Temozolomide, Cixutumumab, and Combination Chemotherapy in Treating Patients With Metastatic Rhabdomyosarcoma

• Feasibility [ Designated as safety issue: No ]
• Immediate and short-term side effects [ Designated as safety issue: Yes ]

• Response rate assessed by Response Evaluation Criteria for Solid Tumors (RECIST) [ Time Frame: Up to 10 years ] [ Designated as safety issue: No ]
  An O'Brien-Fleming monitoring boundary (truncated at 3 standard deviations) and a spending function approach will be employed for interim monitoring of efficacy. A futility analysis will also be performed, testing a 'null hypothesis' that the relative risk of failure with this therapy is 0.60 (compared to the ID/IE therapy experience), with consideration of suspension of accrual should this hypothesis be rejected at any of the scheduled interim looks at a significance level of 0.005.
• Event-free survival [ Time Frame: Up to 10 years ] [ Designated as safety issue: No ]

• Preliminary response rate [ Designated as safety issue: No ]
• Preliminary efficacy [ Designated as safety issue: No ]
• Effectiveness of FDG PET in detecting metastatic disease [ Designated as safety issue: No ]
• Levels of IGF-I, IGF-II, and IGF-BP3 [ Designated as safety issue: No ]

This clinical trial is studying the side effects and how well giving temozolomide and cixutumumab together with combination chemotherapy works in treating patients with metastatic rhabdomyosarcoma. Drugs used in chemotherapy, such as temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as cixutumumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Giving temozolomide and cixutumumab together with combination chemotherapy may kill more tumor cells.

PRIMARY OBJECTIVES:

I. To determine the feasibility of administering cixutumumab in combination with an intensive multi-agent interval compressed chemotherapy regimen for the treatment of high-risk metastatic rhabdomyosarcoma (RMS).

II. To determine the feasibility of adding temozolomide to vincristine and irinotecan in these patients.

III. To assess immediate and short-term side effects of concurrent temozolomide, vincristine, and irinotecan with radiotherapy in these patients.

SECONDARY OBJECTIVES:

I. To gain a preliminary estimate of the response rate to cixutumumab or temozolomide, vincristine, and irinotecan in these patients.

II. To obtain preliminary efficacy data for cixutumumab or temozolomide in combination with an intensive multi-agent interval compressed chemotherapy regimen in these patients.

III. To determine the effectiveness of detecting metastatic disease with fludeoxyglucose F 18 positron emission tomography (FDG PET) and to compare assessment of response using standard imaging techniques with response assessed by FDG PET.

IV. To assess changes in serum levels of IGF-I, IGF-II, IGF-BP3 as biomarkers of IGF-IR inhibition.

OUTLINE: This is a dose-escalation study of cixutumumab. Patients are assigned to 1 of 2 treatment groups according to the timing of their enrollment onto the study.

GROUP 1: Patients receive vincristine sulfate IV on day 1 of weeks 1-5, 7, 8, 11, 12, 15, 16, 20-24, 28, 29, 32, 33, 35, 38, 41-44, 47, 48, 50, and 51; irinotecan hydrochloride IV over 90 minutes on days 1-5 of weeks 1, 4, 20, 23, 47, and 50; ifosfamide IV over 1 hour and etoposide IV over 1-2 hours on days 1-5 of weeks 9, 13, 17, 26, and 30; doxorubicin hydrochloride IV on days 1 and 2 of weeks 7, 11, 15, 28, and 32; cyclophosphamide IV over 30-60 minutes on day 1 of weeks 7, 11, 15, 28, 32, 35, 38, 41, and 44; dactinomycin IV on day 1 of weeks 35, 38, 41, and 44; and cixutumumab IV over 1 hour on day 1 of weeks 1-51. Patients also undergo radiotherapy* on days 1-5 of weeks 20-24.

GROUP 2: Patients receive vincristine sulfate, irinotecan hydrochloride, ifosfamide, etoposide, doxorubicin hydrochloride, cyclophosphamide, and dactinomycin and undergo radiotherapy* as in group 1. Patients also receive oral temozolomide on days 1-5 of weeks 1, 4, 20, 23, 47, and 50.

GROUP 3: Patients receive vincristine sulfate, irinotecan hydrochloride, ifosfamide, etoposide, doxorubicin hydrochloride, cyclophosphamide, dactinomycin, and cixutumumab and undergo radiotherapy* as in group 1. Patients also receive temozolomide as in group 2. (Discontinued as of January 2013)

NOTE: *Patients with parameningeal tumors and evidence of intracranial extension or those requiring emergency radiotherapy may receive radiotherapy starting in week 1; cixutumumab should be withheld during radiotherapy.

After completion of study therapy, patients are followed up periodically for up to 10 years.

• Adult Rhabdomyosarcoma
• Alveolar Childhood Rhabdomyosarcoma
• Embryonal Childhood Rhabdomyosarcoma
• Metastatic Childhood Soft Tissue Sarcoma
• Previously Untreated Childhood Rhabdomyosarcoma
• Stage IV Adult Soft Tissue Sarcoma

• Biological: cixutumumab
  Given IV
  Other Names:

  • anti-IGF-1R recombinant monoclonal antibody IMC-A12
  • IMC-A12
• Drug: doxorubicin hydrochloride
  Given IV
  Other Names:

  • ADM
  • ADR
  • Adria
  • Adriamycin PFS
  • Adriamycin RDF
• Drug: irinotecan hydrochloride
  Given IV
  Other Names:

  • Campto
  • Camptosar
  • CPT-11
  • irinotecan
  • U-101440E
• Drug: liposomal vincristine sulfate
  Given IV
  Other Names:

  • liposomal vincristine
  • Marqibo
  • vincristine liposomal
  • vincristine sulfate liposome injection
• Drug: ifosfamide
  Given IV
  Other Names:

  • Cyfos
  • Holoxan
  • IFF
  • IFX
  • IPP
• Drug: etoposide
  Given IV
  Other Names:

  • EPEG
  • VP-16
  • VP-16-213
• Drug: cyclophosphamide
  Given IV
  Other Names:

  • CPM
  • CTX
  • Cytoxan
  • Endoxan
  • Endoxana
• Biological: dactinomycin
  Given IV
  Other Names:

  • ACT-D
  • actinomycin C1
  • AD
  • Cosmegen
  • DACT
• Drug: temozolomide
  Given orally
  Other Names:

  • SCH 52365
  • Temodal
  • Temodar
  • TMZ

• Experimental: Group 1 (chemotherapy, radiation therapy, cixutumumab)
  Patients receive vincristine sulfate IV on day 1 of weeks 1-5, 7, 8, 11, 12, 15, 16, 20-24, 28, 29, 32, 33, 35, 38, 41-44, 47, 48, 50, and 51; irinotecan hydrochloride IV over 90 minutes on days 1-5 of weeks 1, 4, 20, 23, 47, and 50; ifosfamide IV over 1 hour and etoposide IV over 1-2 hours on days 1-5 of weeks 9, 13, 17, 26, and 30; doxorubicin hydrochloride IV on days 1 and 2 of weeks 7, 11, 15, 28, and 32; cyclophosphamide IV over 30-60 minutes on day 1 of weeks 7, 11, 15, 28, 32, 35, 38, 41, and 44; dactinomycin IV on day 1 of weeks 35, 38, 41, and 44; and cixutumumab IV over 1 hour on day 1 of weeks 1-51. Patients also undergo radiotherapy on days 1-5 of weeks 20-24.
  Interventions:

  • Biological: cixutumumab
  • Drug: doxorubicin hydrochloride
  • Drug: irinotecan hydrochloride
  • Drug: liposomal vincristine sulfate
  • Drug: ifosfamide
  • Drug: etoposide
  • Drug: cyclophosphamide
  • Biological: dactinomycin
• Experimental: Group 2 (chemotherapy, radiation therapy, temozolomide)
  Patients receive vincristine sulfate, irinotecan hydrochloride, ifosfamide, etoposide, doxorubicin hydrochloride, cyclophosphamide, and dactinomycin and undergo radiotherapy as in group 1. Patients also receive oral temozolomide on days 1-5 of weeks 1, 4, 20, 23, 47, and 50.
  Interventions:

  • Drug: doxorubicin hydrochloride
  • Drug: irinotecan hydrochloride
  • Drug: liposomal vincristine sulfate
  • Drug: ifosfamide
  • Drug: etoposide
  • Drug: cyclophosphamide
  • Biological: dactinomycin
  • Drug: temozolomide

Inclusion Criteria:

• Newly diagnosed, biopsy-confirmed metastatic rhabdomyosarcoma (RMS) or ectomesenchymoma

  • Stage IV, Clinical Group IV
• RMS with parameningeal and paraspinal primary tumors, including those with intracranial extension by contrast magnetic resonance imaging (MRI) showing that the primary tumor touches, displaces, invades, distorts, or otherwise causes signal abnormality of the dura in brain or spinal cord in contiguity to the primary site, are allowed; ICE is also presumed to exist if the cerebrospinal fluid (CSF) cytopathology is positive for tumor at diagnosis
• Has undergone initial surgery (including biopsy) that provided the definitive diagnosis within the past 42 days
• Enrollment on COG-D9902 required
• Patients must have a performance status corresponding to Eastern Cooperative Oncology Group (ECOG) scores of 0, 1, or 2; use Karnofsky for patients > 16 years of age and Lansky for patients =< 16 years of age

• Absolute neutrophil count (ANC) >= 750/μL

  • Abnormal blood counts are permissible if there is bone marrow biopsy or aspirate proven bone marrow involvement by RMS

• Platelet count >= 75,000/μL

  • Abnormal blood counts are permissible if there is bone marrow biopsy or aspirate proven bone marrow involvement by RMS

• Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 mL/min OR maximum serum creatinine based on age/gender as follows:

  • 0.4 mg/dL (for patients 1 to 5 months of age)
  • 0.5 mg/dL (for patients 6 to 11 months of age)
  • 0.6 mg/dL (for patients 1 year of age)
  • 0.8 mg/dL (for patients 2 to 5 years of age)
  • 1.0 mg/dL (for patients 6 to 9 years of age)
  • 1.2 mg/dL (for patients 10 to 12 years of age)
  • 1.5 mg/dL (males) or 1.4 mg/dL (females) (for patients 13 to 15 years of age)
  • 1.7 mg/dL (males) or 1.4 mg/dL (females) (for patients >= 16 years of age)
• Patients with urinary tract obstruction by tumor must meet the renal function criteria listed above AND must have unimpeded urinary flow established via decompression of the obstructed portion of the urinary tract
• Total bilirubin =< 1.5 times upper limit of normal (ULN) for age (unless there is evidence of biliary obstruction by the tumor)
• Shortening fraction >=≥ 27% by echocardiogram (ECHO) OR ejection fraction >= 50% by radionuclide angiogram
• Not pregnant or nursing
• Negative pregnancy test
• Sexually active patients of childbearing potential must agree to use effective contraception during therapy (groups1 and 2) and for at least 3 months after the last dose of cixutumumab (group 1)
• No uncontrolled infection
• No known type I or type II diabetes mellitus (for patients enrolled in group 1)

• No prior chemotherapy or radiotherapy except corticosteroids or emergent radiotherapy

  • Patients requiring emergency radiation are eligible
• No concurrent growth hormone therapy
• All patients and/or their parents or legal guardians must sign a written informed consent