Altering the Selection and Timing of Therapies for the Treatment of Widely Metastatic Ewing Sarcoma and CIC-Rearranged Sarcoma

PRIMARY OBJECTIVE:

I. To evaluate the safety and feasibility of an evolutionary-inspired schedule of sequential second strikes in the WMES population.

SECONDARY OBJECTIVES:

I. To determine the 3-year event-free survival (EFS) for WMES and metastatic CIC-rearranged sarcoma treated on this regimen.

II. To determine the 3-year off-treatment event-free survival (otEFS) for WMES treated on this regimen.

III. To determine the 3-year overall survival (OS) for WMES and metastatic CIC-rearranged sarcoma treated on this regimen.

EXPLORATORY OBJECTIVES:

I. To describe the grade 3+ and other significant toxicities of this regimen per Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5.

II. To build and improve mathematical models for predicting and tracking responses to therapies with the goal of improving strategies for preventing resistance and identifying potentially superior strategies for utilizing different doses, schedules or agents in the management of WMES and metastatic CIC-rearranged sarcoma.

III. To assess additional biomarkers by quantifying circulating tumor DNA (ctDNA) in patients and determine if ctDNA changes over time in a manner that reflects tumor burden, presence of resistant cancer cells, response to therapy, predicts risk of progression, and informs the mathematical models.

IV. To evaluate a set of radiomic biomarkers calculated from baseline and post-therapy computed tomography (CT) and magnetic resonance imaging (MRI) scans, and compare results with treatment response and mathematical model predictions.

V. To perform single cell sequencing of circulating tumor cells (CTC) to evaluate changes over time and explore their relationship with disease progression.

VI. To collect tumor biopsy samples prior to and during treatment, and if applicable, at progression/recurrence that may be used to evaluate the effect of the therapy on subpopulations and resistance patterns within the patients’ cancer.

OUTLINE:

INDUCTION:

WEEKS 1-8: Patients receive vincristine intravenously (IV) push on day 1, doxorubicin IV over 15-30 minutes on day 1 or days 1 and 2, and cyclophosphamide IV over 60 minutes on day 1 of each cycle. Cycles repeat every 14 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity.

WEEKS 9-14: Patients receive vincristine IV push on days 1, 8, and 15, ifosfamide IV over 4 hours on days 1 and 2, dactinomycin (actinomycin) IV over 1-5 minutes on day 1 and irinotecan IV over 60 minutes on days 8-12 of each cycle. Cycles repeat every 21 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity.

CONSOLIDATION:

WEEKS 15-20: Patients receive cabozantinib orally (PO) once daily (QD) for up to 42 days during radiation therapy to the primary site in the absence of disease progression or unacceptable toxicity.

WEEKS 21-26: Patients receive topotecan IV over 30 minutes on days 1-5 and cyclophosphamide IV over 15-30 minutes on days 1-5 of each cycle. Cycles repeat every 21 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity.

WEEKS 27-32: Patients receive ifosfamide IV over 4 hours on days 1-5 of each cycle. Cycles repeat every 21 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity.

WEEKS 33-38: Patients undergo conventional radiation or SBRT to metastatic sites. Patients also receive temozolomide IV over 60 minutes or PO on days 1-5 and irinotecan IV over 90 minutes or PO on days 1-5 and 8-12 of each cycle. Cycles repeat every 21 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity.

MAINTENANCE WEEKS 39-104:

BLOCK 1: Patients receive cyclophosphamide PO QD on days 1-14 and etoposide PO QD on days 15-28 of each cycle. Cycles of Block 1 repeat every 28 days alternating with cycles of Block 2 for at least 6 cycles.

BLOCK 2: Patients receive pegylated liposomal doxorubicin hydrochloride (liposomal doxorubicin) IV over 60 minutes on day 1 and vincristine IV push on day 1 of each cycle. Cycles of Block 2 repeat every 28 days alternating with cycles of Block 1 for at least 6 cycles.

Maintenance treatment continues for up to a total of 2 years of treatment in the absence of disease progression or unacceptable toxicity.

Patients also undergo echocardiography, blood sample collection and positron emission tomography (PET)/CT and MRI or CT throughout the study. Additionally, patients may undergo tumor biopsy and bone marrow aspiration and biopsy throughout the study.

After completion of study treatment, patients are followed for 30 days, then every 3-12 months for up to 5 years.