A Study to Compare Early Use of Vinorelbine and Maintenance Therapy for Patients with High Risk Rhabdomyosarcoma
0 - 50 Years, Male and Female
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.
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.
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.
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.
- 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
** Stage 4, group IV, >= 10 years of age
** 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
**Clinical trials are research studies that involve people. These studies test new ways to prevent, detect, diagnose, or treat diseases. People who take part in cancer clinical trials have an opportunity to contribute to scientists’ knowledge about cancer and to help in the development of improved cancer treatments. They also receive state-of-the-art care from cancer experts... Click here to learn more about clinical trials