A Study to Compare Early Use of Vinorelbine and Maintenance Therapy for Patients With High Risk Rhabdomyosarcoma

• ClinicalTrials.gov Identifier: NCT04994132
• Recruitment Status: Recruiting
• First Posted: August 6, 2021
• Last Update Posted: April 22, 2024
• Sponsor: Children's Oncology Group
• Collaborator: National Cancer Institute (NCI)
• Information provided by (Responsible Party): Children's Oncology Group

Tracking Information

• First Submitted Date: July 9, 2021
• First Posted Date: August 6, 2021
• Last Update Posted Date: April 22, 2024
• Actual Study Start Date: September 14, 2021
• Estimated Primary Completion Date: September 30, 2027 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: February 13, 2023)

Event-free survival [ Time Frame: Time from randomization to an event defined as disease relapse/progression, second malignancy, or death, whichever occurs first, assessed up to 5 years from study enrollment ]

Will be estimated using the Kaplan-Meier method and will be compared between the two regimens using a log-rank test.

Original Primary Outcome Measures (submitted: July 29, 2021)

Event-free survival [ Time Frame: Time from randomization to an event defined as disease relapse/progression, second malignancy, or death, whichever occurs first, assessed up to 4 years ]

Will be estimated using the Kaplan-Meier method and will be compared between the two regimens using a log-rank test.

Current Secondary Outcome Measures (submitted: February 13, 2023)

• Overall survival [ Time Frame: Time from randomization to death of any cause, assessed up to 5 years from study enrollment ]
  Will be estimated using the Kaplan-Meier method and will be compared between the therapy groups using a log-rank test.
• Radiologic response rate [ Time Frame: At week 12 after study enrollment ]
  Includes both complete response and partial response. Response Evaluation Criteria in Solid Tumors 1.1 criteria will be used to define complete and partial responses. Will be compared between arms using chi square test.
• Incidence of adverse events [ Time Frame: Up to 5 years from study enrollment ]
  Adverse events of particular interest including grade 4 hematologic toxicity, grade 2 sinusoidal obstruction syndrome, grade 3 or higher neuropathy and any non-hematologic toxicity that result in delays > 14 days in the delivery of a 21-day cycle of therapy or results in a dose reduction of any chemotherapy drugs.
• Feasibility and safety assessed by the adverse events, toxicities and treatment delays [ Time Frame: From study enrollment to completion of the initial 12 weeks of therapy ]
  If more than 40% of patients enrolled in the safety phase experience one or more of the toxicities, the study will be paused, the study team will review the data and determine if an amendment is needed. Specifically, toxicities of interest include:

  1. Hematological toxicities that delay the administration of subsequent chemotherapy cycles by more than two weeks.
  2. Grade 2 or higher sinusoidal obstruction syndrome.
  3. Grade 3 or higher neuropathy.
  4. Other Grade 3 or higher non-hematological toxicities that delay the administration of subsequent chemotherapy cycles by more than 2 weeks.

Original Secondary Outcome Measures (submitted: July 29, 2021)

• Overall survival [ Time Frame: Time from randomization to death of any cause, assessed up to 4 years ]
  Will be estimated using the Kaplan-Meier method and will be compared between the therapy groups using a log-rank test.
• Radiologic response rate [ Time Frame: At week 12 ]
  Includes both complete response and partial response. RECIST 1.1 criteria will be used to define complete and partial responses. Will be compared between arms using chi square test.
• Incidence of adverse events [ Time Frame: Up to 4 years ]
  Adverse events of particular interest including grade 4 hematologic toxicity, grade 2 sinusoidal obstruction syndrome, grade 3 or higher neuropathy and any non-hematologic toxicity that result in delays > 14 days in the delivery of a 21-day cycle of therapy or results in a dose reduction of any chemotherapy drugs.
• Feasibility and safety assessed by the adverse events, toxicities and treatment delays [ Time Frame: From study enrollment to completion of the initial 12 weeks of therapy ]
  If more than 40% of patients enrolled in the safety phase experience one or more of the toxicities, the study will be paused, the study team will review the data and determine if an amendment is needed. Specifically, toxicities of interest include:

  1. Hematological toxicities that delay the administration of subsequent chemotherapy cycles by more than two weeks.
  2. Grade 2 or higher sinusoidal obstruction syndrome
  3. Grade 3 or higher neuropathy
  4. Other Grade 3 or higher non-hematological toxicities that delay the administration of subsequent chemotherapy cycles by more than 2 weeks.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Study to Compare Early Use of Vinorelbine and Maintenance Therapy for Patients With High Risk Rhabdomyosarcoma
• Official Title: A Randomized Phase 3 Trial of Vinorelbine, Dactinomycin, and Cyclophosphamide (VINO-AC) Plus Maintenance Chemotherapy With Vinorelbine and Oral Cyclophosphamide (VINO-CPO) vs Vincristine, Dactinomycin and Cyclophosphamide (VAC) Plus VINO-CPO Maintenance in Patients With High Risk Rhabdomyosarcoma (HR-RMS)
• Brief Summary: This phase III trial compares the safety and effect of adding vinorelbine to vincristine, dactinomycin, and cyclophosphamide (VAC) for the treatment of patients with high risk rhabdomyosarcoma (RMS). High risk refers to cancer that is likely to recur (come back) after treatment or spread to other parts of the body. This study will also examine if adding maintenance therapy after VAC therapy, with or without vinorelbine, will help get rid of the cancer and/or lower the chance that the cancer comes back. Vinorelbine and vincristine are in a class of medications called vinca alkaloids. They work by stopping cancer cells from growing and dividing and may kill them. Dactinomycin is a type of antibiotic that is only used in cancer chemotherapy. It works by damaging the cell's deoxyribonucleic acid (DNA) and may kill cancer cells. Cyclophosphamide is in a class of medications called alkylating agents. It works by damaging the cell's DNA and may kill cancer cells. It may also lower the body's immune response. Vinorelbine, vincristine, dactinomycin and cyclophosphamide are chemotherapy medications that work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. This trial may have the potential to eliminate rhabdomyosarcoma for a long time or for the rest of patient's life.

Detailed Description

PRIMARY OBJECTIVE:

I. To compare event-free survival (EFS) of patients with high-risk rhabdomyosarcoma (HR-RMS) treated with vinorelbine, dactinomycin and cyclophosphamide (VINO-AC) followed by 24 weeks of vinorelbine and oral cyclophosphamide (VINO-CPO) maintenance therapy to that of patients treated with vincristine, dactinomycin and cyclophosphamide (VAC) followed by 24 weeks of VINO-CPO maintenance therapy.

SECONDARY OBJECTIVES:

I. To assess the safety and feasibility of administering VINO-AC in newly diagnosed patients with HR-RMS.

II. To describe the toxicity experience of patients with HR-RMS treated with VINO-AC compared to VAC.

III. To compare overall survival (OS) of patients with HR-RMS treated with VINO AC followed by 24 weeks of VINO-CPO maintenance therapy to that of patients treated with VAC followed by 24 weeks of VINO-CPO maintenance therapy.

IV. To compare objective radiologic response rates at week 12 between patients with HR-RMS treated with VINO-AC to those treated with VAC.

V. To determine whether the addition of 24 weeks of VINO-CPO maintenance therapy improves EFS in patients with HR-RMS when compared to historical controls.

EXPLORATORY OBJECTIVE:

I. To collect serial blood samples and tumor tissue for banking at baseline, during treatment, at the end of therapy, and at the time of progression for future tumor and liquid biopsy studies.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM A: Patients receive vincristine sulfate intravenously (IV) on days 1, 8 and 15 of cycles 1-4, 7, 8, 11, and 12, and day 1 of cycles 5, 6, 9, 10, 13, and 14. Patients also receive dactinomycin IV over 1-15 minutes or IV push (IVP) over 1-5 minutes on day 1 of cycles 1-5, 8-10, and 11-14, and cyclophosphamide IV over 60 minutes on day 1 of each cycle. Treatment repeats every 21 days for up to 14 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo radiation therapy on weeks 13 and 40.

ARM B: Patients receive vinorelbine tartrate IV over 6-10 minutes on days 1 and 8, vincristine sulfate IV on day 15, dactinomycin IV over 1-15 minutes or IVP over 1-5 minutes on day 1 of cycles 1-5 and 8-14, and cyclophosphamide IV over 60 minutes on day 1. Treatment repeats every 21 days for up to 14 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo radiation therapy on weeks 13 and 40.

MAINTENANCE: All patients receive vinorelbine tartrate IV over 6-10 minutes on days 1, 8, and 15 and cyclophosphamide orally (PO) on days 1-28. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.

Patients in both arms undergo computed tomography (CT), magnetic resonance imaging (MRI), positron emission tomography (PET), x-ray imaging, and/or bone scan, as well as blood sample collection throughout the trial. Patients may also undergo bone marrow aspiration and/or biopsy as clinically indicated

After completion of study treatment, patients are followed up every 3 months for year 1, every 4 months for years 2-3, and every 6 months for years 4-5.

• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Alveolar Rhabdomyosarcoma
• Botryoid-Type Embryonal Rhabdomyosarcoma
• Embryonal Rhabdomyosarcoma
• Metastatic Embryonal Rhabdomyosarcoma
• Metastatic Rhabdomyosarcoma
• Solid Alveolar Rhabdomyosarcoma
• Spindle Cell Rhabdomyosarcoma
• Spindle Cell/Sclerosing Rhabdomyosarcoma

Intervention

• Procedure: Biospecimen Collection
  Undergo blood sample collection
  Other Names:

  • Biological Sample Collection
  • Biospecimen Collected
  • Specimen Collection
• Procedure: Bone Marrow Aspiration
  Undergo bone marrow aspiration
• Procedure: Bone Marrow Biopsy
  Undergo bone marrow biopsy
  Other Names:

  • Biopsy of Bone Marrow
  • Biopsy, Bone Marrow
• Procedure: Bone Scan
  Undergo bone scan
  Other Name: Bone Scintigraphy
• Procedure: Computed Tomography
  Undergo CT
  Other Names:

  • CAT
  • CAT Scan
  • Computed Axial Tomography
  • Computerized Axial Tomography
  • Computerized axial tomography (procedure)
  • Computerized Tomography
  • Computerized Tomography (CT) scan
  • CT
  • CT Scan
  • tomography
• Drug: Cyclophosphamide
  Given IV or PO
  Other Names:

  • (-)-Cyclophosphamide
  • 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate
  • Asta B 518
  • B-518
  • 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
  • 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
• Procedure: Magnetic Resonance Imaging
  Undergo MRI
  Other Names:

  • Magnetic Resonance
  • Magnetic Resonance Imaging (MRI)
  • Magnetic resonance imaging (procedure)
  • Magnetic Resonance Imaging Scan
  • Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance
  • MR
  • MR Imaging
  • MRI
  • MRI Scan
  • MRIs
  • NMR Imaging
  • NMRI
  • Nuclear Magnetic Resonance Imaging
  • sMRI
  • Structural MRI
• Procedure: Positron Emission Tomography
  Undergo PET
  Other Names:

  • Medical Imaging, Positron Emission Tomography
  • PET
  • PET Scan
  • Positron emission tomography (procedure)
  • Positron Emission Tomography Scan
  • Positron-Emission Tomography
  • proton magnetic resonance spectroscopic imaging
  • PT
• Radiation: Radiation Therapy
  Undergo radiation therapy
  Other Names:

  • Cancer Radiotherapy
  • Energy Type
  • ENERGY_TYPE
  • Irradiate
  • Irradiated
  • Irradiation
  • Radiation
  • Radiation Therapy, NOS
  • Radiotherapeutics
  • Radiotherapy
  • RT
  • Therapy, Radiation
• Drug: Vincristine Sulfate
  Given IV
  Other Names:

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

  • Biovelbin
  • Eunades
  • KW-2307
  • Navelbine
  • Navelbine Ditartrate
  • NVB
  • Vinorelbine Ditartrate
• Procedure: X-Ray Imaging
  Undergo x-ray imaging
  Other Names:

  • Conventional X-Ray
  • Diagnostic Radiology
  • Medical Imaging, X-Ray
  • Plain film radiographs
  • Radiographic Imaging
  • Radiographic imaging procedure (procedure)
  • Radiography
  • RG
  • Static X-Ray
  • X-Ray

Study Arms

• Experimental: Arm A (VAC, VINO-CPO)

  Patients receive vincristine sulfate IV on days 1, 8 and 15 of cycles 1-4, 7, 8, 11, and 12, and day 1 of cycles 5, 6, 9, 10, 13, and 14. Patients also receive dactinomycin IV over 1-15 minutes or IVP over 1-5 minutes on day 1 of cycles 1-5, 8-10, and 11-14, and cyclophosphamide IV over 60 minutes on day 1 of each cycle. Treatment repeats every 21 days for up to 14 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo radiation therapy on weeks 13 and 40.

  MAINTENANCE: Patients receive vinorelbine tartrate IV over 6-10 minutes on days 1, 8, and 15, and cyclophosphamide PO on days 1-28. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.

  Patients in both arms undergo CT, MRI, PET, x-ray imaging, and/or bone scan, as well as blood sample collection throughout the trial. Patients may also undergo bone marrow aspiration and/or biopsy as clinically indicated.

  Interventions:

  • Procedure: Biospecimen Collection
  • Procedure: Bone Marrow Aspiration
  • Procedure: Bone Marrow Biopsy
  • Procedure: Bone Scan
  • Procedure: Computed Tomography
  • Drug: Cyclophosphamide
  • Biological: Dactinomycin
  • Procedure: Magnetic Resonance Imaging
  • Procedure: Positron Emission Tomography
  • Radiation: Radiation Therapy
  • Drug: Vincristine Sulfate
  • Drug: Vinorelbine Tartrate
  • Procedure: X-Ray Imaging
• Experimental: Arm B (vinorelbine, VAC, VINO-CPO)

  Patients receive vinorelbine tartrate IV over 6-10 minutes on days 1 and 8, vincristine sulfate IV on day 15, dactinomycin IV over 1-15 minutes or IVP over 1-5 minutes on day 1 of cycles 1-5 and 8-14, and cyclophosphamide IV over 60 minutes on day 1. Treatment repeats every 21 days for up to 14 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo radiation therapy on weeks 13 and 40.

  MAINTENANCE: Patients receive vinorelbine tartrate IV over 6-10 minutes on days 1, 8, and 15, and cyclophosphamide PO on days 1-28. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.

  Patients in both arms undergo CT, MRI, PET, x-ray imaging, and/or bone scan, as well as blood sample collection throughout the trial. Patients may also undergo bone marrow aspiration and/or biopsy as clinically indicated.

  Interventions:

  • Procedure: Biospecimen Collection
  • Procedure: Bone Marrow Aspiration
  • Procedure: Bone Marrow Biopsy
  • Procedure: Bone Scan
  • Procedure: Computed Tomography
  • Drug: Cyclophosphamide
  • Biological: Dactinomycin
  • Procedure: Magnetic Resonance Imaging
  • Procedure: Positron Emission Tomography
  • Radiation: Radiation Therapy
  • Drug: Vincristine Sulfate
  • Drug: Vinorelbine Tartrate
  • Procedure: X-Ray Imaging

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: February 13, 2023): 118
• Original Estimated Enrollment (submitted: July 29, 2021): 100
• Estimated Study Completion Date: September 30, 2027
• Estimated Primary Completion Date: September 30, 2027 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Patients must be =< 50 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. FOXO1 fusion status must be determined by week 4 (day 28) of therapy. RMS types included under embryonal RMS (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 2020 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 RMS (ARMS) in the 2020 WHO Classification is the same as in the ICR and includes classic and solid variants

  • ERMS

    • Stage 4, group IV, >= 10 years of age

  • ARMS

    • Stage 4, group IV Patients will be eligible to remain on protocol therapy based upon stage, group, and age
• Bone marrow metastatic disease is based on morphologic evidence of RMS based on hematoxylin and eosin (H&E) stains. In the absence of morphologic evidence of marrow involvement on H&E, patients with bone marrow involvement detected ONLY by flow cytometry, reverse transcriptase (RT)-polymerase chain reaction (PCR), fluorescence in situ hybridization (FISH), or immunohistochemistry will NOT be considered to have clinical bone marrow involvement for the purposes of this study

• 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 (must be performed within 7 days prior to enrollment):

  • Age; Maximum serum creatinine (mg/dL)
  • 1 month to < 6 months; 0.4 mg/dL (male); 0.4 mg/dL (female)
  • 6 months to < 1 year; 0.5 mg/dL (male); 0.5 mg/dL (female)
  • 1 to < 2 years; 0.6 mg/dL (male); 0.6 mg/dL (female)
  • 2 to < 6 years; 0.8 mg/dL (male); 0.8 mg/dL (female)
  • 6 to < 10 years; 1 mg/dL (male); 1 mg/dL (female)
  • 10 to < 13 years; 1.2 mg/dL (male); 1.2 mg/dL (female)
  • 13 to < 16 years; 1.5 mg/dL (male); 1.4 mg/dL (female)
  • >= 16 years; 1.7 mg/dL (male); 1.4 mg/dL (female)

• Total bilirubin =< 1.5 x upper limit of normal (ULN) for age (must be performed within 7 days prior to enrollment)

  • If there is evidence of biliary obstruction by tumor, then total bilirubin must be < 3 x 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 with evidence of uncontrolled infection are not eligible
• RMS that is considered a second malignancy and previous cancer(s) that were treated with chemotherapy and/or radiation. Surgical resection alone of previous cancer(s) is allowed

• Patients with central nervous system involvement of RMS as defined below:

  • Malignant cells detected in cerebrospinal fluid
  • Intra-parenchymal brain metastasis separate and distinct from primary tumor (i.e., direct extension from parameningeal primary tumors is allowed).
  • Diffuse leptomeningeal disease

• Patients who have received any chemotherapy (excluding steroids) and/or radiation therapy for RMS prior to enrollment.

  • Note: the following exception:

    • Patients requiring emergency radiation therapy for RMS. These patients are eligible, provided they are consented to ARST2031 prior to administration of radiation
  • Note: Patients who have received or are receiving chemotherapy or radiation for non-malignant conditions (e.g. autoimmune diseases) are eligible. Patients must discontinue chemotherapy for non-malignant conditions prior to starting protocol therapy
• Vincristine and vinorelbine are sensitive substrates of CYP450 3A4 isozyme. Patients must not have received drugs that are moderate to strong CYP3A4 inhibitors and inducers within 7 days prior to study enrollment
• Female patients who are pregnant since fetal toxicities and teratogenic effects have been noted for several of the study drugs. A pregnancy test is required for female patients of childbearing potential
• Lactating females who plan to breastfeed their infants
• Sexually active patients of reproductive potential who have not agreed to use an effective contraceptive method for the duration of their study participation

Sex/Gender

• Sexes Eligible for Study: All

• Ages: up to 50 Years (Child, Adult)
• Accepts Healthy Volunteers: No
• Listed Location Countries: Australia, Canada, Puerto Rico, Saudi Arabia, United States

Administrative Information

• NCT Number: NCT04994132
• Other Study ID Numbers: ARST2031; NCI-2021-06711 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ); ARST2031 ( Other Identifier: Children's Oncology Group ); ARST2031 ( Other Identifier: CTEP ); U10CA180886 ( U.S. NIH Grant/Contract )
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Children's Oncology Group
• Original Responsible Party: Same as current
• Current Study Sponsor: Children's Oncology Group
• Original Study Sponsor: Same as current
• Collaborators: National Cancer Institute (NCI)

Investigators

• Principal Investigator: Wendy Allen-Rhoades; Children's Oncology Group

• PRS Account: Children's Oncology Group
• Verification Date: April 2024