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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores new treatments for Ewing sarcoma and desmoplastic small round cell tumor, focusing on the effectiveness of chemotherapy and targeted therapy. For Ewing sarcoma, it compares standard treatment with a new combination for higher-risk individuals, such as those with cancer that has spread or is located in the pelvis. Individuals with Ewing sarcoma or desmoplastic small round cell tumor who have not received previous cancer treatments and meet specific health criteria may find this trial suitable. Researchers will monitor participants for 10 years to assess the treatments' effectiveness and safety. As a Phase 2 trial, the research measures how well the treatment works in an initial, smaller group of people.

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.

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

Research shows that the chemotherapy drugs used in Group A for standard-risk Ewing sarcoma are generally well-tolerated. These drugs include vincristine, doxorubicin, cyclophosphamide, ifosfamide, and etoposide, which form the usual treatment for this condition. While these drugs can cause side effects, they are commonly used, and doctors have extensive experience managing these effects.

Group B, which involves a high-risk treatment plan, includes additional drugs alongside those in Group A. These drugs are irinotecan, temozolomide, temsirolimus, bevacizumab, and sorafenib. Although this combination is more complex, research has previously used these drugs in various ways. Each drug has known side effects, but doctors are skilled in handling them.

As this trial is in an early phase, researchers continue to study how well participants tolerate these treatments. Participants receive close monitoring for any side effects. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for Ewing Sarcoma because they combine traditional chemotherapy with targeted therapies, aiming for a more personalized approach. Unlike standard treatments that typically rely solely on chemotherapy, this approach includes drugs like temsirolimus and sorafenib, which specifically target cancer cell growth pathways. Additionally, the inclusion of bevacizumab, an anti-angiogenic agent, aims to cut off the blood supply to tumors, potentially enhancing treatment effectiveness. This combination of traditional and targeted therapies holds promise for improved outcomes, especially in high-risk patients.

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

Research has shown that treatments using vincristine, doxorubicin, and cyclophosphamide have been successful for standard-risk Ewing sarcoma. In this trial, participants in the standard-risk group will receive these drugs, often combined with ifosfamide and etoposide, which are effective when the cancer hasn't spread.

For high-risk cases, where the cancer has spread or is more difficult to treat, this trial tests a combination of chemotherapy and targeted therapies. Participants in the high-risk group will receive drugs like irinotecan and temozolomide, which aim to attack cancer cells more precisely. Previous studies suggest these combinations might improve outcomes for high-risk patients, especially when traditional treatments are insufficient. ^{2 3 4 6 7}

Who Is on the Research Team?

Sara M Federico, MD

Principal Investigator

St. Jude Children's Research Hospital

Are You a Good Fit for This Trial?

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 blood sugar levels are within the normal range.

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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 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]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/9506366/

Neoadjuvant chemotherapy for Ewing's sarcoma of bone: ... The purpose of this article is to report the results achieved in a new neoadjuvant protocol in which IF and ET were added to the conventional VACA regimen.

2. clinicaltrials.gov clinicaltrials.gov/study/NCT01946529

NCT01946529 | Therapeutic Trial for Patients With Ewing ... Participants will receive vincristine, doxorubicin, cyclophosphamide, ifosfamide, etoposide, irinotecan, temozolomide, temsirolimus, bevacizumab, and sorafenib.

3. researchgate.net researchgate.net/publication/232611543_Randomized_Controlled_Trial_of_Interval-Compressed_Chemotherapy_for_the_Treatment_of_Localized_Ewing_Sarcoma_A_Report_From_the_Children's_Oncology_Group

Randomized Controlled Trial of Interval-Compressed ... In localized Ewing's sarcoma, thus, a combination of vincristine, ifosfamide, doxorubicin, and etoposide should be discouraged in favor of the ...

4. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/28550026/

Localized Adult Ewing Sarcoma: Favorable Outcomes with ... We reviewed treatment outcomes in adults with localized ES treated with cyclophosphamide, doxorubicin, and vincristine in alternation with ...

5. onlinelibrary.wiley.com onlinelibrary.wiley.com/doi/10.1155/2017/1278268

Desmoplastic Small Round Blue Cell Tumor: A Review of ... Use of a combined surgery and a Ewing-based chemotherapy regimen of vincristine, doxorubicin, and cyclophosphamide (VAC) and ifosfamide + ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6540207/

Management of recurrent or refractory Ewing sarcoma The current standard first-line chemotherapy for EWS includes vincristine, doxorubicin, cyclophosphamide (VDC), ifosfamide and etoposide (IE), ...

7. emedicine.medscape.com emedicine.medscape.com/article/990378-medication

Ewing Sarcoma Medication: Antineoplastic Agents ... Treatment of Ewing sarcoma lasts 6-9 months and consists of alternating courses of 2 chemotherapeutic regimens: (1) vincristine, doxorubicin ...