphamide, doxorubicin, and vincristine improves 5-year overall survival rates to 70%-80% in children with localized Ewing sarcoma. In adults, similar drug combinations have shown a 5-year overall survival rate of 72.2% for patients with localized disease. ^{1 2 3 4 5}

Is the combination of chemotherapy and targeted therapy for Ewing Sarcoma generally safe in humans?

The combination of drugs like vincristine, ifosfamide, doxorubicin, and etoposide has been used in clinical trials for Ewing Sarcoma, and safety assessments have been conducted. Adverse reactions were evaluated in the EURO-E.W.I.N.G. 99 trial, which included these drugs, indicating that safety data exists for these treatments in humans. ^{2 3 5 6 7}

How is the chemotherapy and targeted therapy for Ewing Sarcoma different from other treatments?

This treatment for Ewing Sarcoma combines multiple drugs, including cyclophosphamide, doxorubicin, etoposide, ifosfamide, temozolomide, and vincristine, which are used in various combinations to improve survival rates. It is unique because it includes temozolomide, a drug not commonly used in standard regimens for Ewing Sarcoma, potentially offering a novel approach to treatment. ^{1 3 5 6 7}

Research Team

Sara M Federico, MD

Principal Investigator

St. Jude Children's Research Hospital

Eligibility Criteria

This trial is for children under 14 with non-pelvic ESFT and young adults up to 25 years old with high-risk ESFT or DSRCT, including those with metastatic disease, pelvic tumors, or intra-abdominal DSRCT. Participants must have proper organ function and no prior cancer treatments (except emergency radiation). They should not be pregnant/breastfeeding and must agree to use birth control.

Inclusion Criteria

I am newly diagnosed with a specific type of abdominal cancer that cannot be surgically removed or has spread.

I am newly diagnosed with Ewing sarcoma, and it has spread or is in my pelvis, or I was 14 or older when diagnosed.

My liver is functioning well, with bilirubin levels at or below 3.0 mg/dL.

Exclusion Criteria

Participant is pregnant or breastfeeding.

I had cancer before, but it wasn't skin cancer or it's been 5 years since my skin cancer was treated and I'm in remission without having had chemo, immunotherapy, or radiation.

Inability or unwillingness of research participant or legal guardian/representative to give written informed consent.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment - Group A

Participants receive interval compressed chemotherapy with vincristine, doxorubicin, and cyclophosphamide (VDC) and with ifosfamide and etoposide (IE). Local control measures are instituted after 6 courses of chemotherapy.

29 weeks

Treatment - Group B

Participants receive two courses of mTOR inhibitor, temsirolimus, in combination with temozolomide and irinotecan, followed by induction chemotherapy and maintenance therapy.

33 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

10 years

Treatment Details

Interventions

• Bevacizumab
• Cyclophosphamide
• Doxorubicin
• Etoposide
• Ifosfamide
• Radiation
• Sorafenib
• Surgery
• Temozolomide
• Temsirolimus
• Vincristine

Trial Overview The study tests standard treatment in Group A (standard risk) children under 14 without pelvic tumors or spread of the disease. Group B (high risk), older than 14, with pelvic tumors or metastasis receive more aggressive therapy. Treatments include chemotherapy drugs like vincristine and doxorubicin, targeted therapies such as temsirolimus and sorafenib, surgery, radiation, plus long-term follow-up.

Participant Groups

Group I: Group A (Standard Risk) Active Control 7 Interventions

Participants will receive vincristine, doxorubicin, cyclophosphamide, ifosfamide and etoposide. Doxorubicin will be omitted following a total cumulative dose of 375 mg/m\^2. Depending on the size and location of the participant's tumor, they will have surgery alone, radiation alone, or surgery followed by radiation. Local control measures (surgery and/or radiation therapy) will be instituted after 6 courses of chemotherapy. Total duration of treatment is approximately 29 weeks.

Group II: Group B (High Risk) Active Control 10 Interventions

Participants will receive vincristine, doxorubicin, cyclophosphamide, ifosfamide, etoposide, irinotecan, temozolomide, temsirolimus, bevacizumab, and sorafenib. Depending on the size and location of the participant's tumor, they will have surgery alone, radiation alone or surgery followed by radiation.

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?

St. Jude Children's Research Hospital

Lead Sponsor

Trials

451

Recruited

5,326,000+

University of Tennessee Health Science Center

Collaborator

Trials

49

Recruited

24,600+

University of Tennessee

Collaborator

Trials

202

Recruited

146,000+

Nemours Children's Clinic

Collaborator

Trials

128

Recruited

18,000+

University of Florida

Collaborator

Trials

1,428

Recruited

987,000+

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]

References

1. 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]

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

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

3. 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]

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

Treatment of metastatic Ewing's sarcoma or primitive neuroectodermal tumor of bone: evaluation of combination ifosfamide and etoposide--a Children's Cancer Group and Pediatric Oncology Group study. [2022]

5. 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]

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

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