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

Conditions

• Rhabdomyosarcoma

Eligibility Criteria

Sex

ALL

Age

N/A - 22 Years

Healthy Volunteers

Not accepted

Interventions

• Vincristine — DRUG
  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
• Dactinomycin — DRUG
  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
• Cyclophosphamide — DRUG
  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
• Surgical Resection — PROCEDURE
  Low, Intermediate and High-risk
• Proton beam radiation or external beam radiation or brachytherapy — PROCEDURE
  Low, Intermediate and High-risk
• Liposomal irinotecan — DRUG
  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.
• Vinorelbine — DRUG
  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.
• Temozolomide — DRUG
  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.
• Filgrastim, peg-filgrastim — DRUG
  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.

Study Details

This is a phase II study to determine safety and efficacy of combining liposomal irinotecan with vincristine alternating with VAC in intermediate-risk patients, liposomal irinotecan with temozolomide and vincristine alternating with VAC in high-risk patients and the chemotherapy combinations when given with concomitant radiation therapy in intermediate and high risk patients. Primary Objective * Estimate event-free survival for intermediate-risk participants treated with VAC and vincristine and liposomal irinotecan (VLI) with the addition of maintenance therapy with vinorelbine and cyclophosphamide. * Estimate the event-free survival for high-risk patients treated with VAC and vincristine, liposomal irinotecan, and temozolomide with the addition of maintenance therapy with vinorelbine and cyclophosphamide. Secondary Objectives * To assess the relation between pharmacogenetic variation in CEP72 genotype and vinca alkaloid (vincristine; vinorelbine) disposition in children with rhabdomyosarcoma. * To assess the relation between the pharmacogenetic variation in drug metabolizing enzymes and drug transporters, and the pharmacokinetics of vinca alkaloids, liposomal irinotecan, and cyclophosphamide in children with rhabdomyosarcoma. * To assess the extent of inter-patient variability in the pharmacokinetics of vinca alkaloids, liposomal irinotecan, and cyclophosphamide in children with rhabdomyosarcoma, and explore possible associations between drug disposition and patient specific covariates (e.g., age, sex, race, weight). * Estimate the cumulative incidence of local recurrence and overall 3-year event-free survival in patients with low-risk disease, intermediate-risk disease or high-risk disease treated with either no adjuvant radiation or minimal volume radiation and compare these outcomes with the outcomes achieved on RMS13.

Key Dates

Start date

Mar 13, 2024

Status verified

Aug 2025

Primary completion

Oct 31, 2034

Completion

Oct 31, 2037

Study Design

Enrollment

135 participants (estimated)

Allocation

NON_RANDOMIZED

Intervention model

SINGLE_GROUP

Primary purpose

TREATMENT

Arms

• Experimental: Low -risk
  The participant will receive 12 weeks (4 cycles) of VAC chemotherapy (vincristine, dactinomycin and cyclophosphamide) followed by 12 weeks (4 cycles) of VA chemotherapy (vincristine, dactinomycin). Each cycle of VAC/VA chemotherapy will last for 3 weeks, for a total of 12 weeks (VAC or VA will be given in Week 1 of each cycle and vincristine will be given Weeks 2 and 3). At week 12, the participant will have scans and tests to reevaluate your tumor's response to the treatment. After surgery and radiation, the participant will receive an additional 12 weeks (4 cycles) of the same chemotherapy without cyclophosphamide. Vincristine and dactinomycin, also called "VA". After 4 cycles of VA, The investigator will re-evaluate the tumor again at week 24 and the patient will not get any more chemotherapy, but will be closely watched for any signs of tumor recurrence.
• Experimental: Intermediate-risk
  The purpose of this part of the study is to find out if adding a drug called liposomal irinotecan (also called Onivyde) to standard chemotherapy/radiation/surgery will result in better treatment outcomes for patients with intermediate and high risk rhabdomyosarcoma. The investigators also want to find the best radiation dose to give for intermediate and high risk patients who have large tumors (\> 5 cm). The patient will receive 42 weeks of VAC chemotherapy (vincristine, actinomycin D/dactinomycin and cyclophosphamide) alternating with VLI chemotherapy (vincristine/liposomal irinotecan). The participant will also have surgery to remove the tumor and radiation therapy during this time. After this therapy is completed you will get an additional 6 months of maintenance chemotherapy with vinorelbine and oral (by mouth) cyclophosphamide.
• Experimental: High-risk
  The purpose of this part of the study is to find out if adding a drug called liposomal irinotecan (also called Onivyde) to standard chemotherapy/radiation/surgery will result in better treatment outcomes for patients with high risk rhabdomyosarcoma. The investigator also want to find the best radiation dose to give for high risk patients who have large tumors (\> 5 cm). The patient will receive 42 weeks of VAC chemotherapy (vincristine, actinomycin D/dactinomycin and cyclophosphamide) alternating with VLIT chemotherapy (vincristine/liposomal irinotecan/temozolomide). Also having surgery to remove the participants tumor and radiation therapy during this time. After this therapy is completed the patient will get an additional 6 months of maintenance chemotherapy with vinorelbine and oral (by mouth) cyclophosphamide.

Primary Outcome Measure

Maximum tolerated doses (MTDs) [ Time Frame: 4 years ]

Central Contacts

• Alberto Pappo, MD
  (901) 595-2322
  [email protected]

Locations (3)

Find similar trials in Palo Alto, CA

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