Purpose

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 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 chemotherapy plus temsirolimus is more effective than chemotherapy alone in treating patients with intermediate-risk rhabdomyosarcoma.

Category

IRB Number
20160538HU
NCT Number
NCT02567435
Sponsor
National Cancer Institute (NCI) -



Study Contact

Principal Investigator
Anne-Marie Langevin

Virginia Diaz
210-562-9149
diazvr@uthscsa.edu

Jaclyn Hung
210-450-5358
hungj@uthscsa.edu



Eligibility

Eligible Ages
Under40 Years
Eligible Genders
All
Accepts Healthy Volunteers
No

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 since fetal toxicities or teratogenic effects have been noted for several of the study drugs; 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

Study Design

Phase
Phase 3
Study Type
Interventional
Allocation
Randomized
Intervention Model
Parallel Assignment
Primary Purpose
Treatment
Masking
None (Open Label)
Condition
  • Alveolar Rhabdomyosarcoma
  • Botryoid-Type Embryonal Rhabdomyosarcoma
  • Embryonal Rhabdomyosarcoma
  • Rhabdomyosarcoma
  • Sclerosing Rhabdomyosarcoma
  • Spindle Cell Rhabdomyosarcoma
  • Arm Groups

    ArmDescriptionIntervention
    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 or 10-15 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.
  • 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
    • Dactinomy

  • Other: Laboratory Biomarker Analysis

    Correlative studies

  • Radiation: Radiation Therapy

    Undergo RT

    Other names:

    • Cancer Radiotherapy
    • ENERGY_TYPE
    • Irradiate
    • Irradiated
    • Irradiation
    • Radiation
    • Radiation Therapy, NOS
    • Radiotherapeutics
    • Radiotherapy
    • RT
    • Therapy, Radia

  • Drug: Vincristine Sulfate

    Given IV

    Other names:

    • Kyocristine
    • Leurocristine Sulfate
    • Leurocristine, sulfate
    • Oncovin
    • Vincasar
    • Vincosid
    • Vincrex
    • Vincristine, sulfate

  • 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 <

  • Other: Questionnaire Administration

    Ancillary studies

  • 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 or 10-15 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.
  • 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
    • Dactinomy

  • Other: Laboratory Biomarker Analysis

    Correlative studies

  • Radiation: Radiation Therapy

    Undergo RT

    Other names:

    • Cancer Radiotherapy
    • ENERGY_TYPE
    • Irradiate
    • Irradiated
    • Irradiation
    • Radiation
    • Radiation Therapy, NOS
    • Radiotherapeutics
    • Radiotherapy
    • RT
    • Therapy, Radia

  • Drug: Vincristine Sulfate

    Given IV

    Other names:

    • Kyocristine
    • Leurocristine Sulfate
    • Leurocristine, sulfate
    • Oncovin
    • Vincasar
    • Vincosid
    • Vincrex
    • Vincristine, sulfate

  • 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 <

  • 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

  • Other: Questionnaire Administration

    Ancillary studies

  • Drug: Temsirolimus

    Given IV

    Other names:

    • CCI-779
    • CCI-779 Rapamycin Analog
    • Cell Cycle Inhibitor 779
    • Rapamycin Analog
    • Rapamycin Analog CCI-779
    • Torisel

  • Drug: Vinorelbine

    Given IV

    Other names:

    • Dihydroxydeoxynorvinkaleukoblastine

  • 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 or 10-15 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.
  • 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
    • Dactinomy

  • Other: Laboratory Biomarker Analysis

    Correlative studies

  • Radiation: Radiation Therapy

    Undergo RT

    Other names:

    • Cancer Radiotherapy
    • ENERGY_TYPE
    • Irradiate
    • Irradiated
    • Irradiation
    • Radiation
    • Radiation Therapy, NOS
    • Radiotherapeutics
    • Radiotherapy
    • RT
    • Therapy, Radia

  • Drug: Vincristine Sulfate

    Given IV

    Other names:

    • Kyocristine
    • Leurocristine Sulfate
    • Leurocristine, sulfate
    • Oncovin
    • Vincasar
    • Vincosid
    • Vincrex
    • Vincristine, sulfate

  • 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 <

  • 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

  • Other: Questionnaire Administration

    Ancillary studies