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Combination Chemotherapy With or Without Temsirolimus in Treating Patients With Intermediate Risk Rhabdomyosarcoma

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ClinicalTrials.gov Identifier: NCT02567435
Recruitment Status : Recruiting
First Posted : October 5, 2015
Last Update Posted : August 16, 2019
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Brief Summary:
This randomized phase III trial studies how well combination chemotherapy (vincristine sulfate, dactinomycin, cyclophosphamide alternated with vincristine sulfate and irinotecan hydrochloride or vinorelbine) works compared to combination chemotherapy plus temsirolimus in treating patients with rhabdomyosarcoma (cancer that forms in the soft tissues, such as muscle), and has an intermediate chance of coming back after treatment (intermediate risk). Drugs used in chemotherapy 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. Combination chemotherapy and temsirolimus may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It is not yet known whether combination chemotherapy or combination chemotherapy plus temsirolimus is more effective in treating patients with intermediate-risk rhabdomyosarcoma.

Condition or disease Intervention/treatment Phase
Alveolar Rhabdomyosarcoma Botryoid-Type Embryonal Rhabdomyosarcoma Embryonal Rhabdomyosarcoma Rhabdomyosarcoma Sclerosing Rhabdomyosarcoma Spindle Cell Rhabdomyosarcoma Untreated Childhood Rhabdomyosarcoma Drug: Cyclophosphamide Biological: Dactinomycin Drug: Irinotecan Hydrochloride Other: Laboratory Biomarker Analysis Other: Questionnaire Administration Radiation: Radiation Therapy Drug: Temsirolimus Drug: Vincristine Sulfate Drug: Vinorelbine Phase 3

  Show Detailed Description

Layout table for study information
Study Type : Interventional
Estimated Enrollment : 397 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Randomized Phase 3 Study of Vincristine, Dactinomycin, Cyclophosphamide (VAC) Alternating With Vincristine and Irinotecan (VI) Versus VAC/VI Plus Temsirolimus (TORI, Torisel, NSC# 683864) in Patients With Intermediate Risk (IR) Rhabdomyosarcoma (RMS)
Actual Study Start Date : May 23, 2016
Estimated Primary Completion Date : January 1, 2025


Arm Intervention/treatment
Experimental: Regimen A (VAC/VI)
Patients receive 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, 7, 13, 22, 28, 34, and 40, cyclophosphamide IV over 60 minutes on day 1 of weeks 1, 7, 13, 22, 28, 34, and 40, irinotecan hydrochloride IV over 90 minutes on days 1-5 of weeks 4, 10, 16, 19, 25, 31, and 37. Patients also undergo primary site RT beginning at week 13 or metastatic site RT beginning at week 43 for up to 6.5 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity. Patients then receive vinorelbine IV over 6-10 minutes on days 1, 8, and 15 and cyclophosphamide PO QD on days 1-28. Cycles repeats every 28 days for 24 weeks in the absence of disease progression or unacceptable toxicity.
Drug: Cyclophosphamide
Given IV and PO
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
  • Cycloblastine
  • Cyclophospham
  • Cyclophosphamid monohydrate
  • Cyclophosphamide Monohydrate
  • Cyclophosphamidum
  • Cyclophosphan
  • Cyclophosphane
  • Cyclophosphanum
  • Cyclostin
  • Cyclostine
  • Cytophosphan
  • Cytophosphane
  • Cytoxan
  • Fosfaseron
  • Genoxal
  • Genuxal
  • Ledoxina
  • Mitoxan
  • Neosar
  • Revimmune
  • Syklofosfamid
  • WR- 138719

Biological: Dactinomycin
Given IV
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

Drug: Irinotecan Hydrochloride
Given IV
Other Names:
  • Campto
  • Camptosar
  • Camptothecin 11
  • Camptothecin-11
  • CPT 11
  • CPT-11
  • Irinomedac
  • Irinotecan Hydrochloride Trihydrate
  • Irinotecan Monohydrochloride Trihydrate
  • U-101440E

Other: Laboratory Biomarker Analysis
Correlative studies

Other: Questionnaire Administration
Ancillary studies

Radiation: Radiation Therapy
Undergo RT
Other Names:
  • Cancer Radiotherapy
  • Irradiate
  • Irradiated
  • irradiation
  • Radiation
  • Radiotherapeutics
  • RADIOTHERAPY
  • RT
  • Therapy, Radiation

Drug: Vincristine Sulfate
Given IV
Other Names:
  • Kyocristine
  • Leurocristine sulfate
  • Leurocristine, sulfate
  • Oncovin
  • Vincasar
  • Vincosid
  • Vincrex
  • Vincristine, sulfate

Experimental: Regimen B (VAC/VI/temsirolimus)
Patients receive 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, 7, 13, 22, 28, 34, and 40, cyclophosphamide IV over 60 minutes on day 1 of weeks 1, 7, 13, 22, 28, 34, and 40, irinotecan hydrochloride IV over 90 minutes on days 1-5 of weeks 4, 10, 16, 19, 25, 31, and 37 and temsirolimus IV over 30-60 minutes on day 1 of weeks 1-12 and 21-42. Patients also undergo RT as in Regimen A. Treatment continues in the absence of disease progression or unacceptable toxicity. Patients then receive vinorelbine IV over 6-10 minutes on days 1, 8, and 15 and cyclophosphamide PO QD on days 1-28. Cycles repeats every 28 days for 24 weeks in the absence of disease progression or unacceptable toxicity.
Drug: Cyclophosphamide
Given IV and PO
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
  • Cycloblastine
  • Cyclophospham
  • Cyclophosphamid monohydrate
  • Cyclophosphamide Monohydrate
  • Cyclophosphamidum
  • Cyclophosphan
  • Cyclophosphane
  • Cyclophosphanum
  • Cyclostin
  • Cyclostine
  • Cytophosphan
  • Cytophosphane
  • Cytoxan
  • Fosfaseron
  • Genoxal
  • Genuxal
  • Ledoxina
  • Mitoxan
  • Neosar
  • Revimmune
  • Syklofosfamid
  • WR- 138719

Biological: Dactinomycin
Given IV
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

Drug: Irinotecan Hydrochloride
Given IV
Other Names:
  • Campto
  • Camptosar
  • Camptothecin 11
  • Camptothecin-11
  • CPT 11
  • CPT-11
  • Irinomedac
  • Irinotecan Hydrochloride Trihydrate
  • Irinotecan Monohydrochloride Trihydrate
  • U-101440E

Other: Laboratory Biomarker Analysis
Correlative studies

Other: Questionnaire Administration
Ancillary studies

Radiation: Radiation Therapy
Undergo RT
Other Names:
  • Cancer Radiotherapy
  • Irradiate
  • Irradiated
  • irradiation
  • Radiation
  • Radiotherapeutics
  • RADIOTHERAPY
  • RT
  • Therapy, Radiation

Drug: Temsirolimus
Given IV
Other Names:
  • CCI-779
  • CCI-779 Rapamycin Analog
  • Cell Cycle Inhibitor 779
  • Rapamycin Analog
  • Rapamycin Analog CCI-779
  • Torisel

Drug: Vincristine Sulfate
Given IV
Other Names:
  • Kyocristine
  • Leurocristine sulfate
  • Leurocristine, sulfate
  • Oncovin
  • Vincasar
  • Vincosid
  • Vincrex
  • Vincristine, sulfate

Drug: Vinorelbine
Given IV
Other Name: Dihydroxydeoxynorvinkaleukoblastine

Experimental: Regimen C (FOXO1 fusion negative, VAC/VA)
Patients receive vincristine sulfate IV over 1 minute on day 1 of weeks 1-10 and 13-22, dactinomycin IV over 1-5 minutes on day 1 of weeks 1, 4, 7, 10, 13, 16, 19, and 22, cyclophosphamide IV over 60 minutes on day 1 of weeks 1, 4, 7, and 10. Patients undergo RT beginning at week 13 for up to 6.5 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.
Drug: Cyclophosphamide
Given IV and PO
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
  • Cycloblastine
  • Cyclophospham
  • Cyclophosphamid monohydrate
  • Cyclophosphamide Monohydrate
  • Cyclophosphamidum
  • Cyclophosphan
  • Cyclophosphane
  • Cyclophosphanum
  • Cyclostin
  • Cyclostine
  • Cytophosphan
  • Cytophosphane
  • Cytoxan
  • Fosfaseron
  • Genoxal
  • Genuxal
  • Ledoxina
  • Mitoxan
  • Neosar
  • Revimmune
  • Syklofosfamid
  • WR- 138719

Biological: Dactinomycin
Given IV
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

Other: Laboratory Biomarker Analysis
Correlative studies

Other: Questionnaire Administration
Ancillary studies

Radiation: Radiation Therapy
Undergo RT
Other Names:
  • Cancer Radiotherapy
  • Irradiate
  • Irradiated
  • irradiation
  • Radiation
  • Radiotherapeutics
  • RADIOTHERAPY
  • RT
  • Therapy, Radiation

Drug: Vincristine Sulfate
Given IV
Other Names:
  • Kyocristine
  • Leurocristine sulfate
  • Leurocristine, sulfate
  • Oncovin
  • Vincasar
  • Vincosid
  • Vincrex
  • Vincristine, sulfate




Primary Outcome Measures :
  1. Event-free survival (EFS) [ Time Frame: Time from study enrollment to the first occurrence of progression, relapse, second malignant neoplasm or death as a first event ]
    EFS distributions will be estimated using the Kaplan-Meier method and will be compared between the randomized treatment groups using the log-rank test.


Secondary Outcome Measures :
  1. Overall survival (OS) [ Time Frame: Time from study enrollment to death from any cause, assessed up to 10 years ]
    OS distributions will be estimated using the Kaplan-Meier method and will be compared between the randomized treatment groups using the log-rank test.


Other Outcome Measures:
  1. Frequency of circulating tumor DNA (ctDNA) at diagnosis and subsequent time-points [ Time Frame: Up to 10 years ]
    Will determine the frequency with which of ctDNA is detected in patients with intermediate-risk (IR) rhabdomyosarcoma (RMS) at diagnosis and how these levels change over time with. In addition, the level of ctDNA as a percent of total cell-free DNA will be summarized by reporting the median and range. Since no prior data are available on the rate of positivity nor the change over time, the analysis will be purely descriptive. Changes over time will be plotted to visually determine and compare the trajectories of ctDNA during the early and late stages of therapy.

  2. Patient outcome based on their forkhead box O1 protein (FOXO1) partner, by evaluating PAX3 vs. PAX7 in all patients found to be FOXO1 fusion positive [ Time Frame: Up to 10 years ]
  3. Patient outcome based on their [F18]-fluorodeoxy-D-glucose-positron emission tomography (FDG-positron emission tomography [PET]) response [ Time Frame: At week 9 ]
    Assessed by Deauville Criteria (5-point).

  4. Patient outcomes based on (vincristine, dactinomycin, and cyclophosphamide [VAC]/vincristine and irinotecan [VI] with or without temsirolimus) who have received maintenance therapy on ARST1431 to those who received VAC/VI on ARST0531 [ Time Frame: Up to 10 years ]
    The two-sample log-rank test will be performed.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   up to 40 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Feasibility Phase: Patients must be < 21 years of age at the time of enrollment; please note: the feasibility phase is complete, effective with amendment #1
  • Efficacy Phase: Patients must be =< 40 years of age at the time of enrollment
  • Patients with newly diagnosed RMS of any subtype, except adult-type pleomorphic, based upon institutional histopathologic classification, are eligible to enroll on the study based upon stage, group, and age, as below
  • RMS types included under embryonal rhabdomyosarcoma (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 2013 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); classification of alveolar rhabdomyosarcoma (ARMS) in the 2013 WHO classification is the same as in the ICR and includes classic and solid variants

    • ERMS

      • Stage 1, group III (non-orbit)
      • Stage 3, group I/II
      • Stage 2/3, group III
      • Stage 4, group IV, < 10 years old
    • ARMS:

      • Stages 1-3, groups I-III
  • Specimen Submission: Patients must have sufficient tissue available for the required biology study
  • Lansky performance status score >= 50 for patients =< 16 years of age; Karnofsky performance status score >= 50 for patients > 16 years of age
  • Peripheral absolute neutrophil count (ANC) >= 750/uL
  • Platelet count >= 75,000/uL
  • 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 old: 0.4 mg/dl (male), 0.4 mg/dl (female)
    • 6 months to < 1 year old: 0.5 mg/dl (male), 0.5 mg/dl (female)
    • 1 to < 2 years old: 0.6 mg/dl (male), 0.6 mg/dl (female)
    • 2 to < 6 years old: 0.8 mg/dl (male), 0.8 mg/dl (female)
    • 6 to < 10 years old: 1 mg/dl (male), 1 mg/dl (female)
    • 10 to < 13 years old: 1.2 mg/dl (male), 1.2 mg/dl (female)
    • 13 to < 16 years old: 1.5 mg/dl (male), 1.4 mg/dl (female)
    • >= 16 years old: 1.7 mg/dl (male), 1.4 mg/dl (female)
    • Patients with an elevated serum creatinine due to obstructive hydronephrosis secondary to tumor are still eligible; however, patients with urinary tract obstruction by tumor must have unimpeded urinary flow established via diversion (i.e. percutaneous nephrostomies or ureteric stents) of the urinary tract
  • Total bilirubin =< 1.5 x upper limit of normal (ULN) for age
  • 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 previously received temsirolimus, another mTOR inhibitor, or any other investigational agent
  • Patients who have received any chemotherapy (excluding steroids) and/or RT prior to this enrollment
  • Patients with uncontrolled hyperglycemia
  • Patients with uncontrolled hyperlipidemia
  • 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; Note: a pregnancy test is required for female patients of childbearing potential prior to study entry
  • Lactating females who plan to breastfeed their infants are not eligible

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): NCT02567435


  Show 349 Study Locations
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
Layout table for investigator information
Principal Investigator: Abha A Gupta Children's Oncology Group

Layout table for additonal information
Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT02567435     History of Changes
Other Study ID Numbers: NCI-2015-01644
NCI-2015-01644 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
ARST1431 ( Other Identifier: Childrens Oncology Group )
ARST1431 ( Other Identifier: CTEP )
U10CA180886 ( U.S. NIH Grant/Contract )
First Posted: October 5, 2015    Key Record Dates
Last Update Posted: August 16, 2019
Last Verified: March 2019

Additional relevant MeSH terms:
Layout table for MeSH terms
Sarcoma
Rhabdomyosarcoma
Rhabdomyosarcoma, Embryonal
Rhabdomyosarcoma, Alveolar
Myosarcoma
Neoplasms, Muscle Tissue
Neoplasms, Connective and Soft Tissue
Neoplasms by Histologic Type
Neoplasms
Sirolimus
Dactinomycin
Cyclophosphamide
Irinotecan
Vincristine
Vinorelbine
Everolimus
Camptothecin
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
Antineoplastic Agents, Phytogenic