Drug Combination for Ewing Sarcoma

(METTSEO Trial)

Recruiting at 16 trial locations

Overseen By Jessica Crimella

Age: Any Age

Sex: Any

Trial Phase: Phase 1

Sponsor: H. Lee Moffitt Cancer Center and Research Institute

Must not be taking: Investigational agents

Disqualifiers: Localized disease, CNS tumors, others

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

Compensation: Varies

Number of Visits: Unknown

15 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new approach to treating widely metastatic Ewing sarcoma or metastatic CIC-rearranged sarcoma. The research aims to determine if a combination of drugs—Actinomycin, Cyclophosphamide, Doxorubicin, Etoposide, Ifosfamide, Irinotecan, Liposomal doxorubicin, Temozolomide, and Vincristine—can effectively reduce and eventually eliminate cancer cells by initially targeting them aggressively, followed by ongoing treatment. Participants should have a new diagnosis of the specified sarcoma types and must not have received certain cancer treatments before joining. As a Phase 1 trial, this research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this potentially groundbreaking therapy.

Do I have to stop taking my current medications for the trial?

The trial does not specify if you need to stop taking your current medications, but you cannot be on any other cancer treatments while participating.

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

A previous study found that the drugs vincristine, doxorubicin, and cyclophosphamide effectively treat Ewing sarcoma, but monitoring for cyclophosphamide's side effects is crucial. Patients with relapsed Ewing sarcoma have tolerated irinotecan and temozolomide well, demonstrating both effectiveness and safety. Some studies found that cabozantinib causes side effects similar to those in other cancers, suggesting they are generally manageable. Reports indicate that high-dose ifosfamide is better tolerated when administered continuously.

The combination of topotecan and cyclophosphamide is considered tolerable, though it may be less effective in adults with recurring sarcoma. Oral etoposide has shown efficacy in fighting tumors even in relapsed patients. Finally, vincristine with liposomal doxorubicin has an acceptable level of side effects.

This trial is in Phase 1, focusing on assessing the safety of these drug combinations. At this early stage, researchers gather safety data, so information on drug tolerance may be limited. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about this treatment for Ewing Sarcoma because it combines multiple chemotherapy agents in a unique sequential therapy approach. While standard treatments often rely on a consistent regimen of drugs like Vincristine, Doxorubicin, and Cyclophosphamide, this experimental approach varies the drugs over time and incorporates newer options like Liposomal Doxorubicin and targeted therapies like Cabozantinib. This method aims to maximize effectiveness while potentially reducing resistance, offering hope for improved outcomes in treating this aggressive cancer.

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

This trial will evaluate a sequential therapy approach for Ewing Sarcoma, using different drug combinations at various stages. Research has shown that combining vincristine, doxorubicin, and cyclophosphamide, administered during weeks 1-8, greatly improves survival rates for patients with Ewing Sarcoma. Adding ifosfamide and etoposide in the trial's maintenance phase has led to even better outcomes. The combination of irinotecan and temozolomide, used in weeks 33-38, effectively shrinks tumors and is considered safe for patients with recurrent Ewing Sarcoma. Studies on cabozantinib, given with radiation therapy during weeks 15-20, showed that 26% of patients responded positively, with the cancer not worsening for an average of 4.4 months. High doses of ifosfamide, used in weeks 27-32, have been found to be more effective for treating recurring Ewing Sarcoma, helping patients live longer without the cancer returning. Each of these treatments targets and reduces cancer cells in different ways. ^{1 2 3 6 7}

Who Is on the Research Team?

Matteo Trucco, MD

Principal Investigator

Cleveland Clinic Hospital

Jonathan Metts, MD

Principal Investigator

Moffitt Cancer Center

Are You a Good Fit for This Trial?

This trial is for individuals over 1 year old with a new diagnosis of widely metastatic Ewing sarcoma or CIC-rearranged sarcoma, who haven't had much prior treatment. They must be healthy enough to handle the therapy and agree to use two contraception methods if applicable. Those with previous cancer treatments, uncontrolled illnesses, CNS tumors, or pregnant/breastfeeding women can't join.

Inclusion Criteria

Patients, in the opinion of the enrolling investigator, must be healthy enough to tolerate protocol therapy

My organs are functioning well.

I am older than 1 year.

Exclusion Criteria

Patients receiving any other investigational agents for their cancer

Patients with uncontrolled intercurrent illness

Pregnant or breast-feeding women

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Initial Intense Treatment

Initial intense first strike to deplete the bulk of the cancer cells using Vincristine/Doxorubicin/Cyclophosphamide

8 weeks

Weekly visits (in-person)

Sequential Second Strikes

Sequential second strikes to eliminate residual, resistant populations with various chemotherapy regimens

30 weeks

Bi-weekly visits (in-person)

Maintenance Chemotherapy

Prolonged period of maintenance chemotherapy to eliminate any remnant cells

65 weeks

Monthly visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

3 years

What Are the Treatments Tested in This Trial?

Interventions

• Actinomycin
• Cabozantinib
• Cyclophosphamide
• Doxorubicin
• Etoposide
• Ifosfamide
• Irinotecan
• Liposomal doxorubicin
• Temozolomide
• Topotecan
• Vincristine

Trial Overview The study tests an intensive chemotherapy approach on metastatic Ewing's Sarcoma by first using high-dose chemo to reduce most cancer cells, followed by varied treatments targeting resistant cells and maintenance therapy. Drugs include Vincristine, Doxorubicin (and its liposomal form), Cyclophosphamide, Ifosfamide, Actinomycin D, Irinotecan, Temozolomide, Etoposide Cabozantinib and Topotecan.

How Is the Trial Designed?

Group I: Sequential Therapy Experimental Treatment 11 Interventions

Weeks 1-8, Vincristine/Doxorubicin/Cyclophosphamide. Weeks 9-14, Irinotecan, Ifosfamide, Vincristine, Actinomycin (IrIVA). Weeks 15-20, Cabozantinib w/ primary site radiation. Weeks 21-26, Topotecan/Cyclophosphamide. Weeks 27-32, High Dose Ifosfamide. Weeks 33-38, Irinotecan/Temozolomide. Maintenance, Weeks 39 up to 104, will consist of alternating 28-day blocks of chemotherapy (Block 1 and Block 2). Oral Cyclophosphamide / Oral Etoposide (Block 1). Vincristine/ Liposomal Doxorubicin (Block 2).

Who Is Running the Clinical Trial?

H. Lee Moffitt Cancer Center and Research Institute

Lead Sponsor

Trials

576

Recruited

145,000+

National Pediatric Cancer Foundation

Collaborator

Trials

8

Recruited

300+

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9918141/

Real-World Data on Cabozantinib in Advanced Osteosarcoma ... No objective response was noted, and 9/16 patients exhibited stable disease outcomes. Progression-free survival varied from 1 to 8 (median; 5) ...

2. thelancet.com thelancet.com/journals/lanonc/article/PIIS1470-2045(19)30825-3/abstract

Cabozantinib in patients with advanced Ewing sarcoma or ... The primary endpoint for Ewing sarcoma was best objective response within 6 months of treatment onset; for osteosarcoma, a dual primary endpoint ...

3. journals.lww.com journals.lww.com/co-oncology/fulltext/2020/07000/cabozantinib_as_an_emerging_treatment_for_sarcoma.13.aspx

Cabozantinib as an emerging treatment for sarcoma For the efficacy evaluable patients with Ewing sarcoma (n = 39), ORR was 26% (n = 10) by 6 months, median PFS was 4.4 months (95% CI 3.7–5.6), and median OS ...

4. sciencedirect.com sciencedirect.com/science/article/abs/pii/S1470204519308253

Cabozantinib in patients with advanced Ewing sarcoma or ... The primary endpoint for Ewing sarcoma was best objective response within 6 months of treatment onset; for osteosarcoma, a dual primary endpoint of 6-month ...

5. clinicaltrials.gov clinicaltrials.gov/study/NCT06156410

Cabozantinib With Ifosfamide in Ewing's Sarcoma and ... The purpose of this study is to better understand how safe and effective the drug cabozantinib in combination with high-dose ifosfamide is in the treatment of ...

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/32078813/

Cabozantinib in patients with advanced Ewing sarcoma or ... All enrolled patients who received at least one dose of cabozantinib were included in the safety analysis, and all participants who received at least one ...

7. annalsofoncology.org annalsofoncology.org/article/S0923-7534(19)50473-2/fulltext

Cabozantinib in patients with advanced osteosarcomas ... Cabozantinib has shown meaningful clinical activity in OS and ES patients with heavily pre-treated advanced disease and reached the primary endpoint of ...