NCT00354835 · CITED IN SOURCE DOCUMENTS

Combination Chemotherapy and Radiation Therapy in Treating Patients With Newly Diagnosed Rhabdomyosarcoma

An NCI or FDA source cites this study. A citation does not establish that it applies to an individual diagnosis.

Phase: PHASE3
Status at capture: COMPLETED
Registry last update: 2023-01-31

This randomized phase III trial is studying two different combination chemotherapy regimens to compare how well they work when given together with radiation therapy in treating patients with newly diagnosed rhabdomyosarcoma. Drugs used in chemotherapy, such as vincristine sulfate, dactinomycin, cyclophosphamide, and irinotecan hydrochloride, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Radiation therapy uses high-energy x-rays to kill tumor cells. Giving combination chemotherapy together with radiation therapy may kill more tumor cells. It is not yet known which combination chemotherapy regimen is more effective when given together with radiation therapy in treating patients with rhabdomyosarcoma.

Open the original ClinicalTrials.gov record → · Download preserved record

What did the study report?

Outcomes, safety and baseline populations are separate source sections. Quality-of-life measures appear under their original outcome titles.

flow

Participant flow

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baseline

Baseline characteristics

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outcome · POSTED

Event Free Survival (EFS)

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outcome · POSTED

Response Rate (RR)

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outcome · POSTED

Overall Survival (OS)

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outcome · POSTED

Event Free Survival (EFS) Probability VAC and Early (Week 4) Radiotherapy Compared to Delayed (Week 10) Radiotherapy, Using IRSIV for Historic Comparison

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outcome · POSTED

Local Failure

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outcome · POSTED

Overall Survival (OS) Probability VAC and Early (Week 4) Radiotherapy Compared to Delayed (Week 10) Radiotherapy, Using IRSIV for Historic Comparison

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outcome · POSTED

Incidence of Toxicity

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outcome · POSTED

Acute and Late Effects of VAC as Delivered on This Study to D9803 VAC

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outcome · POSTED

Compare Event Free Survival (EFS) With Respect to the Level of % Change in FDG PET Maximum Standard Uptake Value (SUVmax) at Week 4

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outcome · POSTED

Compare Event Free Survival (EFS) With Respect to the Level of % Change in FDG PET Maximum Standard Uptake Value (SUVmax) at Week 15

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outcome · POSTED

Incidence of Toxicity Related to VI Treatment in Patients With UGT1A1 Genotype

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outcome · POSTED

Toxicity With CYP2B6 Genotypes

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outcome · POSTED

Toxicity With GSTA1 and CYP2C9 Genotypes

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outcome · POSTED

Event Free Survival (EFS) by PAX Status

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outcome · POSTED

Incidence of Bladder Dysfunction

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adverse events

Adverse events

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more info

Limitations, agreements, and source contact

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Who could take part

eligibility Criteria: Inclusion Criteria: * Patients with newly diagnosed embryonal RMS, botryoid or spindle cell variants of embryonal RMS, ectomesenchymoma, or alveolar RMS are eligible for this study * Enrollment on COG-D9902 to confirm local histologic diagnosis with central pathology review is required for all patients * Patients may be enrolled on ARST0531 and start protocol treatment prior to receipt of central pathology review results * Patient must have Intermediate-risk RMS defined as: * Embryonal, botryoid, or spindle cell RMS, or ectomesenchymoma: stage 2 or 3 and group III OR * Alveolar RMS: stage 1-3 and group I-III * Staging ipsilateral retroperitoneal lymph node dissection (SIRLND) is required for all patients \>= 10 years of age with paratesticular tumors and for patients \< 10 years with clinically or radiographically involved lymph nodes (except when extensive lymph node involvement, defined as two or more lymph nodes \> 2 cm in dimension, is identified by imaging studies) * Regional lymph node sampling or sentinel lymph node procedure is required for histologic evaluation in patients with extremity tumors * Clinically or radiographically enlarged nodes should be sampled for histologic evaluation * Detection of metastasis by optional FDG PET (not required for study enrollment); FDG PET may detect abnormalities suggestive of metastasis not identified by bone scan, computed tomography (CT), or bone marrow aspiration/biopsy; the prognostic significance of FDG PET-detected abnormalities is not clear; FDG PET-detected abnormalities MUST be confirmed to be metastases by an additional imaging modality (such as magnetic resonance imaging \[MRI\] or CT) OR pathologic confirmation; unless FDG PET abnormalities are confirmed by another imaging modality or biopsy, FDG PET abnormalities will NOT be considered evidence of metastasis * Patients must have a performance status of 0, 1, or 2; the Lansky performance score should be used for patients \< 16 years and the Karnofsky performance score for patients \>= 16 years * Patients who have received prior chemotherapy (excluding steroids) or radiation therapy, except for patients transferring from ARST0331 (low-risk study), are not eligible * Creatinine clearance or radioisotope glomerular filtration rate (GFR) \>= 70 ml/min/1.73 m\^2 or a serum creatinine based on age/gender as follows: * 1 month to \< 6 months: 0.4 mg/dL * 6 months to \< 1 year: 0.5 mg/dL * 1 to \< 2 years: 0.6 mg/dL * 2 to \< 6 years: 0.8 mgt/dL * 6 to \< 10 years: 1 mg/dL * 10 to \< 13 years: 1.2 mg/dL * 13 to \< 16 years: 1.5 mg/dL (males) or 1.4 mg/dL (females) * \>= 16 years: 1.7 mg/dL (males) or 1.4 mg/dL (females) * Patients with urinary tract obstruction by tumor must meet the renal function criteria AND must have unimpeded urinary flow established via decompression of the obstructed portion of the urinary tract * Total bilirubin =\< 1.5 x upper limit of normal for age * Peripheral absolute neutrophil count (ANC) \>= 750/uL * Platelet count \>= 75,000/uL (transfusion independent) * No evidence of uncontrolled infection * Patients must be able to undergo radiation therapy, if necessary, as specified in the protocol * Female patients of childbearing potential must have a negative pregnancy test * Female patients who are breast feeding must agree to stop breast feeding * Sexually active patients of childbearing potential must be willing to use effective contraception during therapy and for at least 1 month after treatment is completed * 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
healthy Volunteers: false
maximum Age: 49 Years
sex: ALL
std Ages: CHILD
ADULT

Treatment arms and interventions

arm Groups

description
Patients receive VAC chemotherapy comprising vincristine IV over 1 minute on day 1 of weeks 1-13, 16, 19-25, 28, 31-37, and 40; dactinomycin IV over 1-5 minutes on day 1 of weeks 1, 4, 13, 16, 19, 22, 25, 28, 31, 34, 37,and 40; and cyclophosphamide IV over 1 hour on day 1 of weeks 1, 4, 7, 10, 13, 16, 19, 22, 25, 28, 31, 34, 37, and 40. Patients may also undergo radiotherapy 5 days a week for 4-6 weeks beginning in week 4.
intervention Names
Drug: Cyclophosphamide
Biological: Dactinomycin
Other: Laboratory Biomarker Analysis
Other: Questionnaire Administration
Radiation: Radiation Therapy
Drug: Vincristine Sulfate
label
Arm I (chemotherapy, radiotherapy)
type
ACTIVE_COMPARATOR
description
Patients receive VAC chemotherapy alternating with VI chemotherapy comprising vincristine IV over 1 minute on day 1 of weeks 1-13, 16, 17, 19, 20, 22-26, 28, 31-34, 37, 38, and 40; dactinomycin IV over 1-5 minutes on day 1 of weeks 1, 13, 22, 28, 34, and 40; cyclophosphamide IV over 1 hour on day 1 of weeks 1,10, 13, 22, 28, 34, and 40; and irinotecan hydrochloride IV over 1 hour on days 1-5 of weeks 4, 7, 16, 19, 25, 31, and 37. Patients may also undergo radiotherapy 5 days a week for 4-6 weeks beginning in week 4.
intervention Names
Drug: Cyclophosphamide
Biological: Dactinomycin
Drug: Irinotecan Hydrochloride
Other: Laboratory Biomarker Analysis
Other: Questionnaire Administration
Radiation: Radiation Therapy
Drug: Vincristine Sulfate
label
Arm II (chemotherapy, radiotherapy)
type
EXPERIMENTAL

interventions

arm Group Labels
Arm I (chemotherapy, radiotherapy)
Arm II (chemotherapy, radiotherapy)
description
Given IV
name
Cyclophosphamide
other Names
(-)-Cyclophosphamide
2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate
Carloxan
Ciclofosfamida
Ciclofosfamide
Cicloxal
Clafen
Claphene
CP monohydrate
CTX
CYCLO-cell
Cycloblastin
type
DRUG
arm Group Labels
Arm I (chemotherapy, radiotherapy)
Arm II (chemotherapy, radiotherapy)
description
Given IV
name
Dactinomycin
other Names
Actinomycin A IV
Actinomycin C1
Actinomycin D
Actinomycin I1
Actinomycin IV
Actinomycin X 1
Actinomycin-[thr-val-pro-sar-meval]
Cosmegen
DACT
Dactinomycine
Lyovac Cosmegen
Meractinomycin
type
BIOLOGICAL
arm Group Labels
Arm II (chemotherapy, radiotherapy)
description
Given IV
name
Irinotecan Hydrochloride
other Names
Campto
Camptosar
Camptothecin 11
Camptothecin-11
CPT 11
CPT-11
Irinomedac
Irinotecan Hydrochloride Trihydrate
Irinotecan Monohydrochloride Trihydrate
U-101440E
type
DRUG
arm Group Labels
Arm I (chemotherapy, radiotherapy)
Arm II (chemotherapy, radiotherapy)
description
Correlative studies
name
Laboratory Biomarker Analysis
type
OTHER
arm Group Labels
Arm I (chemotherapy, radiotherapy)
Arm II (chemotherapy, radiotherapy)
description
Ancillary studies
name
Questionnaire Administration
type
OTHER
arm Group Labels
Arm I (chemotherapy, radiotherapy)
Arm II (chemotherapy, radiotherapy)
description
Undergo radiotherapy
name
Radiation Therapy
other Names
Cancer Radiotherapy
ENERGY_TYPE
Irradiate
Irradiated
Irradiation
Radiation
Radiation Therapy, NOS
Radiotherapeutics
Radiotherapy
RT
Therapy, Radiation
type
RADIATION
arm Group Labels
Arm I (chemotherapy, radiotherapy)
Arm II (chemotherapy, radiotherapy)
description
Given IV
name
Vincristine Sulfate
other Names
Kyocristine
Leurocristine Sulfate
Leurocristine, sulfate
Oncovin
Vincasar
Vincosid
Vincrex
Vincristine, sulfate
type
DRUG

Study design

allocation

RANDOMIZED

intervention Model

PARALLEL

masking Info

masking: NONE

primary Purpose

TREATMENT

Enrollment

count: 481
type: ACTUAL

Registered outcome plans (not posted results)

primary Outcomes

description
Probability of no relapse, secondary malignancy, or death after 4 year in the study
measure
Event Free Survival (EFS)
time Frame
4 years
description
Proportion of patients with complete or partial response. Complete Response (CR): Complete disappearance of the tumor confirmed at \> 4 weeks; Partial Response (PR): At least 64% decrease in volume compared to the baseline; Overall Response (OR) = CR + PR.
measure
Response Rate (RR)
time Frame
Reporting Period 1 (Weeks 1 - 15)
description
Probability of being alive after 4 years in the study.
measure
Overall Survival (OS)
time Frame
4 years

secondary Outcomes

description
Compare 4-year EFS using eligible participants only to the historical rate of 0.65 with IRSI-V. The 4-year EFS is probability of no relapse, secondary malignancy, or death after 4 years in the study. The Delayed (Week 10) Radiotherapy is from IRSI-V, and the number of participants of IRSI-V is unknown, but we have the rate of 0.65.
measure
Event Free Survival (EFS) Probability VAC and Early (Week 4) Radiotherapy Compared to Delayed (Week 10) Radiotherapy, Using IRSIV for Historic Comparison
time Frame
4 years
description
Compare 2-year local failure rate to the historical rate of 0.13 with IRSI-V. The Delayed (Week 10) Radiotherapy is from IRSI-V, and the number of participants of IRSI-V is unknown, but we have the rate of 0.13.
measure
Local Failure
time Frame
2 years
description
Compare 4-year OS using eligible participants only to the historical rate of 0.70 with IRSI-V. The 4-year OS is probability of being alive after 4 years in the study. The Delayed (Week 10) Radiotherapy is from IRSI-V, and the number of participants of IRSI-V is unknown, but we have the rate of 0.70.
measure
Overall Survival (OS) Probability VAC and Early (Week 4) Radiotherapy Compared to Delayed (Week 10) Radiotherapy, Using IRSIV for Historic Comparison
time Frame
4 years
description
Grade 3 or 4 nausea, diarrhea, dehydration, radiation dermatitis, mucositis due to radiation. Severe and undesirable adverse event is considered as grade 3; Life-threatening or disabling adverse event is grade 4. Grade 4 is worse than grade 3.
measure
Incidence of Toxicity
time Frame
Up to 15 weeks
description
The toxicity rates will be estimated for each phase and course of treatment, and will be compared to the fixed rates under D9803 using one-sided lower confidence intervals for a single proportion without adjustment for multiple comparisons.
measure
Acute and Late Effects of VAC as Delivered on This Study to D9803 VAC
time Frame
Up to 43 weeks
description
4-year EFS (probability of no relapse, secondary malignancy, or death after 4 years in the study).
measure
Compare Event Free Survival (EFS) With Respect to the Level of % Change in FDG PET Maximum Standard Uptake Value (SUVmax) at Week 4
time Frame
4 years
description
4-year EFS (probability of no relapse, secondary malignancy, or death after 4 years in the study)
measure
Compare Event Free Survival (EFS) With Respect to the Level of % Change in FDG PET Maximum Standard Uptake Value (SUVmax) at Week 15
time Frame
4 years
description
Severe and undesirable adverse event is considered as grade 3; Life-threatening or disabling adverse event is grade 4. Grade 4 is worse than grade 3.
measure
Incidence of Toxicity Related to VI Treatment in Patients With UGT1A1 Genotype
time Frame
Weeks 4-9 (the first exposure to VI)
description
Incidence of toxicity related to VAC treatment in patients with CYP2B6 genotypes.
measure
Toxicity With CYP2B6 Genotypes
time Frame
During the study
description
Incidence of toxicity related to VAC treatment in patients with GSTA1 and CYP2C9 genotypes.
measure
Toxicity With GSTA1 and CYP2C9 Genotypes
time Frame
During the study
measure
Event Free Survival (EFS) by PAX Status
time Frame
4 years
description
Number of patients with a summary score greater than 8.5
measure
Incidence of Bladder Dysfunction
time Frame
3-6 years after enrollment

Full study description

brief Summary: This randomized phase III trial is studying two different combination chemotherapy regimens to compare how well they work when given together with radiation therapy in treating patients with newly diagnosed rhabdomyosarcoma. Drugs used in chemotherapy, such as vincristine sulfate, dactinomycin, cyclophosphamide, and irinotecan hydrochloride, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Radiation therapy uses high-energy x-rays to kill tumor cells. Giving combination chemotherapy together with radiation therapy may kill more tumor cells. It is not yet known which combination chemotherapy regimen is more effective when given together with radiation therapy in treating patients with rhabdomyosarcoma.
detailed Description: PRIMARY OBJECTIVES: I. To compare the early response rates, failure-free survival (FFS), and survival of patients with intermediate-risk rhabdomyosarcoma (RMS) treated with surgery, radiotherapy, and vincristine (vincristine sulfate), dactinomycin and cyclophosphamide (VAC) or VAC alternating with vincristine, irinotecan (irinotecan hydrochloride) (VI). SECONDARY OBJECTIVES: I. To compare FFS, local control, and survival of patients with intermediate-risk RMS treated with VAC and early (week 4) radiotherapy vs delayed (week 10) radiotherapy, using data from Intergroup Rhabdomyosarcoma Study (IRS)-IV for historic comparison. II. To compare the acute and late effects of VAC to VAC alternating with VI, including the toxicity associated with concurrent VI and radiotherapy. III. To compare the acute and late effects of VAC as delivered on this study to D9803 VAC. IV. To correlate change in fludeoxyglucose F-18 positron emission tomography (FDG-PET) maximum standard uptake value (SUVmax) from week 1 to week 4 and 15 with FFS. V. For VI treated patients, to correlate patient UDP glucuronosyltransferase 1 family, polypeptide A1 (UGT1A1) genotype with VI toxicity. VI. To correlate cytochrome P450, family 2, subfamily B, polypeptide 6 (CYP2B6), cytochrome P450, family 2, subfamily C, polypeptide 9 (CYP2C9), and glutathione S-transferase alpha 1 (GSTA1) genotypes with VAC toxicity. VII. To prospectively evaluate and validate gene expression values with the intent to define the best diagnostic predictors and more powerful prognostic classifiers. VIII. To assess the frequency of bladder dysfunction in patients with bladder, prostate, and pelvic sites of RMS 3-6 years after study enrollment. OUTLINE: Patients are randomized to 1 of 2 treatment arms within 42 days of initial surgery or biopsy. ARM I (VAC): Patients receive VAC chemotherapy comprising vincristine sulfate IV over 1 minute on day 1 of weeks 1-13, 16, 19-25, 28, 31-37, and 40; dactinomycin IV over 1-5 minutes on day 1 of weeks 1, 4, 13, 16, 19, 22, 25, 28, 31, 34, 37, and 40; and cyclophosphamide IV over 1 hour on day 1 of weeks 1, 4, 7, 10, 13, 16, 19, 22, 25, 28, 31, 34, 37, and 40. ARM II (VAC/VI): Patients receive VAC chemotherapy alternating with VI chemotherapy comprising vincristine sulfate IV over 1 minute on day 1 of weeks 1-13,16, 17, 19, 20, 22-26, 28, 31-34, 37, 38, and 40; dactinomycin IV over 1-5 minutes on day 1 of weeks 1,13, 22, 28, 34, and 40; cyclophosphamide IV over 1 hour on day 1 of weeks 1,10, 13, 22, 28, 34, and 40; and irinotecan hydrochloride IV over 90 minutes on days 1-5 of weeks 4, 7, 16, 19, 25, 31, and 37. In both arms, treatment continues in the absence of disease progression or unacceptable toxicity. Patients\* in both arms also undergo radiotherapy 5 days a week for 4-6 weeks beginning in week 4 (except patients with alveolar RMS rendered group I by amputation OR patients needing week 1 emergency radiotherapy for symptomatic spinal cord compression). NOTE: \*Individualized local control plan that deviates from protocol-mandated radiotherapy allowed for patients =\< 24 months of age. After completion of study treatment, patients are followed up every 2-4 months for 4 years and then annually for 5-10 years.

Source references

references

citation
de Traux de Wardin H, Dermawan JK, Vanoli F, Jiang SC, Singer S, Chi P, Tap W, Wexler LH, Antonescu CR. NF1-Driven Rhabdomyosarcoma Phenotypes: A Comparative Clinical and Molecular Study of NF1-Mutant Rhabdomyosarcoma and NF1-Associated Malignant Triton Tumor. JCO Precis Oncol. 2024 Apr;8:e2300597. doi: 10.1200/PO.23.00597.
pmid
38603649
type
DERIVED
citation
Casey DL, Chi YY, Donaldson SS, Hawkins DS, Tian J, Arndt CA, Rodeberg DA, Routh JC, Lautz TB, Gupta AA, Yock TI, Wolden SL. Increased local failure for patients with intermediate-risk rhabdomyosarcoma on ARST0531: A report from the Children's Oncology Group. Cancer. 2019 Sep 15;125(18):3242-3248. doi: 10.1002/cncr.32204. Epub 2019 Jun 7.
pmid
31174239
type
DERIVED
citation
Hawkins DS, Chi YY, Anderson JR, Tian J, Arndt CAS, Bomgaars L, Donaldson SS, Hayes-Jordan A, Mascarenhas L, McCarville MB, McCune JS, McCowage G, Million L, Morris CD, Parham DM, Rodeberg DA, Rudzinski ER, Shnorhavorian M, Spunt SL, Skapek SX, Teot LA, Wolden S, Yock TI, Meyer WH. Addition of Vincristine and Irinotecan to Vincristine, Dactinomycin, and Cyclophosphamide Does Not Improve Outcome for Intermediate-Risk Rhabdomyosarcoma: A Report From the Children's Oncology Group. J Clin Oncol. 2018 Sep 20;36(27):2770-2777. doi: 10.1200/JCO.2018.77.9694. Epub 2018 Aug 9.
pmid
30091945
type
DERIVED