Chemotherapy and Radiation with or without Liposomal Irinotecan using Molecular Risk for the Treatment of Children with Rhabdomyosarcoma

Status: active

This phase II trial tests the safety and effectiveness of liposomal irinotecan along with chemotherapy and radiation, using molecular risk to determine treatment, for children with rhabdomyosarcoma. Vincristine is in a class of medications called vinca alkaloids. It works by stopping tumor cells from growing and dividing and may kill them. Dactinomycin is a type of antibiotic that is only used in cancer chemotherapy (antineoplastic antibiotic). It works by damaging the cell’s DNA and may kill tumor cells. Cyclophosphamide is in a class of medications called alkylating agents. It works by damaging the cell’s DNA and may kill tumor cells. It may also lower the body’s immune response. Irinotecan is in a class of antineoplastic medications called topoisomerase I inhibitors. It blocks a certain enzyme needed for cell division and DNA repair and may kill tumor cells. Liposomal irinotecan is a form of the anticancer drug irinotecan that is contained inside very tiny, fat-like particles. Liposomal irinotecan may have fewer side effects and work better than other forms of the drug. Chemotherapy drugs, such as vinorelbine and temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Radiation therapy uses high energy x-rays, particles, or radioactive seeds to kill tumor cells and shrink tumors. Giving chemotherapy with liposomal irinotecan and radiation using molecular risk may be safe, tolerable and/or effective in treating children with rhabdomyosarcoma.

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 MYOD negative, AND ** Embryonal, congenital/infantile spindle cell, or spindle cell/sclerosing FOXO1 fusion negative histology with one of the following characteristics: *** Stage 1 Group I, Group II, OR *** Stage 1 Group III orbital only, OR *** Stage 2 Group I, Group II * Intermediate-risk: ** TP53 and MYOD negative, AND ** Embryonal, congenital/infantile spindle cell, or spindle cell/sclerosing FOXO1 fusion negative histology with one of the following characteristics: *** Stage 1 Group III non orbit, *** Stage 3 Group I/II, OR *** Stage 2/3 Group III, OR *** Stage 4 Group IV AND Oberlin 0-1, ** FOXO1 fusion positive alveolar histology with the following characteristics: *** Stage 1-3, Group I-III N0 * High-risk: ** All MYOD or TP53 mutant tumors regardless of stage and Group ** Embryonal, congenital/infantile spindle cell or spindle cell/sclerosing FOXO1 fusion negative with the following characteristics: *** Group IV AND Oberlin ≥ 2 ** FOXO1 fusion positive alveolar histology with the following characteristics: *** N1, OR *** Group IV
Age < 22 years (eligible for enrollment until 22nd birthday)
Performance level corresponding to Eastern Cooperative Oncology Group (ECOG) score of 0, 1, or 2. The Lansky performance score should be used for participants < 16 years
Participant has received no prior radiotherapy or chemotherapy for rhabdomyosarcoma (excluding steroids) unless an emergency situation requires local tumor treatment (discuss with principal investigator [PI]). Patients requiring emergency radiation therapy are eligible for enrollment on this trial
Initiation of chemotherapy is planned within 6 weeks (42 days) of the definitive biopsy or surgical resection
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 glomerular filtration rate (GFR) ≥ 70 mL/min/1.73^2 or serum creatinine based on age as follows: * 1 month to < 6 months: Male (0.4mg/dL); Female (0.4mg/dL) * 6 months to < 1 year: Male (0.5mg/dL); Female (0.5mg/dL) * 6 months to < 1 year: Male (0.5mg/dL); Female (0.5mg/dL) * 1 to < 2 years: Male (0.6mg/dL); Female (0.6mg/dL) * 2 to < 6 years: Male (0.8mg/dL); Female (0.8mg/dL) * 6 to < 10 years: Male (1mg/dL); Female (1mg/dL) * 10 to < 13 years: Male (1.2mg/dL); Female (1.2mg/dL) * 13 to < 16 years: Male (1.5mg/dL); Female (1.4mg/dL) * > 16 years: Male (1.7mg/dL); Female (1.4mg/dL) * The threshold creatinine values in this table were derived from the Schwartz formula for estimating GFR utilizing child length and stature. Data published by the Centers for Disease Control and Prevention (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
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 radiation therapy (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

Additional locations may be listed on ClinicalTrials.gov for NCT06023641.

State:

United States

California

Palo Alto

Lucile Packard Children's Hospital Stanford University

Status: Active

Contact: Raya Saab

Phone: 650-723-5535

Email: rsaab@stanford.edu

Tennessee

Memphis

Saint Jude Children's Research Hospital

Status: Active

Contact: Alberto S. Pappo

Phone: 901-595-4616

Email: Alberto.Pappo@stjude.org

PRIMARY OBJECTIVES:

I. Estimate event-free survival for intermediate-risk participants treated with vincristine, dactinomycin and cyclophosphamide (VAC) and vincristine and liposomal irinotecan (VLI) with the addition of maintenance therapy with vinorelbine and cyclophosphamide.

II. 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:

I. To assess the relation between pharmacogenetic variation in CEP72 genotype and vinca alkaloid (vincristine; vinorelbine) disposition in children with rhabdomyosarcoma.

II. 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.

III. 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).

IV. 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.

EXPLORATORY OBJECTIVES:

I. Investigate the feasibility of performing radiomic assessment of rhabdomyosarcoma.

II. Document the incidence and severity of peripheral neuropathy during treatment for rhabdomyosarcoma (RMS).

III. Describe the trajectory of onset and potential recovery from acute neuropathy in children with rhabdomyosarcoma.

IV. To determine if the CEP72 promoter single nucleotide polymorphism (SNP) (rs924607) is associated with the incidence and severity of vincristine induced peripheral neuropathy (VIPN) in children receiving treatment for RMS.

V. To assess the significance of CEP72 promoter SNP (rs924607) on the risk and severity of VIPN in a multivariate model that includes patient age, ancestry, and cumulative vincristine/vinorelbine dosages and systemic exposure.

VI. To determine the incidence, severity and trajectory of patient-reported outcomes and patient-reported adverse events during treatment for RMS.

VII. To estimate the frequency of patients with circulating tumor DNA (ctDNA) at diagnosis and subsequent time points, and correlate levels throughout therapy with clinical outcome.

VIII. To establish an understanding of the interpatient genomic variability between RMS tumors in each risk stratum.

OUTLINE: Patients are assigned to 1 of 3 arms based on risk.

ARM I (LOW RISK): Patients receive vincristine intravenously (IV) over 1 minute on days 1, 8, and 15 of each cycle, as well as dactinomycin IV over 1-5 minutes and cyclophosphamide IV over 30-60 minutes on day 1 of each cycle. Treatment repeats every 21 days for 4 cycles in the absence of disease progression or unacceptable toxicity. Patients then receive vincristine IV over 1 minute on days 1, 8, and 15 of each cycle and dactinomycin IV over 1-5 minutes on day 1 of each cycle. Treatment repeats every 21 days for 4 cycles in the absence of disease progression or unacceptable toxicity. Patients do not receive dactinomycin during week 16 (6th overall treatment cycle) if radiation is currently ongoing. Patients may undergo surgery, if indicated after week 10. Patients receive radiation therapy between weeks 13-18.

ARM II (INTERMEDIATE RISK): Patients receive vincristine IV over 1 minute on days 1, 8 and 15 of each cycle, dactinomycin IV over 1-5 minutes on day 1 of odd numbered cycles, cyclophosphamide IV over 30-60 minutes on day 1 of odd numbered cycles, and liposomal irinotecan IV over 90 minutes on even numbered cycles. Treatment repeats every 21 days for 14 cycles in the absence of disease progression or unacceptable toxicity. Patients do not receive dactinomycin during week 19 (cycle 7) if radiation is currently ongoing. Patients then receive vinorelbine IV over 6-10 minutes on days 1, 8 and 15 of each cycle and cyclophosphamide orally (PO) once daily (QD) on days 1-28 of each cycle. Cycles repeat every 28 days for 6 cycles in the absence of disease progression or unacceptable toxicity. Patients may undergo surgery, if indicated after week 10. Patients receive radiation therapy between weeks 4-9 or 13-18 dependent upon surgical outcomes and risk factors.

ARM III (HIGH RISK): Patients receive vincristine IV over 1 minute on days 1, 8 and 15 of each cycle, dactinomycin IV over 1-5 minutes on day 1 of odd numbered cycles, cyclophosphamide IV over 30-60 minutes on day 1 of odd numbered cycles, temozolomide PO on days 1-5 of even numbered cycles, and liposomal irinotecan IV over 90 minutes on day 1 of even numbered cycles. Cycles repeat every 21 days for 14 cycles in the absence of disease progression or unacceptable toxicity. Patients do not receive dactinomycin during week 19 (cycle 7) if radiation is currently ongoing. Patients then receive vinorelbine IV over 6-10 minutes on days 1, 8 and 15 of each cycle and cyclophosphamide PO on days 1-28 of each cycle. Treatment repeats every 28 days for 6 cycles in the absence of disease progression or unacceptable toxicity. Patients may undergo surgery, if indicated after week 12. Patients receive radiation therapy between weeks 4-9 or 13-18 dependent upon surgical outcomes and risk factors, as well as between weeks 37-42.

All patients undergo magnetic resonance imaging (MRI), computed tomography (CT) scan, positron emission tomography (PET) scan and blood and urine sample collection throughout the trial. Patients may undergo bone marrow biopsy, lumbar puncture and lymph node biopsy during screening.

After completion of study treatment, patients are followed up every 3-4 months for 3 years, every 6 months for the next year and then yearly for up to 10 years.

Have a question?
We're here to help

Chat with us: LiveHelp
Call us: 1-800-4-CANCER
(1-800-422-6237)

Which trials are right for you?

Use the checklist in our guide to gather the information you’ll need.

Chemotherapy and Radiation with or without Liposomal Irinotecan using Molecular Risk for the Treatment of Children with Rhabdomyosarcoma

Description

Eligibility Criteria

Locations & Contacts

Trial Objectives and Outline

Trial Phase & Type

Lead Organization

Trial IDs

Have a question?We're here to help

Which trials are right for you?

Have a question?
We're here to help