PRIMARY OBJECTIVE:
I. To compare the event-free survival (EFS) of patients with intermediate-risk (IR)
rhabdomyosarcoma (RMS) treated with surgery, radiotherapy, and vincristine (vincristine
sulfate), dactinomycin, and cyclophosphamide (VAC) alternating with vincristine and
irinotecan (irinotecan hydrochloride) (VI) (VAC/VI) with maintenance to that of patients
treated with surgery, radiotherapy and VAC/VI plus temsirolimus with maintenance.
SECONDARY OBJECTIVE:
I. To compare the overall survival (OS) of patients with IR RMS treated with surgery,
radiotherapy, and VAC alternating with VI with maintenance to that of patients treated with
surgery, radiotherapy and VAC/VI plus temsirolimus with maintenance.
EXPLORATORY OBJECTIVES:
I. To compare the outcome of patients based on their FOXO1 fusion gene partner, by evaluating
paired box (PAX) 3 versus (vs) PAX7 in all patients found to be FOXO1 fusion positive.
II. To compare the outcome of patients based on their [F18]-fluorodeoxy-D-glucose-positron
emission tomography (FDG-PET) response at week 9 (positive or negative), as assessed by
Deauville criteria (5-point).
III. To estimate the frequency of patients with circulating tumor deoxyribonucleic acid (DNA)
(ctDNA) at diagnosis and subsequent time-points, and explore whether tumor-specific somatic
variants are detectable in the ctDNA.
IV. To compare the outcome of patients (VAC/VI with or without temsirolimus) who have
received maintenance therapy on ARST1431 to those who received VAC/VI on ARST0531.
OUTLINE:
FEASIBILITY PHASE (THE FEASIBILITY PHASE IS COMPLETE, EFFECTIVE WITH AMENDMENT #1A): (< 21
years old): This is a dose-escalation study of temsirolimus.
Patients receive vincristine sulfate intravenously (IV) over 1 minute on day 1 of weeks 1-13,
16, 17, 19, 20, 22-26, 28, 31-34, 37, 38, and 40, dactinomycin IV over 1-5 or 10-15 minutes
on day 1 of weeks 1, 7, 13, 22, 28, 34, and 40, cyclophosphamide IV over 60 minutes on day 1
of weeks 1, 7, 13, 22, 28, 34, and 40, irinotecan hydrochloride IV over 90 minutes on days
1-5 of weeks 4, 10, 16, 19, 25, 31, and 37, and temsirolimus IV over 30-60 minutes on days 1,
8, and 15. Patients also undergo radiation therapy (RT) beginning week 13 for up to 6.5
weeks. Courses with temsirolimus repeat every 21 days for 12 weeks in the absence of disease
progression or unacceptable toxicity.
EFFICACY PHASE: Patients are randomized to Regimen A or B. Patients with disease that is ARMS
FOXO1 fusion negative (stage I, group I/II, stage 1, group III [orbit] or stage II, group
I/II) are assigned to Regimen C.
REGIMEN A (VAC/VI): Patients receive vincristine sulfate IV over 1 minute on day 1 of weeks
1-13, 16, 17, 19, 20, 22-26, 28, 31-34, 37, 38, and 40, dactinomycin IV over 1-5 or 10-15
minutes on day 1 of weeks 1, 7, 13, 22, 28, 34, and 40, cyclophosphamide IV over 60 minutes
on day 1 of weeks 1, 7, 13, 22, 28, 34, and 40, irinotecan hydrochloride IV over 90 minutes
on days 1-5 of weeks 4, 10, 16, 19, 25, 31, and 37. Patients also undergo primary site RT
beginning at week 13 or metastatic site RT beginning at week 43 for up to 6.5 weeks.
Treatment continues in the absence of disease progression or unacceptable toxicity. Patients
then receive vinorelbine IV over 6-10 minutes on days 1, 8, and 15 and cyclophosphamide
orally (PO) once daily (QD) on days 1-28. Cycles repeats every 28 days for 24 weeks in the
absence of disease progression or unacceptable toxicity.
REGIMEN B (VAC/VI TEMSIROLIMUS): Patients receive vincristine sulfate IV over 1 minute on day
1 of weeks 1-13, 16, 17, 19, 20, 22-26, 28, 31-34, 37, 38, and 40, dactinomycin IV over 1-5
or 10-15 minutes on day 1 of weeks 1, 7, 13, 22, 28, 34, and 40, cyclophosphamide IV over 60
minutes on day 1 of weeks 1, 7, 13, 22, 28, 34, and 40, irinotecan hydrochloride IV over 90
minutes on days 1-5 of weeks 4, 10, 16, 19, 25, 31, and 37 and temsirolimus IV over 30-60
minutes on day 1 of weeks 1-12 and 21-42. Patients also undergo RT as in Regimen A. Treatment
continues in the absence of disease progression or unacceptable toxicity. Patients then
receive vinorelbine IV over 6-10 minutes on days 1, 8, and 15 and cyclophosphamide PO QD on
days 1-28. Cycles repeats every 28 days for 24 weeks in the absence of disease progression or
unacceptable toxicity.
MAINTENANCE PHASE (Patients in Regimen A or Regimen B): Patients receive vinorelbine IV over
6-10 minutes on days 1, 8, and 15 and cyclophosphamide orally (PO) once daily (QD) on days
1-28. Treatment repeats every 28 days for up to 6 cycles.
REGIMEN C (FOXO1 FUSION NEGATIVE): Patients receive vincristine sulfate IV over 1 minute on
day 1 of weeks 1-10 and 13-22, dactinomycin IV over 1-5 or 10-15 minutes on day 1 of weeks 1,
4, 7, 10, 13, 16, 19, and 22, cyclophosphamide IV over 60 minutes on day 1 of weeks 1, 4, 7,
and 10. Patients undergo RT beginning at week 13 for up to 6.5 weeks. Treatment continues in
the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up every 3 months for 1 year,
every 4 months for 2 years, every 6 months for 1 year, and then annually for up to 10 years.