Rhabdomyosarcoma (RMS) is a type of cancer that occurs in the soft tissues of the body like the muscles. This study will compare the safety and effect of adding vinorelbine to vincristine, dactinomycin, and cyclophosphamide (VAC) for the treatment of patients with high risk rhabdomyosarcoma (RMS). High risk refers to cancer that is likely to recur (come back) after treatment or spread to other parts of the body. This study will also examine if adding maintenance therapy after VAC therapy, with or without vinorelbine, will help get rid of the cancer and/or lower the chance that the cancer comes back. 

Vinorelbine and vincristine are in a class of medications called vinca alkaloids. They work by stopping cancer cells from growing and dividing and may kill them. Dactinomycin is a type of antibiotic that is only used in cancer chemotherapy. It works by damaging the cell's deoxyribonucleic acid (DNA) and may kill cancer cells. Cyclophosphamide is in a class of medications called alkylating agents. It works by damaging the cell's DNA and may kill cancer cells. Vinorelbine, vincristine, dactinomycin and cyclophosphamide are chemotherapy medications that work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading.  

Participants in this study will be randomized to receive 1 of 2 treatment plans. Randomization is like flipping a coin and there is a 50/50 chance of being assigned to either plan. Arm A will receive the standard therapy of vincristine, dactinomycin and cyclophosphamide (VAC). Arm B will receive the chemotherapy regimen of vinorelbine, dactinomycin, and cyclophosphamide (VINO-AC) with vincristine.

All participants will receive maintenance therapy with the drugs vinorelbine and cyclophosphamide. These combinations, including the maintenance therapy, are considered experimental, which means they have not yet been approved by the U.S. Food and Drug Administration (FDA).

Treatment on this study will last for approximately 16 months. After treatment, participants will have follow-up examinations and medical tests done in the office and may also be asked to participate in additional follow-up appointments after the completion of the study.