Title
A Prospective Phase 3 Study of Patients with Newly Diagnosed Very Low-risk and Low-risk Fusion Negative Rhabdomyosarcoma

Description
Rhabdomyosarcoma is a type of cancer that occurs in the soft tissues in the body. This phase III trial aims to maintain excellent outcomes in patients with very low risk rhabdomyosarcoma (VLR-RMS) while decreasing the burden of therapy using treatment with 24 weeks of vincristine and dactinomycin (VA) and examines the use of centralized molecular risk stratification in the treatment of rhabdomyosarcoma. Another aim of the study it to find out how well patients with low risk rhabdomyosarcoma (LR-RMS) respond to standard chemotherapy when patients with VLR-RMS and patients who have rhabdomyosarcoma with DNA mutations get separate treatment. Finally, this study examines the effect of therapy intensification in patients who have RMS cancer with DNA mutations to see if their outcomes can be improved.

Objective
PRIMARY OBJECTIVES:

I. To evaluate the failure free survival (FFS) of patients with very low-risk (VLR) rhabdomyosarcoma (RMS) (fusion negative [FN], stage 1, clinical group [CG] I, MYOD1 wildtype [WT], TP53 [WT]) when treated with 24 weeks of vincristine and dactinomycin (VA).

II. To evaluate the FFS of patients with low-risk (LR) RMS (FN, stage 1 CG II, or stage 2 CG I/II or CG III [orbit only], MYOD1 WT, TP53 WT) when treated with 12 weeks of vincristine, dactinomycin and cyclophosphamide (VAC) followed by 12 weeks of VA.

SECONDARY OBJECTIVES:

I. To evaluate the overall survival (OS) of patients with VLR RMS treated with 24 weeks of VA.

II. To evaluate the OS of patients with LR RMS treated with 12 weeks of VAC followed by 12 weeks of VA.

III. To demonstrate the feasibility of central molecular risk stratification of patients with newly diagnosed RMS in the context of a prospective clinical trial.

EXPLORATORY OBJECTIVES:

I. To collect blood and tissue samples for banking at baseline, during treatment, at the end of therapy, and at the time of progression to bank for future research.

II. To describe the methylation array profile of patients with fusion negative, low-risk rhabdomyosarcoma.

III. To describe the outcomes of patients with VLR or LR RMS and MYOD1 or TP53 mutations treated with intensified therapy.

OUTLINE: Patients are assigned to 1 of 2 regimens based on clinical features. Patients with positive mutation status are transitioned to a third regimen, Regimen M.

REGIMEN VA: Patients with VLR RMS receive vincristine intravenously (IV) on day 1 of each cycle and days 8 and 15 of cycles 1, 3, 5, and 7 and dactinomycin IV over 1-5 minutes or over 10-15 minutes on day 1 of each cycle. Treatment repeats every 21 days for 8 cycles in the absence of disease progression or unacceptable toxicity. Patients with MYOD1 or TP53 mutated tumors transition to Regimen M at cycle 2 (if mutation status is determined to be positive at week 3) or cycle 3 (if mutation status is determined to be positive after week 3).

REGIMEN VAC/VA: Patients with LR RMS receive vincristine IV on day 1 of each cycle and days 8 and 15 of cycles 1-3. Patients also receive dactinomycin IV over 1-5 minutes or 10-15 minutes and cyclophosphamide IV over 60 minutes on day 1 of each cycle. Treatment repeats every 21 days for 4 cycles in the absence of disease progression or unacceptable toxicity. Patients then receive vincristine IV on day 1 of each cycle and days 8 and 15 of cycles 5-7 and dactinomycin IV over 1-5 minutes or over 10-15 minutes on day 1 of each cycle. Treatment repeats every 21 days for 4 cycles in the absence of disease progression or unacceptable toxicity. Patients with MYOD1 or TP53 mutated tumors transition to Regimen M at cycle 2 (if mutation status is determined to be positive at week 3) or cycle 3 (if mutation status is determined to be positive after week 3). Patients may also undergo radiation therapy at cycle 5.

REGIMEN M: Patients receive vincristine IV on day 1 of each cycle and days 8 and 15 of cycles 2-4, 7-8, and 11-12 and dactinomycin IV over 1-5 minutes or 10-15 minutes on day 1 of cycles 2-5 and 8-14. Patients also receive cyclophosphamide IV over 60 minutes on day 1 of each cycle. Treatment repeats every 21 days for 12-13 cycles in the absence of disease progression or unacceptable toxicity. Patients may also undergo radiation therapy at cycle 5.

After completion of study treatment, patients are followed up every 3 months during the first year, then every 4 months for years 2 and 3, every 6 months for year 4, and finally at 5 years post treatment conclusion date.

Treatment Patients will be assigned to the VLR (Regimen VA) or LR (Regimen VAC/VA) group based on clinical criteria at diagnosis. Patients with VLR-RMS will receive one to two cycles of VA chemotherapy initially, whereas patients with LR-RMS will receive one to two cycles of VAC chemotherapy. FOXO1 fusion status and MYOD1/TP53 mutation status will be determined through the CCDI Molecular Characterization Initiative via APEC14B1 by Week 6 of therapy.
Patients with MYOD1 wildtype (WT) or TP53 WT tumors will remain on their assigned treatment regimen (Regimens VA or VAC/VA). Patients with FOXO1 fusion positive tumors will be
removed from study. Patients with MYOD1 or TP53 mutated tumors will transition to Regimen M at Week 4 (Cycle 2) or Week 7 (Cycle 3) to complete a total of 42 weeks of therapy with VAC. Patients who have indeterminate TP53 or MYOD1 mutational results through the CCDI MCI will be allowed to remain on study and will continue on their original treatment Regimen (VA or VAC/VA).

Key Eligibility For full study eligibility, see this study's ClinicalTrials.gov record.

Applicable Disease Sites
Bladder; Colon and Rectum; Endocrine cancers; Esophagus; Gastrointestinal cancers, other; Genitourinary cancers, other; Head and Neck; Kidney; Liver; Lung; Melanoma/Skin cancer; Ovary; Pancreas; Prostate; Sarcoma; Stomach; Thyroid

Participating Institutions
Gundersen Health System; UW Health University Hospital