Evolutionary Therapy for Rhabdomyosarcoma

Study Overview
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Brief Summary
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This clinical trial will evaluate 4 different strategies of chemotherapy schedules in newly diagnosed participants with metastatic Fusion Positive (alveolar) Rhabdomyosarcoma. The participant and their physician will choose from: Arm A) a first strike therapy, Arm B) a first strike-second strike (maintenance) therapy, Arm C) an adaptively timed therapy, and Arm D) conventional chemotherapy.

Official Title
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Evolutionary Inspired Therapy for Newly Diagnosed, Metastatic, Fusion Positive Rhabdomyosarcoma

Conditions
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Rhabdomyosarcoma

Intervention / Treatment
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* Drug: Vincristine
* Drug: Cyclophosphamide
* Drug: Vinorelbine
* Drug: Actinomycin D
* Drug: Cyclophosphamide Pill


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants must have a new histologic diagnosis of rhabdomyosarcoma Participants must have FISH, PCR or other molecular confirmation of PAX/FOXO1 fusion per institutional standards Participants must have sufficient tissue (up to 10 unstained FFPE) for correlative testing All participants must have distant metastatic disease; either biopsy positive or 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 Participants 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: Participants with regional lymph nodes as the only site of disease are not eligible. Distant nodal sites alone are eligible Participants who are receiving any other investigational agents for rhabdomyosarcoma are ineligible Participants 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 Participants 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 pregnant or breastfeeding are not eligible because there is no available information regarding human fetal or teratogenic toxicities. Females of childbearing potential must have a negative serum or urine pregnancy test within 24 hours of starting protocol therapy. Participants who are considered unable to comply with the safety monitoring requirements of the study are not eligible
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A - First Strike<br>Participants will receive 42 weeks of conventional doses of vinorelbine, actinomycin D and cyclophosphamide | Drug: Cyclophosphamide<br>* IV over 60 minutes with dosing ranging from 220mg to 1200mg<br>Drug: Vinorelbine<br>* IV push over 6-10 minutes with dosing ranging from 4mg-25mg<br>* Other names: Navelbine;Drug: Actinomycin D<br>* Actinomycin D should not be given with radiation. Will be administered through IV over 3-5 minutes with dosing ranging from 0.025mg-0.045mg<br>* Other names: Cosmegen;|
| Experimental: Arm B - Second Strike - Maintenance<br>Participants will receive conventional doses of Vincristine/Actinomycin D/Cyclophosphamide (VAC) until complete response (CR) for 12-42 weeks and then switch to up to 2 years of vinorelbine/oral cyclophoshamide | Drug: Vincristine<br>* IV push over 1 minute with dosing ranging from 0.24mg up to 1.5mg<br>Drug: Cyclophosphamide<br>* IV over 60 minutes with dosing ranging from 220mg to 1200mg<br>Drug: Vinorelbine<br>* IV push over 6-10 minutes with dosing ranging from 4mg-25mg<br>* Other names: Navelbine;Drug: Actinomycin D<br>* Actinomycin D should not be given with radiation. Will be administered through IV over 3-5 minutes with dosing ranging from 0.025mg-0.045mg<br>* Other names: Cosmegen;Drug: Cyclophosphamide Pill<br>* Based on Body Surface Area (BSA) round to nearest 25mg<br>|
| Experimental: Arm C - Adaptive Therapy<br>Therapy with VAC that starts and stops based on response, adaptive timing of therapy, with a prolonged time to progression rather than complete remission goal | Drug: Vincristine<br>* IV push over 1 minute with dosing ranging from 0.24mg up to 1.5mg<br>Drug: Cyclophosphamide<br>* IV over 60 minutes with dosing ranging from 220mg to 1200mg<br>Drug: Actinomycin D<br>* Actinomycin D should not be given with radiation. Will be administered through IV over 3-5 minutes with dosing ranging from 0.025mg-0.045mg<br>* Other names: Cosmegen;|
| Active Comparator: Arm - D Conventional Therapy<br>Participants will receive a chemotherapy combination based on published trials. An example would be 42 weeks of VAC but may also include irinotecan, doxorubicin, ifosfamide, etoposide. | Drug: Vincristine<br>* IV push over 1 minute with dosing ranging from 0.24mg up to 1.5mg<br>Drug: Cyclophosphamide<br>* IV over 60 minutes with dosing ranging from 220mg to 1200mg<br>Drug: Actinomycin D<br>* Actinomycin D should not be given with radiation. Will be administered through IV over 3-5 minutes with dosing ranging from 0.025mg-0.045mg<br>* Other names: Cosmegen;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| First Strike Event Free Survival | Participants who choose the first strike treatment will have event free survival assessed at 3 years after initiating treatment. Event free survival is defined as time from treatment initiation to event which includes (1) any recurrence (local or regional, or distant) and (2) death due to any cause. | Baseline to 3 years | 
| Second Strike Event Free Survival | Participants who choose the second strike treatment will have event free survival assessed at 3 years after initiating treatment. Event free survival is defined as time from treatment initiation to event which includes (1) any recurrence (local or regional, or distant) and (2) death due to any cause | Baseline to 3 years | 
| Adaptive Therapy Event Free Survival | Participants who choose the adaptive therapy will have event free survival assessed at 3 years after initiating treatment. Event free survival is defined as time from treatment initiation to event which includes (1) progression that does not respond to additional VAC dosing and (2) death due to any cause | Baseline to 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | The time to event endpoint of overall survival is defined as the duration of time from diagnosis to death or last follow-up, where event would be death from any cause | 5 years | 
| Treatment-related adverse events of a certain grade or higher | Number of participants with treatment-related adverse events of a certain grade or higher and hematological/biochemical toxicities based on laboratory measurements as assessed by CTCAE v5.0 | Baseline to 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Soft Tissue Cancer, Skeletal Muscle Tissue Cancer, Sarcoma