Treatment of Newly Diagnosed Rhabdomyosarcoma Using Molecular Risk Stratification and Liposomal Irinotecan Based Therapy in Children With Intermediate and High Risk Disease

DRUG

Vincristine

Low -risk Administer IV push over 1 minute (or infusion via minibag as per institutional standards) on Day 1 of Weeks 1,8, 15 (3) doses. The maximum dose is 2 mg for all participants. Intermediate-risk Administer IV, over 1 minute, 3 doses, weekly on day1 High-risk Administer by IV infusion over 1 minute, 3 doses, weekly on day 1,8,15

DRUG

Dactinomycin

Low-risk Administer by slow IV push over 1-5 minutes on Day 1 of Weeks 1, (1) dose. The maximum dose is 2.5 mg for all participants. Intermediate-risk Administer by slow IV over 1-5 minutes., 1 doses weekly on day 1 High-risk Administer by slow IV over 1-5 minutes, day1

DRUG

Cyclophosphamide

Low-risk Administer by IV infusion over 30-60 minutes on Day 1, 91) dose, Mesna and hydration will be given with IV cyclophosphamide according to institutional standards. Intermediate-risk Administer by IV infusion over 30-60 minutes, 1 dose, day 1 High-risk Administer by IV infusion over 30-60 minutes, 1 dose, day1

PROCEDURE

Surgical Resection

Low, Intermediate and High-risk

PROCEDURE

Proton beam radiation or external beam radiation or brachytherapy

Low, Intermediate and High-risk

DRUG

Liposomal irinotecan

Intermediate and High-risk Administer by IV infusion over 90 minutes, 1 dose on day 1 Liposomal irinotecan should be premedicated with dexamethasone (or an equivalent corticosteroid) if not contraindicated. Premedication with diphenhydramine and an H2 receptor antagonist (i.e., famotidine) are also encouraged.

DRUG

Vinorelbine

Intermediate and High-risk Administer via slow IV push over 6-10 minutes (or infusion via minibag as per institutional standards) on Day 1 of Weeks 43-45, 47-49, 51-53, 55-57, 59-61, 63-65.

DRUG

Temozolomide

High-risk Administer PO (or by NG or G tube) 5 doses, on Days 1-5 When administering with liposomal irinotecan, administer temozolomide prior to liposomal irinotecan. Preferably, administer on an empty stomach (at least 1 hour before and 2 hours after food) to improve absorption. When using temozolomide capsules, round dose to the nearest 5 mg capsule. The capsule may be opened, and contents mixed with applesauce or apple juice. A compounded oral suspension is also available. If emesis occurs within 20 minutes of taking a dose of temozolomide, then the dose may be repeated once.

DRUG

Filgrastim, peg-filgrastim

Low, Intermediate and High-risk: Prophylactic myeloid growth factor support (Filgrastim or Pegfilgrastim) should be used after all VAC cycles for patients on the high-risk arm. Start myeloid growth factor support (for example, filgrastim 5 mcg/kg/dose SubQ daily until the ANC is ≥ 2000/μL after the expected nadir OR pegfilgrastim 0.1 mg/kg/dose \[for patients \< 45 kg\] or 6 mg/dose \[for patients ≥ 45 kg\] SubQ x 1 dose) 24-48 hours after VAC cycles. Filgrastim may be continued without regard to VCR. Discontinue filgrastim at least 24 hours before the start of the next cycle. Prophylactic myeloid growth factor support should NOT be used after VLIT cycles or during maintenance chemotherapy.

Maximum tolerated doses (MTDs)

Time frame: 4 years

MTD is defined in the study as the highest treatment dose that would deliver desirable treatment effects without resulting in a target toxicity rate greater than 0.3. For each of three groups (intermediate-risk, high-risk, and intermediate-and-high-risk-with-early-radiation), we will employ the Bayesian optimal interval (BOIN) design to find the MTD.

Event-free survival (EFS)

Time frame: 2 years post, off therapy

We will estimate the 2-year event-free survival for intermediate-risk and high-risk patients, which is the estimated probability of a patient not having any events within the 2-year follow-up. If an event, including local failure, distant failure, death or loss to follow-up occurs for a patient within 2-year, we call it failure, otherwise call it response.

Local recurrence rate (LRR)

Time frame: 2 years

LRR is defined as a binary endpoint in the study. The local recurrence-free survival (LRFS) is defined as time from randomization to the earlier date of the first of local disease recurrence or death due to any cause. The distant failure will be considered to be the competing risk, patients for whom follow-up ended without clinical improvement will be censored. The goal of the local recurrence rate endpoint is to evaluate the 2-year LRR by comparing the administration of 59.4 GyRBE and 68 GyRBE for patients (pooled intermediate- and high-risk groups) with tumor size greater than or equal to 5cm meeting the eligibility criteria for randomization (no biliary tree or specific extremity cases). .

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