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

This is a phase I-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

* The primary objective of the Phase I part is to estimate the maximum tolerated doses (MTDs) and recommended Phase II doses (RP2Ds) 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.
* 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.
* Estimate the local recurrence rate for unresected intermediate- and high-risk patients with initial tumor size with ≥5 cm randomized to between 59.4 GyRBE and 68 GyRBE total proton radiation dose while receiving VAC/VLI (intermediate-risk) or VAC/VLI plus temozolomide (high-risk) and maintenance therapy.

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 in patients with low-risk disease treated with either no adjuvant radiation or minimal volume radiation.

This is a phase I-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. The phase I part (dose-finding phase) is a dose-escalation part using the BOIN design with maximally 18 patients for each of groups (intermediate -risk, high-risk, and intermediate -and-high-risk-with-early-radiation). Phase I part is to find the maximum tolerated dose and recommended phase II dose for the subsequent phase II part. Phase II part has two primary objectives. The first objective will derive the sample size and it is for efficacy and the endpoint is defined as a 2-year event-free survival (EFS) for each stratum, with 4 years enrollment and 2 years follow-up for each patient, by 80% power and 5% type I error rate, a single-arm adaptive phase II design is used to have estimated numbers of patients for intermediate-risk and high-risk groups are 46 and 33, respectively. The study will end once the last enrolled patient has been followed by 2 years. The second objective is to evaluate the local recurrence rate (LRR) of patients with tumor size ≥ 5cm by using a 2:1 randomization design of comparing administration of the two radiation strategies, 59.4 GyRBE and 68 GyRBE. For this part, 27 additional patients will be required.

Eligibility Criteria:
Inclusion Criteria:

• Newly diagnosed participants with the diagnosis of rhabdomyosarcoma (RMS) of any subtype. This includes embryonal rhabdomyosarcoma (fusion negative), alveolar rhabdomyosarcoma (fusion positive), as well as spindle cell and sclerosing

• Must have either low-, intermediate-risk or high-risk disease, defined as:

1. Low-risk: TP53 and MYOD1 negative AND

   • Embryonal, congenital/infantile spindle cell, or spindle cell/sclerosing FOXO1 fusion negative histology
   * Stage 1 Group I, Group II
   * Stage 1 Group III orbital only
   * Stage 2 Group I, Group II
2. Intermediate-risk: MYOD1 and TP53 negative AND

   • Embryonal, congenital/infantile spindle cell, or spindle cell/sclerosing FOXO1 fusion negative histology o Stage 1 Group III non orbit o Stage 3 Group I/II

   o Stage 2/3 Group III
   * Stage 4 Group IV and Oberlin 0-1

     • Alveolar, spindle cell/sclerosing FOXO1 fusion positive histology
   * Stage 1-3, Group I-III N0
3. High-risk: All MYOD1 and TP53 mutant tumors regardless of stage and Group AND/OR

   * Embryonal, congenital/infantile spindle cell or spindle cell/sclerosing FOXO1 fusion negative o Group IV ≥ 10 year of age and Oberlin ≥ 2
   * Alveolar, spindle cell/sclerosing FOXO1 fusion positive

     * N1
     * Stage 4 Group IV

   See Appendices I and II for Staging and Clinical Grouping.

   Age \< 22 years (eligible for enrollment until 22nd birthday)

   • Performance level corresponding to ECOG score of 0, 1, or 2. The Lansky performance score should be used for participants \< 16 years (see Appendix VII).
   * Participant has received no prior radiotherapy or chemotherapy for rhabdomyosarcoma (excluding steroids) unless an emergency situation requires local tumor treatment (discuss with PI).
   * Initiation of chemotherapy is planned within 6 weeks (42 days) of the definitive biopsy or surgical resection.
   * Adequate bone marrow function defined as:
   * Peripheral absolute neutrophil count (ANC) ≥ 750/μL
   * Platelet count ≥ 75,000/μL (transfusion independent)
   * Adequate liver function defined as total bilirubin \< 1.5 x upper limit of normal (ULN) for age. Participants with biliary or hepatic primaries with bilirubin values greater than 1.5 x ULN may be enrolled on study if all other eligibility criteria are met.

   Adequate renal function defined as:

   Creatinine clearance or radioisotope GFR \> 70 mL/min/1.732 or serum creatinine based on age as follows:

   Age Maximum serum creatinine (mg/dL) Male Female

   1 month to \< 6 months 0.4 0.4 6 months to \< 1 year 0.5 0.5 Age Maximum serum creatinine (mg/dL)
   1. to \< 2 years 0.6 0.6
   2. to \< 6 years 0.8 0.8

   6 to \< 10 years 1 1 10 to \< 13 years 1.2 1.2 13 to \< 16 years 1.5 1.4 \> 16 years 1.7 1.4

   The threshold creatinine values in this table were derived from the Schwartz formula for estimating GFR25 utilizing child length and stature. Data published by the CDC.

   Participants with urinary tract obstruction by tumor must meet the renal function criteria listed above AND must have unimpeded urinary flow established via decompression of the obstructed portion of the urinary tract.

   • Adequate pulmonary function defined as: no evidence of dyspnea at rest and a pulse oximetry \> 94% if there is a clinical indication for determination. Pulmonary function tests are not required.

   • Patients requiring emergency radiation therapy are eligible for enrollment on this trial. See Section 4.11 for radiation therapy guidelines.

   • No evidence of active, uncontrolled infection.

   All participants and/or their parents or legal guardians must sign a written informed consent.

   Exclusion Criteria:

   • Patients who have received any chemotherapy (excluding steroids).

   • Patients who have received prior full course RT at the primary site of disease. This does not exclude patients that received emergent radiation.
   * Ongoing or history of non-infectious interstitial lung disease requiring significant medical intervention.
   * Sexually active patients of reproductive potential who have not agreed to use an effective contraceptive method for the duration of their study participation and for at least 3 months after treatment is completed.
   * Female patients who are pregnant are not eligible since fetal toxicities or teratogenic effects have been noted for several of the study drugs. Female participants \> 10 years of age or post-menarchal must have a negative serum or urine pregnancy test within 24 hours prior to beginning treatment.
   * Lactating females who are or plan to breastfeed their infants are not eligible.