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

S
Sandeep Batra, MD

Primary Investigator

Overview

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 riskhabdomyosarcoma (RMS). High risk refers to cancer that is likely to recur (come back) afterd to other parts of the body. This study will also examine if addingherapy after VAC therapy, with or without vinorelbine, will help get rid of thed/or lower the chance that the cancer comes back. Vinorelbine and vincristine are indications 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) andy kill cancer cells. Cyclophosphamide is in a class of medications called alkylatinggents. 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 arehemotherapy medications that work in different ways to stop the growth of cancer cells,her by killing the cells, by stopping them from dividing, or by stopping them fromding. This trial may have the potential to eliminate rhabdomyosarcoma for a long time orhe rest of patient's life.

Description

PRIMARY OBJECTIVE:
I. To compare event-free survival (EFS) of patients with high-risk rhabdomyosarcoma (HR-RMS)d with vinorelbine, dactinomycin and cyclophosphamide (VINO-AC) followed by 24 weeks of vinorelbine and oral cyclophosphamide (VINO-CPO) maintenance therapy to that of patientsd 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 comparedVAC.
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-RMSd with VINO-AC to those treated with VAC.
V. To determine whether the addition of 24 weeks of VINO-CPO maintenance therapy improves EFSwith HR-RMS when compared to historical controls.
EXPLORATORY OBJECTIVE:
I. To collect serial blood samples and tumor tissue for banking at baseline, duringhe 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. Treatmentvery 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 minutesday 1 of cycles 1-5 and 8-14, and cyclophosphamide IV over 60 minutes on day 1. Treatmentvery 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 6ycles in the absence of disease progression or unacceptable toxicity.
Patients in both arms undergo computed tomography (CT), magnetic resonance imaging (MRI),graphy (PET), x-ray imaging, and/or bone scan, as well as blood samplehroughout 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,very 4 months for years 2-3, and every 6 months for years 4-5.

Eligibility

You may be eligible for this study if you meet the following criteria:

  • Conditions:
    Alveolar Rhabdomyosarcoma, Botryoid-Type Embryonal Rhabdomyosarcoma, Embryonal Rhabdomyosarcoma, Metastatic Embryonal Rhabdomyosarcoma, Metastatic Rhabdomyosarcoma, Solid Alveolar Rhabdomyosarcoma, Spindle Cell Rhabdomyosarcoma, Spindle Cell/Sclerosing Rhabdomyosarcoma
  • Age: - 50 Years
  • Gender: All

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, basedupon institutional histopathologic classification are eligible to enroll on the studybased upon stage, group, and age, as below. FOXO1 fusion status must be determined byweek 4 (day 28) of therapy. RMS types included under embryonal RMS (ERMS) includehose classified in the 1995 International Classification of Rhabdomyosarcoma (ICR) asRMS (classic, spindle cell, and botryoid variants), which are reclassified in the2020 World Health Organization (WHO) Classification as ERMS (classic, dense andbotryoid variants) and spindle cell/sclerosing RMS (encompassing the historicaldle cell ERMS variant and the newly recognized sclerosing RMS variant).Classification of alveolar RMS (ARMS) in the 2020 WHO Classification is the same as inhe 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 therapybased 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 marrowvolvement on H&E, patients with bone marrow involvement detected ONLY by flowytometry, reverse transcriptase (RT)-polymerase chain reaction (PCR), fluorescence inu hybridization (FISH), or immunohistochemistry will NOT be considered to havebone marrow involvement for the purposes of this study
  • Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70L/min/1.73 m^2 or a serum creatinine based on age/gender as follows (must bed 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 mustbe < 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 treatedwith chemotherapy and/or radiation. Surgical resection alone of previous cancer(s) iswed
  • 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 aregible, provided they are consented to ARST2031 prior to administration ofdiation
    • Note: Patients who have received or are receiving chemotherapy or radiation for
      non-malignant conditions (e.g. autoimmune diseases) are eligible. Patients mustdiscontinue chemotherapy for non-malignant conditions prior to starting protocolherapy
  • Vincristine and vinorelbine are sensitive substrates of CYP450 3A4 isozyme. Patients
    must not have received drugs that are moderate to strong CYP3A4 inhibitors andducers within 7 days prior to study enrollment
  • Female patients who are pregnant since fetal toxicities and teratogenic effects havebeen noted for several of the study drugs. A pregnancy test is required for femalehildbearing potential
  • Lactating females who plan to breastfeed their infants
  • Sexually active patients of reproductive potential who have not agreed to use anve contraceptive method for the duration of their study participation

Updated on 03 May 2024. Study ID: ARST2031
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