Combination Chemotherapy With or Without Temsirolimus in Treating Patients With Intermediate Risk Rhabdomyosarcoma

PRIMARY OBJECTIVES:

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 OBJECTIVES:

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 forkhead box O1 protein (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.

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 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 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
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 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.

Inclusion Criteria:

- Feasibility Phase: Patients must be < 21 years of age at the time of enrollment;
please note: the feasibility phase is complete, effective with amendment #1

- Efficacy Phase: Patients must be =< 40 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

- RMS types included under embryonal rhabdomyosarcoma (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 2013 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
rhabdomyosarcoma (ARMS) in the 2013 WHO classification is the same as in the ICR and
includes classic and solid variants

- ERMS

- Stage 1, group III (non-orbit)

- Stage 3, group I/II

- Stage 2/3, group III

- Stage 4, group IV, < 10 years old

- ARMS:

- Stages 1-3, groups I-III

- Specimen Submission: Patients must have sufficient tissue available for the required
biology study

- Lansky performance status score >= 50 for patients =< 16 years of age; Karnofsky
performance status score >= 50 for patients > 16 years of age

- Peripheral absolute neutrophil count (ANC) >= 750/uL

- Platelet count >= 75,000/uL

- 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:

- 1 month to < 6 months old: 0.4 mg/dl (male), 0.4 mg/dl (female)

- 6 months to < 1 year old: 0.5 mg/dl (male), 0.5 mg/dl (female)

- 1 to < 2 years old: 0.6 mg/dl (male), 0.6 mg/dl (female)

- 2 to < 6 years old: 0.8 mg/dl (male), 0.8 mg/dl (female)

- 6 to < 10 years old: 1 mg/dl (male), 1 mg/dl (female)

- 10 to < 13 years old: 1.2 mg/dl (male), 1.2 mg/dl (female)

- 13 to < 16 years old: 1.5 mg/dl (male), 1.4 mg/dl (female)

- >= 16 years old: 1.7 mg/dl (male), 1.4 mg/dl (female)

- Patients with an elevated serum creatinine due to obstructive hydronephrosis
secondary to tumor are still eligible; however, patients with urinary tract
obstruction by tumor must have unimpeded urinary flow established via diversion
(i.e. percutaneous nephrostomies or ureteric stents) of the urinary tract

- Total bilirubin =< 1.5 x upper limit of normal (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 who have previously received temsirolimus, another mTOR inhibitor, or any
other investigational agent

- Patients who have received any chemotherapy (excluding steroids) and/or RT prior to
this enrollment

- Patients with uncontrolled hyperglycemia

- Patients with uncontrolled hyperlipidemia

- Sexually active patients of reproductive potential who have not agreed to use an
effective contraceptive method for the duration of their study participation and for
at least 3 months after treatment is completed

- Female patients who are pregnant are not eligible; Note: a pregnancy test is required
for female patients of childbearing potential prior to study entry

- Lactating females who plan to breastfeed their infants are not eligible