Clinical Trials

The James Cancer Center Columbus, OH

open for enrollment

Radiation Therapy with or without Combination Chemotherapy or Pazopanib Hydrochloride before Surgery in Treating Patients with Newly Diagnosed Non-Rhabdomyosarcoma Soft Tissue Sarcomas That Can Be Removed by Surgery

Protocol: COG-NRGARST1321

Full Title

Pazopanib Neoadjuvant Trial in Non-Rhabdomyosarcoma Soft Tissue Sarcomas (PAZNTIS): A Phase II/III Randomized Trial of Preoperative Chemoradiation or Preoperative Radiation Plus or Minus Pazopanib (NSC# 737754, IND# 118613)

Purpose

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.

Study Objective

PRIMARY OBJECTIVES:

I. To identify the dose of pazopanib (pazopanib hydrochloride) that is feasible when given in combination with radiation or chemoradiation in pediatric and adult patients newly diagnosed with unresected intermediate- and high-risk non-rhabdomyosarcoma soft tissue sarcomas (NRSTS).

II. To compare the rates of near complete pathologic response (> 90% necrosis) with the addition of pazopanib to preoperative chemoradiation versus preoperative chemoradiation alone for potentially resectable > 5 cm, grade 3 intermediate to high risk chemotherapy-sensitive NRSTS in the phase II portion of the study for this cohort.

III. To compare the rates of near complete pathologic response (> 90% necrosis) with the addition of pazopanib to preoperative radiotherapy versus preoperative radiotherapy alone for potentially resectable intermediate to high risk adult and pediatric NRSTS in the phase II portion of the study for this cohort (using a phase II decision rule to go onto the phase III portion of the study).

IV. To compare the rates of event-free survival (EFS) with the addition of pazopanib to preoperative radiotherapy versus preoperative radiotherapy alone for localized intermediate to high risk adult and pediatric NRSTS in the phase III portion of the study for this cohort if the phase II decision rule is passed.

SECONDARY OBJECTIVES:

I. To estimate the rates of local failure, regional failure, distant metastasis free survival, disease-free survival, and overall survival with the addition of pazopanib to preoperative chemoradiation or preoperative radiation in intermediate to high risk adult and pediatric NRSTS.

II. To compare the pattern of recurrence (local, regional and distant) between preoperative chemoradiation or radiation with the addition of pazopanib for adult and pediatric NRSTS.

III. To define the toxicities of ifosfamide and doxorubicin (doxorubicin hydrochloride) chemotherapy and radiation when used in combination with pazopanib in intermediate to high risk adult and pediatric NRSTS.

IV. To define the toxicities of preoperative radiotherapy when used in combination with pazopanib in intermediate to high risk adult and pediatric NRSTS.

TERTIARY OBJECTIVES:

I. To gain insight into the disease biology of childhood and adult NRSTS through analysis of actionable mutations and whole genome sequencing.

II. To determine if microvessel density and circulating tumor deoxyribonucleic acid (DNA) predict response to pazopanib and outcome.

III. To determine the effect of pazopanib on doxorubicin exposure in children and adults with NRSTS.

IV. To evaluate change in fludeoxyglucose F 18 (FDG) positron emission tomography (PET) maximum standard uptake value (SUVmax) from baseline to week 10 or 13 in patients with unresected tumors and to correlate this change with pathologic response and EFS.

V. To compare the rate of response by standard imaging and pathologic assessment to determine which correlates better with local tumor control, distant tumor control, EFS, and overall survival.

OUTLINE: This is a dose-escalation study of pazopanib hydrochloride.

CHEMOTHERAPY COHORT: Patients eligible for chemotherapy cohort are randomized to 1 of 2 treatment regimens.

REGIMEN A:

INDUCTION PHASE: Patients receive pazopanib hydrochloride orally (PO) once daily (QD) on weeks 1-12, ifosfamide intravenously (IV) over 2-4 hours on days 1-3 on weeks 1, 4, 7, 10, and doxorubicin hydrochloride IV over 1-15 minutes on days 1-2 on weeks 1 and 4. At least 24 hours after the completion of week 4 doxorubicin hydrochloride, patients undergo radiation therapy on weeks 4-10.

SURGERY: Patients undergo surgery on week 13.

CONTINUATION PHASE: Patients receive pazopanib hydrochloride PO QD on weeks 16-25, ifosfamide IV over 2-4 hours on days 1-3 on weeks 16 and 19, and doxorubicin hydrochloride IV over 1-15 minutes on days 1-2 on weeks 16, 19, and 22. At least 24 hours after the completion of doxorubicin hydrochloride, if required, patients undergo radiation therapy on weeks 16-25 for a total of 45 Gy. Patients with impaired wound healing within 6 weeks of the date of surgery, have week 16 chemotherapy postponed until radiation therapy (if needed) begins. Patients with impaired wound healing within 8 weeks of the date of surgery, are removed from protocol therapy effective the date 8 weeks after week 13 surgery.

REGIMEN B:

INDUCTION PHASE: Patients receive ifosfamide IV over 2-4 hours on days 1-3 on weeks 1, 4, 7, 10 and doxorubicin hydrochloride IV over 1-15 minutes on days 1-2 on weeks 1 and 4. At least 24 hours after the completion of week 4 doxorubicin hydrochloride, patients undergo radiation therapy on weeks 4-10.

SURGERY: Patients undergo surgery on week 13.

CONTINUATION PHASE: Patients receive ifosfamide IV over 2-4 hours on days 1-3 on weeks 16 and 19 and doxorubicin hydrochloride IV over 1-15 minutes on days 1-2 on weeks 16, 19, and 22. At least 24 hours after the completion of doxorubicin hydrochloride, if required, patients undergo radiation therapy on weeks 16-25 for a total of 45 Gy. Patients with impaired wound healing within 6 weeks of the date of surgery, have week 16 chemotherapy postponed until radiation therapy (if needed) begins. Patients with impaired wound healing within 8 weeks of the date of surgery, are removed from protocol therapy effective the date 8 weeks after week 13 surgery.

NON-CHEMOTHERAPY COHORT: Patients eligible for non-chemotherapy cohort are randomized to 1 of 2 treatment regimens.

REGIMEN C:

INDUCTION PHASE: Patients receive pazopanib hydrochloride PO QD on weeks 1-9. Patients undergo radiation therapy on weeks 1-7.

SURGERY: Patients undergo surgery on week 10.

CONTINUATION PHASE: Patients receive pazopanib hydrochloride PO QD on weeks 13-25. Patients undergo radiation therapy on weeks 13-16 for a total of 50 Gy. Patients with impaired wound healing within 8 weeks of the date of surgery, are removed from protocol therapy effective the date 8 weeks after week 10 surgery.

REGIMEN D:

INDUCTION PHASE: Patients undergo radiation therapy on weeks 1-7.

SURGERY: Patients undergo surgery on week 10.

CONTINUATION PHASE: Patients undergo radiation therapy on weeks 13-16 for a total of 50 Gy. Patients with impaired wound healing within 8 weeks of the date of surgery, are removed from protocol therapy effective the date 8 weeks after week 10 surgery.

After completion of study treatment, patients are followed up at 6, 12, 18, 24, 30, 36, 48, and 60 months.

Are you eligible?

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 transaminase [AST]) or serum glutamate pyruvate transaminase [SGPT] (alanine transaminase [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 (eg, 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

Sarcoma