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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02567435
Recruitment Status : Recruiting
First Posted : October 5, 2015
Last Update Posted : October 23, 2020
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Tracking Information
First Submitted Date  ICMJE October 2, 2015
First Posted Date  ICMJE October 5, 2015
Last Update Posted Date October 23, 2020
Actual Study Start Date  ICMJE May 23, 2016
Estimated Primary Completion Date July 1, 2024   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: December 7, 2017)
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.
Original Primary Outcome Measures  ICMJE
 (submitted: October 2, 2015)
  • EFS [ Time Frame: Time from study enrollment to death from any cause, assessed up to 10 years ]
    EFS distributions will be estimated using the Kaplan-Meier method and will be compared between the randomized treatment groups using the log-rank test.
  • Incidence of adverse events with addition of TORI with VAC/VI (Feasibility phase) using Common Terminology Criteria for Adverse Events version 4.0 [ Time Frame: Up to week 12 ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: December 7, 2017)
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.
Original Secondary Outcome Measures  ICMJE
 (submitted: October 2, 2015)
  • Bladder function as self-reported by patient/parent using a 14 point questionnaire [ Time Frame: Up to 6 years ]
  • 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.
  • Self-reported nausea sub-score as measured by PedsQL 3.0 [ Time Frame: Up to 3 months after completion of study treatment ]
  • Self-reported pain sub score as measured by PedsQL 3.0 [ Time Frame: Up to 3 months after completion of study treatment ]
  • Self-reported physical functioning summary score using Pediatric Quality of Life (PedsQL) 4.0 Generic Core Scales [ Time Frame: Up to 3 months after completion of study treatment ]
    Compared between patients receiving VAC/VI versus VAC/VI plus TORI.
Current Other Pre-specified Outcome Measures
 (submitted: January 7, 2019)
  • 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.
  • 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 ]
  • 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).
  • 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.
Original Other Pre-specified Outcome Measures
 (submitted: October 2, 2015)
  • FOXO1 status [ Time Frame: Up to 10 years ]
    Compare the outcome of patients based on their FOXO1 partner, by evaluating PAX3 vs PAX7 in all patients found to be FOXO1 fusion positive. Expected to be primarily descriptive.
  • Phosphorylated proteins involved in the mTOR and IGF-R1 pathways [ Time Frame: Up to 10 years ]
    Commercially-available quantitative proteomics will be used to measure phosphorylated proteins involved in the mTOR and IGF-R1 pathways. Analyses are expected to be primarily descriptive
  • Response based on FDG-PET as assessed by Deauville Criteria (5-point) [ Time Frame: Up to 4 years ]
    Compare the outcome of patients based on their FDG-PET response (positive or negative). Analyses are expected to be primarily descriptive.
 
Descriptive Information
Brief Title  ICMJE Combination Chemotherapy With or Without Temsirolimus in Treating Patients With Intermediate Risk Rhabdomyosarcoma
Official Title  ICMJE 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)
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.
Detailed Description

PRIMARY OBJECTIVES:

I. To compare the event-free survival (EFS) of patients with intermediate-risk (IR) rhabdomyosarcoma (RMS) treated with surgery, radiotherapy, and vincristine (vincristine sulfate), dactinomycin, and cyclophosphamide (VAC) alternating with vincristine and irinotecan (irinotecan hydrochloride) (VI) (VAC/VI) with maintenance to that of patients treated with surgery, radiotherapy and VAC/VI plus temsirolimus with maintenance.

SECONDARY OBJECTIVES:

I. To compare the overall survival (OS) of patients with IR RMS treated with surgery, radiotherapy, and VAC alternating with VI with maintenance to that of patients treated with surgery, radiotherapy and VAC/VI plus temsirolimus with maintenance.

EXPLORATORY OBJECTIVES:

I. To compare the outcome of patients based on their forkhead box O1 protein (FOXO1) fusion gene partner, by evaluating paired box (PAX) 3 versus (vs) PAX7 in all patients found to be FOXO1 fusion positive.

II. To compare the outcome of patients based on their [F18]-fluorodeoxy-D-glucose-positron emission tomography (FDG-PET) response at week 9 (positive or negative), as assessed by Deauville criteria (5-point).

III. To estimate the frequency of patients with circulating tumor deoxyribonucleic acid (DNA) (ctDNA) at diagnosis and subsequent time-points.

IV. To compare the outcome of patients (VAC/VI with or without temsirolimus) who have received maintenance therapy on ARST1431 to those who received VAC/VI on ARST0531.

OUTLINE:

FEASIBILITY PHASE (THE FEASIBILITY PHASE IS COMPLETE, EFFECTIVE WITH AMENDMENT #1A): (< 21 years old): This is a dose-escalation study of temsirolimus.

Patients receive vincristine sulfate intravenously (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 days 1, 8, and 15. Patients also undergo radiation therapy (RT) beginning week 13 for up to 6.5 weeks. Courses with temsirolimus repeat every 21 days for 12 weeks in the absence of disease progression or unacceptable toxicity.

EFFICACY PHASE: Patients are randomized to Regimen A or B. Patients with disease that is ARMS FOXO1 fusion negative (stage I, group I/II, stage 1, group III [orbit] or stage II, group I/II) are assigned to Regimen C.

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 orally (PO) once daily (QD) on days 1-28. Cycles repeats every 28 days for 24 weeks in the absence of disease progression or unacceptable toxicity.

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.

MAINTENANCE PHASE (Patients in Regimen A or Regimen B): Patients receive vinorelbine IV over 6-10 minutes on days 1, 8, and 15 and cyclophosphamide orally (PO) once daily (QD) on days 1-28. Treatment repeats every 28 days for up to 6 cycles.

REGIMEN C (FOXO1 FUSION NEGATIVE): 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.

After completion of study treatment, patients are followed up every 3 months for 1 year, every 4 months for 2 years, every 6 months for 1 year, and then annually for up to 10 years.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Alveolar Rhabdomyosarcoma
  • Botryoid-Type Embryonal Rhabdomyosarcoma
  • Embryonal Rhabdomyosarcoma
  • Rhabdomyosarcoma
  • Sclerosing Rhabdomyosarcoma
  • Spindle Cell Rhabdomyosarcoma
Intervention  ICMJE
  • 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
    • Radiation Therapy, NOS
    • 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
Study Arms  ICMJE
  • 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.
    Interventions:
    • Drug: Cyclophosphamide
    • Biological: Dactinomycin
    • Drug: Irinotecan Hydrochloride
    • Other: Laboratory Biomarker Analysis
    • Other: Questionnaire Administration
    • Radiation: Radiation Therapy
    • Drug: 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.
    Interventions:
    • Drug: Cyclophosphamide
    • Biological: Dactinomycin
    • Drug: Irinotecan Hydrochloride
    • Other: Laboratory Biomarker Analysis
    • Other: Questionnaire Administration
    • Radiation: Radiation Therapy
    • Drug: Temsirolimus
    • Drug: Vincristine Sulfate
    • Drug: Vinorelbine
  • 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.
    Interventions:
    • Drug: Cyclophosphamide
    • Biological: Dactinomycin
    • Other: Laboratory Biomarker Analysis
    • Other: Questionnaire Administration
    • Radiation: Radiation Therapy
    • Drug: Vincristine Sulfate
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: January 7, 2019)
397
Original Estimated Enrollment  ICMJE
 (submitted: October 2, 2015)
465
Study Completion Date  ICMJE Not Provided
Estimated Primary Completion Date July 1, 2024   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE up to 40 Years   (Child, Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Listed Location Countries  ICMJE Australia,   Canada,   New Zealand,   Puerto Rico,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02567435
Other Study ID Numbers  ICMJE NCI-2015-01644
NCI-2015-01644 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
ARST1431 ( Other Identifier: Children's Oncology Group )
ARST1431 ( Other Identifier: CTEP )
U10CA180886 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party National Cancer Institute (NCI)
Study Sponsor  ICMJE National Cancer Institute (NCI)
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Abha A Gupta Children's Oncology Group
PRS Account National Cancer Institute (NCI)
Verification Date September 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP