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

Conditions

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

Trial Phase

Phase 2

Trial Purpose and Description

Trial Purpose


This randomized pilot 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.

Trial Description


PRIMARY OBJECTIVES:

I. To determine the feasibility of administering IMC-A12 (cixutumumab) in combination with a
multi-agent intensive chemotherapy regimen for the treatment of high-risk rhabdomyosarcoma
(RMS).

II. To determine the feasibility of adding temozolomide to vincristine (vincristine
sulfate)/irinotecan (irinotecan hydrochloride) cycles in patients with high-risk RMS.

III. To assess immediate and short-term side effects of delivery of concurrent
temozolomide-vincristine-irinotecan with irradiation in patients with high-risk RMS.

SECONDARY OBJECTIVES:

I. To gain a preliminary estimate of the response rate to IMC-A12 or temozolomide plus
vincristine/irinotecan in previously untreated high-risk RMS.

II. To obtain preliminary efficacy data for IMC-A12 or temozolomide in combination with a
multi-agent interval compressed chemotherapy regimen in previously untreated high-risk RMS.

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 insulin-like growth factor (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 intravenously (IV) over 1 minute 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 over 1-15 minutes 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 over 1-5 minutes 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 radiation
therapy* 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
radiation therapy* as in group 1. Patients also receive temozolomide orally (PO) 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 radiation therapy* 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 radiation therapy starting in week 1;
cixutumumab should be withheld during radiation therapy.

After completion of study therapy, patients are followed up at 3 weeks and then periodically
for up to 5 years.

Participation Guidelines

Age:
N/A - 49 Years
Gender:
Both

Eligibility Criteria


Inclusion Criteria:

- Patients must be eligible for, and enrolled on D9902 prior to enrollment on ARST08P1

- Patients with newly diagnosed, biopsy-proven metastatic rhabdomyosarcoma or
ectomesenchymoma (stage IV, clinical group IV) are eligible for this study; patients
with stage IV, clinical group IV RMS with parameningeal and paraspinal primary
tumors, including those with intracranial extension (ICE) are eligible for ARST08P1;
ICE is defined 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; ICE is also
presumed to exist if the cerebrospinal fluid (CSF) cytopathology is positive for
tumor at diagnosis

- 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

- No prior chemotherapy or radiotherapy except for use of corticosteroids or emergent
radiation therapy; patients requiring emergency radiation are eligible

- Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70
mL/min/1.73m^2 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 x 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

- Absolute neutrophil count (ANC) >= 750/uL; abnormal blood counts are permissible if
there is bone marrow biopsy or aspirate proven bone marrow involvement by
rhabdomyosarcoma

- Platelet count >= 75,000/uL; abnormal blood counts are permissible if there is bone
marrow biopsy or aspirate proven bone marrow involvement by rhabdomyosarcoma

- Sexually active patients of childbearing potential must agree to use effective
contraception during therapy (Pilots 1 and 2) and for at least 3 months after the
last dose of IMC-A12 (Pilots 1)

Exclusion Criteria:

- Female patients who are pregnant are not eligible

- Female patients who are breastfeeding are not eligible; female patients who are
lactating must agree to stop breastfeeding to participate in this study

- Patients receiving growth hormone therapy are not eligible

- Patients with known type I or type II diabetes mellitus are not eligible for
enrollment on Pilot 1

- Patients with evidence of uncontrolled infection are not eligible

- 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
Sponsor:
National Cancer Institute (NCI)
Dates:
January 2010
Last Updated:
November 20, 2014
Study HIC#:

Clinicaltrials.gov ID: NCT01055314