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Chemotherapy for the Treatment of Patients With Newly Diagnosed Very Low-Risk and Low Risk Fusion Negative Rhabdomyosarcoma

PHASE3RECRUITING

Rhabdomyosarcoma is a type of cancer that occurs in the soft tissues in the body. This phase III trial aims to maintain excellent outcomes in patients with very low risk rhabdomyosarcoma (VLR-RMS) while decreasing the burden of therapy using treatment with 24 weeks of vincristine and dactinomycin (VA) and examines the use of centralized molecular risk stratification in the treatment of rhabdomyosarcoma. Another aim of the study it to find out how well patients with low risk rhabdomyosarcoma (LR-RMS) respond to standard chemotherapy when patients with VLR-RMS and patients who have rhabdomyosarcoma with DNA mutations get separate treatment.

Finally, this study examines the effect of therapy intensification in patients who have RMS cancer with DNA mutations to see if their outcomes can be improved.

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Study details:

PRIMARY OBJECTIVES:. I. To evaluate the failure free survival (FFS) of patients with very low-risk (VLR) rhabdomyosarcoma (RMS) (fusion negative \[FN\], stage 1, clinical group \[CG\] I, MYOD1 wildtype \[WT\], TP53 \[WT\]) when treated with 24 weeks of vincristine and dactinomycin (VA).

II. To evaluate the FFS of patients with low-risk (LR) RMS (FN, stage 1 CG II, or stage 2 CG I/II or CG III \[orbit only\], MYOD1 WT, TP53 WT) when treated with 12 weeks of vincristine, dactinomycin and cyclophosphamide (VAC) followed by 12 weeks of VA. SECONDARY OBJECTIVES:.

I. To evaluate the overall survival (OS) of patients with VLR RMS treated with 24 weeks of VA. II.

To evaluate the OS of patients with LR RMS treated with 12 weeks of VAC followed by 12 weeks of VA. III. To demonstrate the feasibility of central molecular risk stratification of patients with newly diagnosed RMS in the context of a prospective clinical trial.

EXPLORATORY OBJECTIVES:. I. To collect blood and tissue samples for banking at baseline, during treatment, at the end of therapy, and at the time of progression to bank for future research.

II. To describe the methylation array profile of patients with fusion negative, low-risk rhabdomyosarcoma. III.

To describe the outcomes of patients with VLR or LR RMS and MYOD1 or TP53 mutations treated with intensified therapy. OUTLINE: Patients are assigned to 1 of 2 regimens based on clinical features. Patients with positive mutation status are transitioned to a third regimen, Regimen M.

REGIMEN VA: Patients with VLR RMS receive vincristine intravenously (IV) on day 1 of each cycle and days 8 and 15 of cycles 1, 3, 5, and 7 and dactinomycin IV over 1-5 minutes or over 10-15 minutes on day 1 of each cycle. Treatment repeats every 21 days for 8 cycles in the absence of disease progression or unacceptable toxicity. Patients with MYOD1 or TP53 mutated tumors transition to Regimen M at cycle 2 (if mutation status is determined to be positive at week 3) or cycle 3 (if mutation status is determined to be positive after week 3).

REGIMEN VAC/VA: Patients with LR RMS receive vincristine IV on day 1 of each cycle and days 8 and 15 of cycles 1-3. Patients also receive dactinomycin IV over 1-5 minutes or 10-15 minutes and cyclophosphamide IV over 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 on day 1 of each cycle and days 8 and 15 of cycles 5-7 and dactinomycin IV over 1-5 minutes or over 10-15 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 with MYOD1 or TP53 mutated tumors transition to Regimen M at cycle 2 (if mutation status is determined to be positive at week 3) or cycle 3 (if mutation status is determined to be positive after week 3).

Patients may also undergo radiation therapy at cycle 5. REGIMEN M: Patients receive vincristine IV on day 1 of each cycle and days 8 and 15 of cycles 2-4, 7-8, and 11-12 and dactinomycin IV over 1-5 minutes or 10-15 minutes on day 1 of cycles 2-5 and 8-14. Patients also receive cyclophosphamide IV over 60 minutes on day 1 of each cycle.

Treatment repeats every 21 days for 12-13 cycles in the absence of disease progression or unacceptable toxicity. Patients may also undergo radiation therapy at cycle 5. Patients undergo computed tomography (CT) scan, magnetic resonance imaging (MRI), bone scan, positron emission tomography (PET) scan and tumor biopsy throughout the study.

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Eligibility criteria

Researchers look for people who fit a certain description, called eligibility criteria. See if you qualify.

Inclusion criteria

All patients must be enrolled on APEC14B1 (NCT02402244) and consented to the Molecular Characterization Initiative (Part A) prior to enrollment and treatment on ARST2032 (this trial).

Patients must be =\< 21 years at the time of enrollment.

Patients must have newly diagnosed embryonal rhabdomyosarcoma (ERMS), spindle cell/sclerosing RMS, or FOXO1 fusion negative alveolar rhabdomyosarcoma (ARMS) (institutional FOXO1 fusion results are acceptable). RMS types included under ERMS include those classified in the 1995 International Classification of Rhabdomyosarcoma (ICR) as ERMS (classic, spindle cell, and botryoid variants), which are reclassified in the 2020 World Health Organization (WHO) classification as ERMS (classic, dense and botryoid variants) and spindle cell/sclerosing RMS (encompassing the historical spindle cell ERMS variant and the newly recognized sclerosing RMS variant). Enrollment in APEC14B1 is required for all patients.

All patients will be evaluated for stage and clinical group. Note that clinical group designation assigned at the time of enrollment on study remains unchanged regardless of any second-look operation that may be performed.

Patients will be eligible for the very low-risk stratum (Regimen VA) if they have Stage 1, CG I disease.

Patients will be eligible for the low-risk stratum (Regimen VAC/VA) if they have Stage 1, CG II disease, Stage 2, CG I or II disease, or Stage 1, CG III (orbit only) disease.

Paratesticular Tumors: Staging ipsilateral retroperitoneal lymph node sampling (SIRLNS) is required for all patients >= 10 years of age with paratesticular tumors who do not have gross nodal involvement on imaging.

Extremity Tumors: Regional lymph node sampling is required for histologic evaluation in patients with extremity tumors.

Clinically or radiographically enlarged nodes must be sampled for histologic evaluation.

Patients must have a Lansky (for patients =\< 16 years of age) or Karnofsky (for patients > 16 years of age) performance status score of >= 50. Patients who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing performance score.

Peripheral absolute neutrophil count (ANC) >= 750/uL (within 7 days prior to enrollment).

Platelet count >= 75,000/uL (transfusion independent) (within 7 days prior to enrollment).

Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 mL/min/1.73 m^2 or a serum creatinine (within 7 days prior to enrollment) based on age/gender.

Total bilirubin =\< 1.5 x upper limit of normal (ULN) for age (within 7 days prior to enrollment), and if there is evidence of biliary obstruction by the tumor, then the total bilirubin must be < 3 x ULN for age.

Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =\< 135 U/L.

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

All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met.

Exclusion criteria

Patients who have received prior chemotherapy and/or radiation therapy for cancer prior to enrollment. Surgical resection alone of previous cancer(s) is permitted.

Patients who have received chemotherapy or radiation for non-malignant conditions (e.g., autoimmune diseases) are eligible. Patients must discontinue chemotherapy for non-malignant conditions prior to starting protocol therapy.

Vincristine is sensitive substrate of the CYP450 3A4 isozyme. Patients must not have received drugs that are moderate to strong CYP3A4 inhibitors and inducers within 7 days prior to study enrollment.

Patients unable to undergo radiation therapy, if necessary, as specified in the protocol.

Evidence of uncontrolled infection.

Female patients who are pregnant since fetal toxicities and teratogenic effects have been noted for several of the study drugs. A pregnancy test is required for female patients of childbearing potential.

Lactating females who plan to breastfeed their infants.

Sexually active patients of reproductive potential who have not agreed to use an effective contraceptive method for the duration of their study participation.

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Eligibility

Age eligible for study : 0 and older

Healthy volunteers accepted : No

Gender eligible for study: All

Things to know

Study dates

Study start: 2022-08-04

Primary completion: 2030-06-30

Study completion finish: 2030-06-30

Study type

TREATMENT

Phase

PHASE3

Trial ID

NCT05304585

Intervention or treatment

PROCEDURE: Biopsy

PROCEDURE: Bone Scan

PROCEDURE: Computed Tomography

DRUG: Cyclophosphamide

BIOLOGICAL: Dactinomycin

PROCEDURE: Magnetic Resonance Elastography

PROCEDURE: Positron Emission Tomography

RADIATION: Radiation Therapy

DRUG: Vincristine

Conditions

• Embryonal Rhabdomyosarcoma
• Spindle Cell/Sclerosing Rhabdomyosarcoma
• Fusion-Negative Alveolar Rhabdomyosarcoma

Image related to Embryonal Rhabdomyosarcoma

Condition: Embryonal Rhabdomyosarcoma, Spindle Cell/Sclerosing Rhabdomyosarcoma and more
PROCEDURE: Biopsy and other drugs
Westmead, New South Wales, Australia and more
Sponsor: Children's Oncology Group

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Find a site

Closest Location:

The Children's Hospital at Westmead

Research sites nearby

Select from list below to view details:

The Children's Hospital at Westmead
Westmead, New South Wales, Australia
Perth Children's Hospital
Perth, Western Australia, Australia

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Participant Group/Arm	Intervention/Treatment
EXPERIMENTAL: Regimen M (positive mutation) Patients receive vincristine IV on day 1 of each cycle and days 8 and 15 of cycles 2-4, 7-8, and 11-12 and dactinomycin IV over 1-5 minutes or 10-15 minutes on day 1 of cycles 2-5 and 8-14. Patients also receive cyclophosphamide IV over 60 minutes on day 1 of each cycle. Treatment repeats every 21 days for 12-13 cycles in the absence of disease progression or unacceptable toxicity. Patients may also undergo radiation therapy at cycle 5. Patients undergo CT scan, MRI, bone scan, PET scan and tumor biopsy throughout the study.	PROCEDURE: Biopsy Undergo tumor biopsy
EXPERIMENTAL: Regimen VA (VLR RMS) Patients with VLR RMS receive vincristine intravenously (IV) on day 1 of each cycle and days 8 and 15 of cycles 1, 3, 5, and 7 and dactinomycin IV over 1-5 minutes or over 10-15 minutes on day 1 of each cycle. Treatment repeats every 21 days for 8 cycles in the absence of disease progression or unacceptable toxicity. Patients with MYOD1 or TP53 mutated tumors transition to Regimen M at cycle 2 (if mutation status is determined to be positive at week 3) or cycle 3 (if mutation status is determined to be positive after week 3). Patients undergo CT scan, MRI, bone scan, PET scan and tumor biopsy throughout the study.	PROCEDURE: Biopsy Undergo tumor biopsy
EXPERIMENTAL: Regimen VAC/VA (VL RMS) Patients with LR RMS receive vincristine IV on day 1 of each cycle and days 8 and 15 of cycles 1-3. Patients also receive dactinomycin IV over 1-5 minutes or 10-15 minutes and cyclophosphamide IV over 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 on day 1 of each cycle and days 8 and 15 of cycles 5-7 and dactinomycin IV over 1-5 minutes or over 10-15 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 with MYOD1 or TP53 mutated tumors transition to Regimen M at cycle 2 (if mutation status is determined to be positive at week 3) or cycle 3 (if mutation status is determined to be positive after week 3). Radiation therapy (if needed) will be administered at cycle 5.Patients undergo CT scan, MRI, bone scan, PET scan and tumor biopsy throughout the study.	PROCEDURE: Biopsy Undergo tumor biopsy

What is the study measuring?

Primary outcome

Primary Outcome Measure	Primary Outcome Description	Primary Outcome Time Frame
Failure free survival (FFS) for very low risk patients	The Kaplan-Meier method will be used to estimate 3-year FFS along with 80% log-minus-log transformed confidence limits for very low risk (VLR) patients.	From study enrollment to disease progression, recurrence, or death as a first event, assessed up to 3 years
Failure free survival (FFS) for low risk patients	The Kaplan-Meier method will be used to estimate 3 year FFS along with 80% log-minus-log transformed confidence limits for low risk (LR) patients.	From study enrollment to disease progression, recurrence, or death as a first event, assessed up to 3 years

Secondary outcome

Secondary Outcome Measure	Secondary Outcome Description	Secondary Outcome Time Frame
Overall survival (OS) for very low risk patients	Log-rank test will be used to compare the OS of patients with VLR rhabdomyosarcoma (RMS) treated with 24 weeks of vincristine, dactinomycin (VA) to the VLR RMS patients from ARST0331 and D9602 with the same inclusion criteria.	From study entry to death of any cause, assessed up to 5 years
Overall survival (OS) for low risk patients	Log-rank test will be used to compare the OS from LR RMS patients to LR RMS patients from ARST0331 and D9602 with the same inclusion criteria.	From study entry to death of any cause, assessed up to 5 years
Feasibility of central molecular risk stratification of patients assessed by the percentage of patients who have molecular testing results returned by 6 weeks	If the percentage of patients who have molecular testing results returned by 6 weeks is \>= 80% then the central molecular risk stratification is considered feasible.	Up to 24 weeks

Frequently Asked Questions

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References

Clinical Trials Gov: Chemotherapy for the Treatment of Patients With Newly Diagnosed Very Low-Risk and Low Risk Fusion Negative Rhabdomyosarcoma