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

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ClinicalTrials.gov Identifier: NCT06023641

Recruitment Status : Recruiting

First Posted : September 5, 2023

Last Update Posted : May 8, 2024

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Sponsor:

Information provided by (Responsible Party):

St. Jude Children's Research Hospital

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Rhabdomyosarcoma	Drug: Vincristine Drug: Dactinomycin Drug: Cyclophosphamide Procedure: Surgical Resection Procedure: Proton beam radiation or external beam radiation or brachytherapy Drug: Liposomal irinotecan Drug: Vinorelbine Drug: Temozolomide Drug: Filgrastim, peg-filgrastim	Phase 1 Phase 2

Detailed Description:

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.

Study Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	100 participants
Allocation:	Non-Randomized
Intervention Model:	Single Group Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	A Protocol for the Treatment of Newly Diagnosed Rhabdomyosarcoma Using Molecular Risk Stratification and Liposomal Irinotecan Based Therapy in Children With Intermediate and High Risk Disease
Actual Study Start Date :	March 13, 2024
Estimated Primary Completion Date :	October 2034
Estimated Study Completion Date :	October 2037

Resource links provided by the National Library of Medicine

Drug Information available for: Irinotecan

Genetic and Rare Diseases Information Center resources: Soft Tissue Sarcoma

U.S. FDA Resources

Arms and Interventions

Arm	Intervention/treatment
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.	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 Other Name: Oncovin 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 Other Name: (actinomycin-D) 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 Other Name: Cytoxan®. Procedure: Surgical Resection Low, Intermediate and High-risk Procedure: Proton beam radiation or external beam radiation or brachytherapy Low, Intermediate and High-risk
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.	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 Other Name: Oncovin 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 Other Name: (actinomycin-D) 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 Other Name: Cytoxan®. 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. Other Name: (Onivyde®) 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. Other Name: Navelbine 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. Other Name: Neupogen
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.	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 Other Name: Oncovin 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 Other Name: (actinomycin-D) 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 Other Name: Cytoxan®. 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. Other Name: (Onivyde®) 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. Other Name: Navelbine 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. Other Name: Temodar 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. Other Name: Neupogen

Outcome Measures

Primary Outcome Measures :

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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Eligibility Criteria

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Ages Eligible for Study:	up to 22 Years (Child, Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

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:

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
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
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.

Contacts and Locations

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT06023641

Contacts

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Contact: Alberto Pappo, MD	(901) 595-2322	alberto.pappo@stjude.org

Locations

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United States, California
Sanford University	Not yet recruiting
Palo Alto, California, United States, 94304
Contact: Raya Saab, MD 650-497-8953 rsaab@stanford.edu
Principal Investigator: Raya Saab, MD
United States, Tennessee
St. Jude Children's Research Hospital	Recruiting
Memphis, Tennessee, United States, 38105
Contact: Alberto Pappo, MD 901-595-2322 referralinfo@stjude.org
United States, Texas
Cook Children's Medical Center	Not yet recruiting
Fort Worth, Texas, United States, 76104-2796
Contact: Karen Albritton, MD 682-885-4007 karen.albritton@cookchildrens.org
Principal Investigator: Karen Albritton

Sponsors and Collaborators

St. Jude Children's Research Hospital

Investigators

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Principal Investigator:	Alberto Pappo, MD	St. Jude Children's Research Hospital

More Information

Additional Information:

St. Jude Children's Research Hospital This link exits the ClinicalTrials.gov site

Clinical Trials Open at St. Jude This link exits the ClinicalTrials.gov site

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Responsible Party:	St. Jude Children's Research Hospital
ClinicalTrials.gov Identifier:	NCT06023641
Other Study ID Numbers:	RMS2021 NCI-2024-00701 ( Other Identifier: NCI Clinical Trial Registration Program )
First Posted:	September 5, 2023 Key Record Dates
Last Update Posted:	May 8, 2024
Last Verified:	February 2024
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD:	Yes
Plan Description:	Individual participant de-identified datasets containing the variables analyzed in the published article will be made available (related to the study primary or secondary objectives contained in the publication). Supporting documents such as the protocol, statistical analyses plan, and informed consent are available through the CTG website for the specific study. Data used to generate the published article will be made available at the time of article publication. Investigators who seek access to individual level de-identified data will contact the computing team in the Department of Biostatistics (ClinTrialDataRequest@stjude.org) who will respond to the data request
Supporting Materials:	Study Protocol Statistical Analysis Plan (SAP) Informed Consent Form (ICF)
Time Frame:	Data will be made available at the time of article publication.
Access Criteria:	Data will be provided to researchers following a formal request with the following information: full name of requestor, affiliation, data set requested, and timing of when data is needed. As an informational point, the lead statistician and study principal investigator will be informed that primary results datasets have been requested.

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Studies a U.S. FDA-regulated Drug Product:	Yes
Studies a U.S. FDA-regulated Device Product:	No
Product Manufactured in and Exported from the U.S.:	Yes

Additional relevant MeSH terms:

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Rhabdomyosarcoma Myosarcoma Neoplasms, Muscle Tissue Neoplasms, Connective and Soft Tissue Neoplasms by Histologic Type Neoplasms Sarcoma Dactinomycin Cyclophosphamide Temozolomide Irinotecan Vincristine Vinorelbine Lenograstim Immunosuppressive Agents	Immunologic Factors Physiological Effects of Drugs Antirheumatic Agents Antineoplastic Agents, Alkylating Alkylating Agents Molecular Mechanisms of Pharmacological Action Antineoplastic Agents Myeloablative Agonists Topoisomerase I Inhibitors Topoisomerase Inhibitors Enzyme Inhibitors Adjuvants, Immunologic Antineoplastic Agents, Phytogenic Tubulin Modulators Antimitotic Agents

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