Clinical Trials /

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

NCT02567435

Description:

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.

Related Conditions:
  • Alveolar Rhabdomyosarcoma
  • Embryonal Rhabdomyosarcoma
Recruiting Status:

Recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: Combination Chemotherapy With or Without Temsirolimus in Treating Patients With Intermediate Risk Rhabdomyosarcoma
  • 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)

Clinical Trial IDs

  • ORG STUDY ID: NCI-2015-01644
  • SECONDARY ID: NCI-2015-01644
  • SECONDARY ID: ARST1431
  • SECONDARY ID: ARST1431
  • SECONDARY ID: ARST1431
  • SECONDARY ID: U10CA180886
  • NCT ID: NCT02567435

Conditions

  • Alveolar Rhabdomyosarcoma
  • Botryoid-Type Embryonal Rhabdomyosarcoma
  • Embryonal Rhabdomyosarcoma
  • Rhabdomyosarcoma
  • Sclerosing Rhabdomyosarcoma
  • Spindle Cell Rhabdomyosarcoma

Interventions

DrugSynonymsArms
Cyclophosphamide(-)-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- 138719Regimen A (VAC/VI)
DactinomycinActinomycin A IV, Actinomycin C1, Actinomycin D, Actinomycin I1, Actinomycin IV, Actinomycin X 1, Actinomycin-[thr-val-pro-sar-meval], Cosmegen, DACT, Dactinomycine, Lyovac Cosmegen, MeractinomycinRegimen A (VAC/VI)
Irinotecan HydrochlorideCampto, Camptosar, Camptothecin 11, Camptothecin-11, CPT 11, CPT-11, Irinomedac, Irinotecan Hydrochloride Trihydrate, Irinotecan Monohydrochloride Trihydrate, U-101440ERegimen A (VAC/VI)
TemsirolimusCCI-779, CCI-779 Rapamycin Analog, Cell Cycle Inhibitor 779, Rapamycin Analog, Rapamycin Analog CCI-779, ToriselRegimen B (VAC/VI/temsirolimus)
Vincristine SulfateKyocristine, Leurocristine Sulfate, Leurocristine, sulfate, Oncovin, Vincasar, Vincosid, Vincrex, Vincristine, sulfateRegimen A (VAC/VI)
VinorelbineDihydroxydeoxynorvinkaleukoblastineRegimen B (VAC/VI/temsirolimus)

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.

Detailed Description

      PRIMARY OBJECTIVE:

      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 OBJECTIVE:

      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 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, and explore whether tumor-specific somatic
      variants are detectable in the ctDNA.

      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 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 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 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
      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
      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.

      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 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.

      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.
    

Trial Arms

NameTypeDescriptionInterventions
Regimen A (VAC/VI)ExperimentalPatients 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.
  • Cyclophosphamide
  • Dactinomycin
  • Irinotecan Hydrochloride
  • Vincristine Sulfate
Regimen B (VAC/VI/temsirolimus)ExperimentalPatients 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.
  • Cyclophosphamide
  • Dactinomycin
  • Irinotecan Hydrochloride
  • Temsirolimus
  • Vincristine Sulfate
  • Vinorelbine
Regimen C (FOXO1 fusion negative, VAC/VA)ExperimentalPatients 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.
  • Cyclophosphamide
  • Dactinomycin
  • Vincristine Sulfate

Eligibility 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 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
      
Maximum Eligible Age:40 Years
Minimum Eligible Age:N/A
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure: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
Safety Issue:
Description: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

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

Details

Phase:Phase 3
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

Last Updated

July 6, 2021