Chemotherapy for the Treatment of Patients With Newly Diagnosed Very Low-Risk and Low Risk Fusion Negative Rhabdomyosarcoma
S
Sandeep Batra, MD
Primary Investigator
Overview
Rhabdomyosarcoma is a type of cancer that occurs in the soft tissues in the body. This phaseutcomes in patients with very low risk rhabdomyosarcoma
(VLR-RMS) while decreasing the burden of therapy using treatment with 24 weeks of vincristined dactinomycin (VA) and examines the use of centralized molecular risk stratification inhe 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 RMSwith DNA mutations to see if their outcomes can be improved.
Description
PRIMARY OBJECTIVES:
I. To evaluate the failure free survival (FFS) of patients with very low-risk (VLR)habdomyosarcoma (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/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 withwly 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 endherapy, and at the time of progression to bank for future research.
II. To describe the methylation array profile of patients with fusion negative, low-riskhabdomyosarcoma.
III. To describe the outcomes of patients with VLR or LR RMS and MYOD1 or TP53 mutationsd with intensified therapy.
OUTLINE: Patients are assigned to 1 of 2 regimens based on clinical features. Patients withve mutation status are transitioned to a third regimen, Regimen M.
REGIMEN VA: Patients with VLR RMS receive vincristine intravenously (IV) on day 1 of eachycle 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 thebsence of disease progression or unacceptable toxicity. Patients with MYOD1 or TP53 mutatedumors 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 8d 15 of cycles 1-3. Patients also receive dactinomycin IV over 1-5 minutes or 10-15 minutesd 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. Patientshen 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. Treatmentvery 21 days for 4 cycles in the absence of disease progression or unacceptabley. Patients with MYOD1 or TP53 mutated tumors transition to Regimen M at cycle 2 (ifutation 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 eachycle. Treatment repeats every 21 days for 12-13 cycles in the absence of disease progressionunacceptable toxicity. Patients may also undergo radiation therapy at cycle 5.
Patients undergo computed tomography (CT) scan, magnetic resonance imaging (MRI), bone scan,graphy (PET) scan and tumor biopsy throughout the study.
Eligibility
You may be eligible for this study if you meet the following criteria:
-
Conditions:
Embryonal Rhabdomyosarcoma, Fusion-Negative Alveolar Rhabdomyosarcoma, Spindle Cell/Sclerosing Rhabdomyosarcoma
-
Age: - 21 Years
-
Gender: All
Inclusion Criteria:
- All patients must be enrolled on APEC14B1 (NCT02402244) and consented to the MolecularCharacterization 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/sclerosing RMS, or FOXO1 fusion negative alveolar rhabdomyosarcoma (ARMS)(institutional FOXO1 fusion results are acceptable). RMS types included under ERMSude those classified in the 1995 International Classification of Rhabdomyosarcoma(ICR) as ERMS (classic, spindle cell, and botryoid variants), which are reclassifiedhe 2020 World Health Organization (WHO) classification as ERMS (classic, dense andbotryoid variants) and spindle cell/sclerosing RMS (encompassing the historicaldle cell ERMS variant and the newly recognized sclerosing RMS variant). EnrollmentAPEC14B1 is required for all patients.
- All patients will be evaluated for stage and clinical group. Note that clinicalgroup designation assigned at the time of enrollment on study remains unchangedgardless of any second-look operation that may be performed.
- Patients will be eligible for the very low-risk stratum (Regimen VA) if theyhave Stage 1, CG I disease.
- Patients will be eligible for the low-risk stratum (Regimen VAC/VA) if theyhave 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 paratesticularumors who do not have gross nodal involvement on imaging.
- Extremity Tumors: Regional lymph node sampling is required for histologicvaluation in patients with extremity tumors.
- Clinically or radiographically enlarged nodes must be sampled for histologicvaluation.
- All patients will be evaluated for stage and clinical group. Note that clinicalgroup designation assigned at the time of enrollment on study remains unchangedgardless of any second-look operation that may be performed.
- 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 unablewalk because of paralysis, but who are up in a wheelchair, will be consideredbulatory for the purpose of assessing performance score.
- Peripheral absolute neutrophil count (ANC) >= 750/uL (within 7 days prior to).
- Platelet count >= 75,000/uL (transfusion independent) (within 7 days prior to).
- Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70L/min/1.73 m^2 or a serum creatinine (within 7 days prior to enrollment) based onge/gender as follows:
- Age: 1 month to < 6 months; Maximum serum creatinine (mg/dL): 0.4 (male) : 0.4(female)
- Age: 6 months to < 1 year; Maximum serum creatinine (mg/dL): 0.5 (male) : 0.5(female)
- Age: 1 to < 2 years; Maximum serum creatinine (mg/dL): 0.6 (male) : 0.6 (female)
- Age: 2 to < 6 years; Maximum serum creatinine (mg/dL): 0.8 (male) : 0.8 (female)
- Age: 6 to < 10 years; Maximum serum creatinine (mg/dL): 1 (male) : 1 (female)
- Age: 10 to < 13 years; Maximum serum creatinine (mg/dL): 1.2 (male) : 1.2(female)
- Age: 13 to < 16 years; Maximum serum creatinine (mg/dL): 1.5 (male) : 1.4(female)
- Age >= 16 years; Maximum serum creatinine (mg/dL): 1.7 (male) : 1.4 (female)
- 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 totalbilirubin must be < 3 x ULN for age.
- Note: For the purpose of this study, the ULN for SGPT (ALT) has been set to thevalue of 45 U/L.
- Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 135
U/L (within 7 days prior to enrollment).
- All patients and/or their parents or legal guardians must sign a written informed.
- 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. 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 forgnant conditions prior to starting protocol therapy.
- Vincristine is sensitive substrate of the CYP450 3A4 isozyme. Patients must not haveved drugs that are moderate to strong CYP3A4 inhibitors and inducers within 7days prior to study enrollment.
- Patients unable to undergo radiation therapy, if necessary, as specified in the.
- Evidence of uncontrolled infection.
- Female patients who are pregnant since fetal toxicities and teratogenic effects havebeen noted for several of the study drugs. A pregnancy test is required for femalehildbearing potential.
- Lactating females who plan to breastfeed their infants.
- Sexually active patients of reproductive potential who have not agreed to use anve contraceptive method for the duration of their study participation.
Updated on
03 May 2024.
Study ID: ARST2032
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