Evolutionary Inspired Therapy for the Treatment of Fusion Positive Newly Diagnosed, Metastatic Rhabdomyosarcoma
This phase II trial investigates evolutionary inspired therapy in treating fusion positive rhabdomyosarcoma that is newly diagnosed and has spread to other places in the body (metastatic). Chemotherapy drugs, such as vinorelbine, vincristine sulfate, and actinomycin D, 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. Cyclophosphamide is used to decrease the body's immune response and may inhibit DNA replication and initiate cell death. This study is being done to determine which of 4 different therapeutic treatments will have the best chance of the disease not worsening or coming back.
Inclusion Criteria
- Patients must have a new histologic diagnosis of rhabdomyosarcoma
- Patients must have fluorescence in situ hybridization (FISH), polymerase chain reaction (PCR) or other molecular confirmation of PAX/FOXO1 fusion per institutional standards NOTE: Patients with pending fusion status at the time of enrollment are eligible to start therapy on any arm of the trial.
- Patients must have sufficient tissue (up to 10 unstained formalin-fixed paraffin-embedded [FFPE]) for correlative testing
- All patients must have distant metastatic disease; either biopsy positive or positron emission tomography (PET) avid extranodal or distant nodal lesions determined by the investigator to be metastatic disease. Patients with a single distant metastatic site that has been excised prior to study entry are eligible
- No prior systemic chemotherapy
- Patients enrolled to Arm B, maintenance, must be able to take oral cyclophosphamide. Note: enteral administration of cyclophosphamide is allowable
- Males and females of reproductive potential may not participate unless they have agreed to the use of, at minimum, two methods of contraception during and after treatment, or abstinence. * Women of childbearing potential should adhere to contraception for a period of 4 months after completion of systematic chemotherapy administration * Men who are sexually active with women of child bearing potential should adhere to contraception for a period of 4 months after completion of systematic chemotherapy administration
- All patients and/or their parents or legal guardians must have the ability to understand and the willingness to sign a written informed consent or assent document
Exclusion Criteria
- Patients with regional lymph nodes as the only site of disease are not eligible. Distant nodal sites alone are eligible
- Patients who are receiving any other investigational agents for rhabdomyosarcoma are ineligible
- Patients must not be receiving any additional medicines being given for the specific purpose of treating cancer. Alternative medications including, but not limited to cannabis based products would not be a reason for exclusion
- Patients are ineligible if they have uncontrolled intercurrent illness including, but not limited to: * Ongoing or active infection not expected to resolve with current antibiotic plan * Cardiac arrhythmia * Psychiatric illness/social situations that would limit compliance with study requirements
- Patients who are considered unable to comply with the safety monitoring requirements of the study are not eligible
- Patients who are pregnant or breastfeeding are not eligible because there is no available information regarding human fetal or teratogenic toxicities. Females of [TKE1] childbearing potential must have a negative serum or urine pregnancy test within 24 hours of starting protocol therapy
Additional locations may be listed on ClinicalTrials.gov for NCT04388839.
See trial information on ClinicalTrials.gov for a list of participating sites.
PRIMARY OBJECTIVE:
I. To evaluate 4 different therapeutic approaches towards improving the 3-year event-free survival (EFS) from its current 6% to 35% in metastatic, fusion-positive rhabdomyosarcoma patients.
SECONDARY OBJECTIVE:
I. To describe the overall survival for patients treated on all 4 therapeutic approaches.
EXPLORATORY OBJECTIVES:
I. To describe the grade 3+ toxicities of the various approaches.
II. To build, improve, and then test mathematical models for predicting and tracking responses to therapies towards improved strategies for preventing resistance and identifying potentially better strategies for utilizing different doses, schedules or agents in the management of fusion-positive rhabdomyosarcoma (FPRMS).
III. To evaluate physician and patient preferences for novel approaches to high risk cancer by accrual to conventional, more and less intensive systemic chemotherapy approaches in metastatic FPRMS.
IV. To suggest additional biomarkers by quantifying circulating tumor deoxyribonucleic acid (DNA) (plasma tumor [pt] DNA) in patients and determine if ptDNA changes over time in a manner that reflects tumor burden, presence of resistant cancer cells, response to therapy, predicts risk of progression, and informs the mathematical models.
V. To evaluate a set of radiomic biomarkers calculated from baseline and post-therapy computed tomography (CT) and magnetic resonance imaging (MRI) scans, and compare results with treatment response and mathematical model predictions.
VI. To perform single cell sequencing of circulating tumor cells to evaluate changes over time.
VII. To compare the number of chemotherapy cycles delivered across all treatment arms.
VIII. To examine parent and patient experiences with treatment decision-making in the setting of multiple therapeutic options and a poor prognosis.
OUTLINE: Patients are assigned to 1 of 4 arms
ARM A (FIRST STRIKE): Patients receive vinorelbine tartrate intravenously (IV) over 6-10 minutes on days 1 and 8, dactinomycin IV over 3-5 minutes on day 1 (except during radiation), and cyclophosphamide IV over 60 minutes on day 1. Cycles repeat every 21 days for 43 weeks in the absence of disease progression or unacceptable toxicity. Patients may also under radiation therapy between weeks 0-25 per treating physician’s discretion.
ARM B (SECOND STRIKE/MAINTENANCE): Patients receive vincristine sulfate IV over 1-10 minutes on days 1, 8, and 15, dactinomycin IV over 3-5 minutes on day 1 (except during radiation), and cyclophosphamide IV over 60 minutes on day 1. Treatment repeats every 21 days for 2 cycles in the absence of disease progression of unacceptable toxicity. Patients with a complete response (CR) at week 6 receive an additional 2 cycles of vincristine sulfate, dactinomycin, and cyclophosphamide then transition to maintenance therapy. Patients with a partial response (PR) continue treatment with vincristine sulfate, dactinomycin, and cyclophosphamide until first CR and then receive an additional 2 more cycles of vincristine sulfate, dactinomycin, and cyclophosphamide and transition to maintenance. Patients with a CR at week 30 receive an additional 2 more cycles of vincristine sulfate, dactinomycin, and cyclophosphamide and transition to maintenance therapy. Patients with stable disease (SD) or PR continue treatment with vincristine sulfate, dactinomycin, and cyclophosphamide until week 42. Patients without progressive disease (PD) at week 42 transition to maintenance therapy. On maintenance therapy, patients receive vinorelbine IV on days 1, 8, and 15 of each cycle and cyclophosphamide orally (PO) daily (QD) on days 1-28. Treatment repeats every 28 days for 24 months in the absence of disease progression or unacceptable toxicity.
ARM C (ADAPTIVE THERAPY):
INTITIAL PHASE: Patients receive vincristine sulfate IV over 1-10 minutes on days 1, 8, and 15, dactinomycin IV over 3-5 minutes on day 1 (except during radiation), and cyclophosphamide IV over 60 minutes on day 1. Cycles repeat every 21 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients with SD receive an additional 2 cycles of vincristine sulfate, dactinomycin, and cyclophosphamide, and patients with a PR proceed to the management phase. Patients may also under radiation therapy between weeks 0-15 per treating physician’s discretion.
MANAGEMENT PHASE: Treatment may consist of any of the following or a modified version or the following: Patients receive vincristine sulfate, dactinomycin, and cyclophosphamide as in the Initial Phase for 2 cycles. Patients with SD receive an additional 2 cycles of vincristine sulfate, dactinomycin, and cyclophosphamide. Patients with a PR receive no treatment and scans are performed every 6 weeks until the cancer returns to the size it was at the beginning of treatment. Once the size is reached, patients then receive an additional 2 cycles vincristine sulfate, dactinomycin, and cyclophosphamide. Patients then follow the treatment structure for SD and PR as above in the absence of disease progression or unacceptable toxicity.
ARM D (CONVENTIONAL CHEMOTHERAPY): Treatment may consist of any of the following or a modified version of the following: Patients receive vincristine sulfate IV over 1-10 minutes on days 1, 8, 15, dactinomycin IV over 3-5 minutes on day 1 (except during radiation), and cyclophosphamide IV over 60 minutes on day 1. Cycles repeat every 21 days for 42-52 weeks in the absence of disease progression or unacceptable toxicity; OR Patients receive vincristine sulfate IV over 1-10 minutes on days 1, 8, and 15, dactinomycin IV over 3-5 minutes on day 1 (except during radiation), cyclophosphamide IV over 60 minutes on day 1, and irinotecan IV over 90 minutes on days 1-5. Cycles repeat every 21 days for 42-52 weeks in the absence of disease progression or unacceptable toxicity; OR Patients receive vincristine sulfate IV over 1-10 minutes on days 1, 8, and 15, dactinomycin IV over 3-5 minutes on day 1 (except during radiation), cyclophosphamide IV over 60 minutes on day 1, irinotecan IV over 90 minutes on days 1-5, ifosfamide IV over 60 minutes on days 1-5, etoposide IV over 30-60 on days 1-5, and doxorubicin over 15 minutes-48 hours on days 1-2 (except during radiation). Cycles with vincristine sulfate, dactinomycin, and cyclophosphamide and vincristine sulfate and irinotecan repeat every 21 days and cycles with vincristine sulfate, doxorubicin, and cyclophosphamide and ifosfamide and etoposide repeat every 14 days for 54 weeks in the absence of disease progression or unacceptable toxicity. Patients may also under radiation therapy between weeks 0-15 per treating physician’s discretion.
After completion of study treatment, patients are followed up for 30 days, every 3 months for 1 year, every 4 months for 1 year, every 6 months for 1 year, and then yearly for 2 years.
Trial PhasePhase II
Trial Typetreatment
Lead OrganizationMoffitt Cancer Center
Principal InvestigatorDamon Russell Reed
- Primary IDMCC-20339
- Secondary IDsNCI-2020-07020
- ClinicalTrials.gov IDNCT04388839