Metastatic Ewing's Trial Testing Schedule Enhancement to Improve Outcomes

Not Applicable

Recruiting

• Conditions: Metastatic Ewing Sarcoma
• Interventions: Drug: Vincristine; Drug: Doxorubicin; Drug: Cyclophosphamide; Drug: Ifosfamide; Drug: Actinomycin; Drug: Irinotecan; Drug: Cabozantinib; Drug: Topotecan; Drug: Temozolomide; Drug: Etoposide; Drug: Liposomal doxorubicin

• Registration Number: NCT07194044
• Lead Sponsor: H. Lee Moffitt Cancer Center and Research Institute

Brief Summary

This single arm study is designed to demonstrate the feasibility of a radically different approach for an exceptionally high-risk subset of MES with widely metastatic disease (WMES). We incorporate the use of evolutionary principles that apply to species and population dynamics as related to adaptation and extinction to populations of cancer cells that similarly adapt and that we are attempting to make extinct, resulting in a cure for the patient. Such principles include an initial intense first strike to deplete the bulk of the cancer cells, followed by a series of sequential second strikes towards eliminating residual, resistant populations, followed by a prolonged period of maintenance chemotherapy to eliminate any remnant cells, using agents generally regarded to be active against newly diagnosed ES.

Detailed Description

Not available

Study Timeline

• Status Verified: 2025-09
• Study First Submitted: 2025-09-17
• Study First Submitted QC: 2025-09-25
• Last Update Submitted: 2025-09-25
• Study First Posted: 2025-09-26
• Last Update Posted: 2025-09-26
• Study Start: 2025-10-01
• Primary Completion: 2030-10
• Study Completion: 2030-10-01

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 15

Inclusion Criteria

• Patients must be >1 year of age. There is no upper age limit.
• Patients, in the opinion of the enrolling investigator, must be healthy enough to tolerate protocol therapy.
• Patients must have a new histologic diagnosis of either: widely metastatic Ewing sarcoma or metastatic CIC-rearranged sarcoma.
• Patients must have sufficient tissue submitted (flash frozen tissue, FFPE block, or up to 10 unstained FFPE slides) for correlative testing. This may be from a primary or metastatic site.
• Patients must not have received any prior systemic therapy with the exception that they may have started an initial cycle of vincristine/doxorubicin/cyclophosphamide (VDC) prior to enrollment, i.e. VDC may have been given, but not ifosfamide/etoposide (IE).
• Adequate organ function.
• Males and females of reproductive potential may not participate unless they have agreed to the use of, at minimum, two methods of contraception during and after treatment or abstinence.
• All patients and/or their parents or legal guardians must have the ability to understand and the willingness to sign a written informed consent or assent document.

Exclusion Criteria

• Patients with localized disease or lung only metastases for Ewing sarcoma or localized disease for CIC-rearranged sarcomas.
• Patients with central nervous system (CNS) tumors (primary or metastatic) are not eligible.
• Patients who are receiving any other investigational agents for their cancer.
• Patients with a history of cancer that was treated with myelosuppressive chemotherapy or radiation therapy.
• Patients must not be receiving any additional medicines being given for the specific purpose of treating cancer.
• Patients are ineligible if they have uncontrolled intercurrent illness.
• Pregnancy or Breast Feeding: Pregnant or breast-feeding women will not be entered on this study, because there is no available information regarding human fetal or teratogenic toxicities. Females of childbearing potential must have a negative serum or urine pregnancy test within 72 hours prior to starting protocol therapy.
• Patients who are considered unable to comply with the safety monitoring requirements of the study are not eligible.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Sequential Therapy	Vincristine	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).
Sequential Therapy	Doxorubicin	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).
Sequential Therapy	Cyclophosphamide	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).
Sequential Therapy	Ifosfamide	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).
Sequential Therapy	Actinomycin	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).
Sequential Therapy	Irinotecan	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).
Sequential Therapy	Cabozantinib	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).
Sequential Therapy	Topotecan	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).
Sequential Therapy	Temozolomide	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).
Sequential Therapy	Etoposide	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).
Sequential Therapy	Liposomal doxorubicin	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).

Primary Outcome Measures

Name	Time	Method
Feasibility and Safety - Consolidation	16 months	The treatment will be considered feasible if 70% of Ewing sarcoma patients make it through consolidation.
Feasibility and Safety - Maintenance	16 months	The treatment will be considered feasible if 50% of Ewing sarcoma patients make it through 6 cycles of maintenance.

Secondary Outcome Measures

Name	Time	Method
Event-Free Survival	3 years	EFS is defined as time from treatment initiation to event which includes (1) recurrence, (2) secondary malignancy, and (3) death due to any cause.
Off Treatment Event Free Survival	3 years	otEFS is defined as time from treatment initiation to event 66 which includes (1) any recurrence (local or regional, or distant) that leads to coming off protocol therapy and (2) death due to any cause.
Overall Survival	3 years	The time to event endpoint of overall survival is defined as the duration of time from diagnosis to death or last follow-up timepoint, where event would be death from any cause.

Trial Locations

Locations (16)

University of Alabama at Birmingham (Children's of Alabama); 🇺🇸 Birmingham, Alabama, United States

Phoenix Children's Hospital; 🇺🇸 Phoenix, Arizona, United States

Connecticut Children's Medical Center; 🇺🇸 Hartford, Connecticut, United States

University of Florida; 🇺🇸 Gainesville, Florida, United States

Nemours Jacksonville; 🇺🇸 Jacksonville, Florida, United States

University of Miami; 🇺🇸 Miami, Florida, United States

Moffitt Cancer Center; 🇺🇸 Tampa, Florida, United States

University of Kentucky; 🇺🇸 Lexington, Kentucky, United States

Helen DeVos Children's Hospital; 🇺🇸 Grand Rapids, Michigan, United States

Roswell Park Comprehensive Cancer Center; 🇺🇸 Buffalo, New York, United States

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