Combination Chemotherapy with or without Temsirolimus in Treating Patients with Intermediate Risk Rhabdomyosarcoma

This randomized phase III trial studies how well combination chemotherapy (vincristine sulfate, dactinomycin, cyclophosphamide alternated with vincristine sulfate and irinotecan hydrochloride) works compared to combination chemotherapy plus temsirolimus in treating patients with rhabdomyosarcoma (cancer that forms in the soft tissues, such as muscle), and has an intermediate chance of coming back after treatment (intermediate risk). Drugs used in chemotherapy 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. Combination chemotherapy and temsirolimus may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It is not yet known whether combination chemotherapy or combination chemotherapy plus temsirolimus is more effective in treating patients with intermediate-risk rhabdomyosarcoma.

Inclusion Criteria

• Feasibility Phase: Patients must be < 21 years of age at the time of enrollment
• 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 studies
• 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 (ie. 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
• FOXO1 Fusion Status: * All patients will undergo institutional pathology review and FOXO1 fusion determination; FOXO1 status results must be available by week 3 (day 21) of therapy; patients will be eligible to remain on protocol therapy based upon stage, group, and age: ** FOXO1 fusion negative: *** Stage 1, group III (non-orbit) *** Stage 3, group I/II *** Stage 2/3, group III *** Stage 4, group IV, < 10 years old ** FOXO1 fusion positive: *** Stage 1-3, group I-III Note: FOXO1 fusion status must be performed at local institutions
• Patients with institutional histologic classification of ARMS but FOXO1 fusion negative with the following stage and group can remain on study but will receive VAC/VA therapy on Regimen C instead of the previously assigned treatment regimen; patient consent is required to transfer to Regimen C * Stage 1, group I/II * Stage 1, group III (orbit) * Stage 2, group I/II

Exclusion Criteria

• Patients who have previously received TORI, another mTOR inhibitor, or any other investigational agent
• Patients who have received any chemotherapy (excluding steroids) and/or radiation therapy 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 if sexually active with reproductive potential
• 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

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) to that of patients treated with surgery, radiotherapy and VAC/VI plus temsirolimus (TORI).

SECONDARY OBJECTIVES:

I. To compare the overall survival (OS) of patients with IR RMS treated with surgery, radiotherapy, and VAC alternating with VI to that of patients treated with surgery, radiotherapy and VAC/VI plus TORI.

TERTIARY 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 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).

OUTLINE:

FEASIBILITY PHASE: (< 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 6 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 RT beginning at week 13 for 6 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.

REGIMEN B (VAC/VI TORI): 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 I. Treatment continues in the absence of disease progression or unacceptable toxicity.

REGIMEN C (FOXO1 FUSION NEGATIVE): Patients receive VAC/VA and RT.

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.

Lead Organization
Childrens Oncology Group

Principal Investigator
Abha Anshu Gupta