Clinical Trial Summary

This randomized phase II/III trial studies how well pazopanib hydrochloride, combination
chemotherapy, and radiation therapy work and compares it to radiation therapy alone or in
combination with pazopanib hydrochloride or combination chemotherapy in treating patients
with newly diagnosed non-rhabdomyosarcoma soft tissue sarcomas that can be removed by
surgery. Radiation therapy uses high energy x-rays to kill tumor cells. Drugs used in
chemotherapy, such as ifosfamide and doxorubicin hydrochloride, 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. Pazopanib hydrochloride may stop the growth of tumor
cells by blocking some of the enzymes needed for cell growth. It is not yet known whether
radiation therapy works better when given with or without combination chemotherapy and/or
pazopanib hydrochloride in treating patients with non-rhabdomyosarcoma soft tissue sarcomas.

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Phase

Phase 2/Phase 3

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Funding Agency/Sponsor

National Cancer Institute (NCI)

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Disease

Pediatric Cancer

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Enrollment Eligibility

Inclusion Criteria:
- Newly diagnosed and histopathologically confirmed, potentially resectable NRSTS of the
extremity and trunk will be eligible for the chemotherapy or non-chemotherapy cohort
based on:
- Evidence of chemotherapy sensitivity of the histologic sarcoma subtype based on
existing evidence from prior clinical trials
- Sufficient risk of metastatic disease to warrant chemotherapy based on size and
grade and
- Medically deemed able or unable to undergo chemotherapy
- Notes: an incisional biopsy or core biopsy is preferred; fine needle aspiration
biopsy is not acceptable to establish the diagnosis
- ELIGIBLE SITES:
- Extremities: upper (including shoulder) and lower (including hip)
- Trunk: body wall
- INELIGIBLE SITES: Head and neck, visceral organs (with the exception of embryonal
sarcoma of the liver), retroperitoneum, peritoneum, pelvis within the confines of the
bony pelvis
- ELIGIBILITY FOR CHEMOTHERAPY COHORT:
- Stage T2a/b (> 5 cm) and grade 2 or 3 AND
- One of the following chemosensitive histologies as defined in the World Health
Organization (WHO) classification of soft tissue tumors (with some evidence of good
response to chemoradiation and of sufficient high risk of metastases, or clear
evidence of metastases):
- Unclassified soft tissue sarcomas that are too undifferentiated to be placed in a
specific pathologic category in the WHO classification (often called
"undifferentiated soft tissue sarcoma" or "soft tissue sarcoma not otherwise
specified [NOS]")
- Synovial sarcoma
- Angiosarcoma of soft tissue
- Adult fibrosarcoma
- Mesenchymal (extraskeletal) chondrosarcoma
- Leiomyosarcoma
- Liposarcoma (excluding myxoid liposarcoma)
- Undifferentiated pleomorphic sarcoma
- Embryonal sarcoma of the liver
- Patients meeting the above criteria (histology, size, and grade) with the EXCEPTION of
histologies noted above may enroll on the chemotherapy cohort or the non-chemotherapy
cohort at the discretion of the enrolling investigator; patients meeting these
criteria with the EXCEPTION of histologies noted above but medically deemed unable to
receive chemotherapy or who elect not to receive chemotherapy are eligible for the
non-chemotherapy cohort
- Patients with the following histologies are only eligible for the chemotherapy cohort
and cannot enroll on the non-chemotherapy cohort:
- Unclassified soft tissue sarcomas that are too undifferentiated to be placed in a
specific pathologic category in the WHO classification (often called
"undifferentiated soft tissue sarcoma" or "soft tissue sarcoma NOS") in patients
< 30 years of age
- Synovial sarcoma
- Embryonal sarcoma of the liver
- ELIGIBILITY FOR NON-CHEMOTHERAPY COHORT:
- Patients with any size of grade 2 or 3 of the following "intermediate (rarely
metastasizing)" or "malignant" tumors, as defined in the WHO classification of soft
tissue tumors for which we have consensus data of chemotherapy-resistance are eligible
only for the non-chemotherapy cohort:
- So-called fibrohistiocytic tumors - plexiform fibrohistiocytic tumor, giant cell
tumor of soft tissues
- Fibroblastic/myofibroblastic tumors - solitary fibrous tumor, malignant solitary
fibrous tumor, inflammatory myofibroblastic tumor, low grade myofibroblastic
sarcoma, myxoinflammatory fibroblastic sarcoma, atypical myxoinflammatory
fibroblastic tumor, myxofibrosarcoma, low grade fibromyxoid sarcoma, sclerosing
epithelioid fibrosarcoma
- Tumors of uncertain differentiation - epithelioid sarcoma, alveolar soft part
sarcoma, clear cell sarcoma of soft tissue, angiomatoid fibrous histiocytoma,
ossifying fibromyxoid tumor, myoepithelioma, myoepithelial carcinoma,
extraskeletal myxoid chondrosarcoma, neoplasms with perivascular epithelioid cell
differentiation (PEComa), intimal sarcoma, atypical fibroxanthoma, mixed tumor
NOS, phosphaturic mesenchymal tumor, malignant ossifying fibromyxoid tumor,
malignant mixed tumor, malignant phosphaturic mesenchymal tumor
- Chondro-osseous tumors - extraskeletal osteosarcoma
- Pericytic (perivascular) tumors - malignant glomus tumor
- Nerve sheath tumors - malignant peripheral nerve sheath tumor, malignant granular
cell tumor, epithelioid malignant peripheral nerve sheath tumor, malignant Triton
tumor
- Undifferentiated sarcomas (with a specific pathologic category in the WHO
classification) - undifferentiated round cell sarcoma, undifferentiated
epithelioid sarcoma, undifferentiated spindle cell sarcoma
- Patients meeting the criteria (histology, size, and grade) with the EXCEPTION of
histologies noted above may enroll on the non-chemotherapy cohort at the discretion of
the enrolling investigator; patients meeting these criteria with the EXCEPTION of
histologies noted above but medically deemed unable to receive chemotherapy or who
elect not to receive chemotherapy are eligible for the non-chemotherapy cohort; note
that tumors arising in bone are NOT eligible for this study
- Extent of disease:
- Patients with non-metastatic and metastatic disease are eligible
- Initially unresectable patients, with or without metastatic disease, are eligible
as long as there is a commitment at enrollment to resect the primary tumor
- Sufficient tissue and blood must be available to submit for required biology studies
- Lansky performance status score >= 70 for patients =< 16 years of age
- Karnofsky performance status score >= 70 for patients > 16 years of age
- Absolute neutrophil count >= 1500/uL; Note: no transfusions are permitted 7 days prior
to laboratory studies to determine eligibility
- Platelet count >= 100,000/uL; Note: no transfusions are permitted 7 days prior to
laboratory studies to determine eligibility
- Hemoglobin >= 8 g/dL for patients =< 16 years of age; >= 9 g/dL for patients > 16
years of age; Note: no transfusions are permitted 7 days prior to laboratory studies
to determine eligibility
- Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70
mL/min/1.73 m^2 or normal serum creatinine based on age/gender as follows:
- 2 to < 6 years; 0.8 mg/dL male; 0.8 mg/dL female
- 6 to < 10 years; 1 mg/dL male; 1 mg/dL female
- 10 to < 13 years; 1.2 mg/dL male; 1.2 mg/dL female
- 13 to < 16 years; 1.5 mg/dL male; 1.4 mg/dL female
- >= 16 years; 1.5 mg/dL male; 1.4 mg/dL female
- Total bilirubin =< 1.5 x upper limit of normal (ULN) for age
- Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) or
serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) < 2.5 x
upper limit of normal (ULN) for age
- Shortening fraction of >= 27% by echocardiogram OR ejection fraction of >= 50% by
radionuclide angiogram
- Corrected QT interval (QTc) < 480 msec
- No evidence of dyspnea at rest, no exercise intolerance, and a resting pulse oximetry
reading > 94% on room air if there is clinical indication for determination
- Patients on low molecular weight heparin or Coumadin (with a stable international
normalized ratio [INR]) are eligible
- Patient must have a life expectancy of at least 3 months with appropriate therapy
- 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 with grade 1 NRSTS tumors of any size are not eligible
- Patients with known central nervous system (CNS) metastases are not eligible; Note:
brain imaging is not an eligibility requirement
- Patients with evidence of active bleeding or bleeding diathesis will be excluded
(Note: patients aged > 17 years with excess of 2.5 mL of hemoptysis are not eligible)
- Patients with gross total resection of the primary tumor prior to enrollment on
ARST1321 are NOT eligible; patients who have experienced tumor recurrence after a
gross total tumor resection are NOT eligible
- Patients with uncontrolled hypertension are ineligible; uncontrolled hypertension is
defined as follows:
- Patients aged =< 17 years: greater than 95th percentile systolic and diastolic
blood pressure based on age and height which is not controlled by one
anti-hypertensive medication
- Patients aged > 17 years: systolic blood pressure >= 140 mmHg and/or diastolic
blood pressure >= 90 mmHg that is not controlled by one anti-hypertensive
medication
- Prior Therapy:
- Patients must have had no prior anthracycline (e.g., doxorubicin, daunorubicin)
or ifosfamide chemotherapy
- Patients must have had no prior use of pazopanib or similar multi-targeted
tyrosine kinase inhibitors (TKI)
- Patients must have had no prior radiotherapy to tumor-involved sites
- Note: patients previously treated for a non-NRSTS cancer are eligible provided
they meet the prior therapy requirements; patients who have had chemotherapy or
radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to
entering the study or those who have not recovered from adverse events due to
agents administered more than 4 weeks earlier are excluded
- Other types of invasive malignancy that are not disease free within 3 years except for
non-melanoma skin cancer, lentigo maligna, any carcinoma-in-situ or prostate cancer
with low risk factors
- CYTOCHROME P450 3A4 (CYP3A4) substrates WITH narrow therapeutic indices: patients
chronically receiving medications known to be metabolized by CYP3A4 and with narrow
therapeutic indices within 7 days prior to study enrollment, including but not limited
to pimozide, aripiprazole, triazolam, ergotamine and halofantrine are not eligible;
Note: the use of fentanyl is permitted
- CYP3A4 Inhibitors: patients chronically receiving drugs that are known potent CYP3A4
inhibitors within 7 days prior to study enrollment, including but not limited to
itraconazole, clarithromycin, erythromycin many non-nucleoside reverse-transcriptase
inhibitors (NNRTIs), diltiazem, verapamil, and grapefruit juice are not eligible
- CYP3A4 Inducers: patients chronically receiving drugs that are known potent CYP3A4
inducers within 14 days prior to study enrollment, including but not limited to
carbamazepine, phenobarbital, phenytoin, rifampin, and St. John's wort are not
eligible (with the exception of glucocorticoids)
- Certain medications that are associated with a risk for QTc prolongation and/or
Torsades de Pointes, although not prohibited, should be avoided or replaced with
medications that do not carry these risks, if possible
- Subjects with any condition that may impair the ability to swallow or absorb oral
medications/investigational product including:
- Any lesion, whether induced by tumor, radiation or other conditions, which makes
it difficult to swallow capsules or pills
- Prior surgical procedures affecting absorption including, but not limited to
major resection of stomach or small bowel
- Active peptic ulcer disease
- Malabsorption syndrome
- Subjects with any condition that may increase the risk of gastrointestinal bleeding or
gastrointestinal perforation, including:
- Active peptic ulcer disease
- Known intraluminal metastatic lesions
- Inflammatory bowel disease (e.g., ulcerative colitis, Crohn's disease) or other
gastrointestinal conditions which increase the risk of perforation
- History of abdominal fistula, gastrointestinal perforation or intra-abdominal
abscess within 28 days prior to beginning study treatment
- Subjects with any of the following cardiovascular conditions within the past 6 months
- Cerebrovascular accident (CVA) or transient ischemic attack (TIA)
- Cardiac arrhythmia
- Admission for unstable angina
- Cardiac angioplasty or stenting
- Coronary artery bypass graft surgery
- Pulmonary embolism, untreated deep venous thrombosis (DVT) or DVT which has been
treated with therapeutic anticoagulation for less than 6 weeks
- Arterial thrombosis
- Symptomatic peripheral vascular disease
- Class III or IV heart failure as defined by the New York Heart Association (NYHA)
functional classification system; a subject who has a history of class II heart
failure and is asymptomatic on treatment may be considered eligible
- History of serious or non-healing wound, ulcer, or bone fracture
- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements
- Patients who are unable to swallow whole tablets are not eligible
- Patients with a body surface area < 0.5 m^2 are not eligible
- Human immunodeficiency virus (HIV)-positive subjects on combination antiretroviral
therapy are ineligible
- Patients who are receiving any other investigational agent(s)
- Pregnancy and breast feeding:
- Female patients who are pregnant are ineligible
- Lactating females are not eligible unless they have agreed not to breastfeed
their infants during treatment and for a period of 1 month following completion
of treatment
- Female patients of childbearing potential are not eligible unless a negative
pregnancy test result has been obtained
- Unwillingness to use an effective contraceptive method for the duration of their study
participation and for at least 1 month after treatment is completed if sexually active
with reproductive potential

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