Pazopanib Hydrochloride Followed by Chemotherapy and Surgery in Treating Patients With Soft Tissue Sarcoma

Study Overview
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Brief Summary
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This randomized pilot clinical trial studies pazopanib hydrochloride followed by chemotherapy and surgery in treating patients with soft tissue sarcoma. Pazopanib hydrochloride may stop the growth of tumor cells by blocking some of the enzymes that are needed for cell growth and may also stop the growth of soft tissue sarcoma by blocking blood flow to the tumor. Giving pazopanib hydrochloride and chemotherapy before surgery may make the tumor smaller and reduce the amount of tissue that needs to be removed.

Detailed Description
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PRIMARY OBJECTIVES: I. To determine the absolute values and changes in standardized uptake values (SUV) by fludeoxyglucose F18 (FDG)-positron emission tomography (PET) before and after a 14 day Run-in period of pazopanib (pazopanib hydrochloride) versus placebo, and to compare this to the change in SUV following pre-operative chemotherapy. II. To evaluate the correlation between antiangiogenic activity and pazopanib drug exposure. III. To assess the response rate by Response Evaluation Criteria In Solid Tumors (RECIST) criteria after the 14 day Run-in period of pazopanib versus placebo and compare this to the response rate following pre-operative chemotherapy. SECONDARY OBJECTIVES: I. To examine the activity of antiangiogenic therapy with pazopanib combined with pre-operative chemotherapy for high risk extremity soft tissue sarcomas as measured by: histological necrosis at surgery; change in plasma and tumor biomarker assays of angiogenesis II. To evaluate the safety of sequential treatment with pazopanib and pre-operative chemotherapy with doxorubicin (doxorubicin hydrochloride) and ifosfamide. OUTLINE: Patients are randomized to 1 of 2 treatment arms. ARM I: Patients receive pazopanib hydrochloride orally (PO) once daily (QD). Treatment continues for 14 days in the absence of disease progression or unacceptable toxicity. ARM II: Patients receive placebo PO QD. Treatment continues for 14 days in the absence of disease progression or unacceptable toxicity. All patients then receive neoadjuvant chemotherapy comprising doxorubicin hydrochloride intravenously (IV) continuously over days 1-3 and ifosfamide IV on days 1-5. Treatment repeats every 21 days for 4 courses. Beginning 2-4 weeks later, all patients undergo surgery followed by 2 more courses of chemotherapy 2-4 weeks after completion of surgery. Some patients may also undergo adjuvant external beam radiation therapy 5 days a week for 5 days followed by a boost. Patients treated on Arm I may resume pazopanib hydrochloride 1 week after completion of all adjuvant therapy for up to 1 year. Treatment continues in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 30 days.

Official Title
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The Effect of Antiangiogenic Therapy With Pazopanib Prior to Preoperative Chemotherapy for Subjects With Extremity Soft Tissue Sarcomas: A Randomized Study to Evaluate Response by Imaging

Conditions
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Stage IIA Adult Soft Tissue Sarcoma, Stage III Adult Soft Tissue Sarcoma, Stage IV Adult Soft Tissue Sarcoma

Intervention / Treatment
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* Drug: Doxorubicin Hydrochloride
* Radiation: External Beam Radiation Therapy
* Drug: Ifosfamide
* Other: Laboratory Biomarker Analysis
* Drug: Pazopanib Hydrochloride
* Other: Pharmacological Study
* Other: Placebo
* Procedure: Therapeutic Conventional Surgery


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically confirmed soft-tissue sarcoma, excluding alveolar and embryonal rhabdomyosarcoma, well- and dedifferentiated adipocytic sarcomas, Ewing's, osteosarcoma, or gastrointestinal stromal tumor; American Joint Committee on Cancer (AJCC) (6th Edition) Stage III or T2a Stage II or Stage IV treatment naive patients planned for resection of the primary tumor, with resectable metastatic disease Measurable disease greater than 5 centimeters in greatest dimension; measurable lesions are defined as those that can be accurately measured in at least one dimension (longest diameter for non-nodal lesions and short axis for nodal lesions to be recorded) by chest x-ray, computed tomography (CT) scan, magnetic resonance imaging (MRI) or with calipers by clinical exam; all tumor measurements must be recorded in millimeters (or decimal fractions of centimeters) Intermediate or high grade lesions: 2 or 3 on a scale of 1-3 or grades 2 to 4 on a scale of 1-4 Sarcoma located on upper (includes shoulder) or lower (includes hip) extremities or on the body wall Life expectancy of greater than 6 months Eastern Cooperative Oncology Group (ECOG) performance status =< 1 Karnofsky >= 80% No prior chemotherapy, radiotherapy, or antiangiogenic therapy Absolute neutrophil count (ANC) >= 1500/uL Hemoglobin (Hgb) >= 9.0 g/dL Platelets >= 100,000/uL Creatinine =< 1.5 x upper limit of normal (ULN) Bilirubin =< 1.5 mg/dL Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 1.5 x ULN Prothrombin time (PT)/international normalized ratio (INR)/partial thromboplastin time (PTT) within 1.2 X the ULN unless a subject is receiving Coumadin and has stable INR which is in range for the desired level of anticoagulation Left ventricular ejection fraction (LVEF) >= 50% Blood pressure (BP) no greater than 140 mmHg (systolic) and 90 mmHg (diastolic) for eligibility; initiation or adjustment of BP medication is permitted prior to study entry provided that the average of three BP readings on baseline assessment prior to enrollment is less than 140/90 mmHg Eligibility of subjects receiving any medications or substances known to affect or with the potential to affect the activity or pharmacokinetics of pazopanib will be determined following review of their cases by the Principal Investigator Women of child-bearing potential and men must agree to use adequate contraception A female is eligible to enter and participate in this study if she is of non-childbearing potential (i.e., physiologically incapable of becoming pregnant) or if she is of childbearing potential Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: Subjects with known brain metastases and/or unresectable sarcoma Uncontrolled intercurrent illness including, active serious infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac ventricular arrhythmia requiring anti-arrhythmic therapy, serious hepatic impairment, or psychiatric illness/social situations that would limit compliance with study Pregnant or lactating women Subjects with no additional active malignancy within the last 3 years Subjects receiving other investigational agents Subjects with a history of allergic reactions attributed to compounds of similar chemical or biologic composition to pazopanib or other agents used in the study Subjects who have both bilirubin > ULN and AST/ALT > ULN Subjects with a urine protein/creatinine ratio greater than 1 Subjects with a baseline corrected QT (QTc) of equal to or greater than 480 msecs or other significant electrocardiogram (ECG) abnormalities Certain medications that act through the cytochrome P450 (CYP450) system are specifically prohibited in subjects receiving pazopanib and others should be avoided or administered with extreme caution and require principal investigator (PI) approval Strong inhibitors of CYP3A4 such as ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole may increase pazopanib concentrations and are prohibited; grapefruit juice is also an inhibitor of CYP450 and should not be taken with pazopanib Strong inducers of CYP3A4, such as rifampin, may decrease pazopanib concentrations, are prohibited Medications which have narrow therapeutic windows and are substrates of CYP3A4, CYP2D6, or CYP2C8 should be avoided and, if necessary, administered with caution Pazopanib, 800 mg once daily, has no effect on CYP2C9, CYP1A2, or CYP2C19 in vivo but does in vitro; therefore, therapeutic doses of warfarin, a substrate of CYP2C9, and omeprazole, a substrate of CYP2C19 are permitted; caffeine, a substrate of CYP1A2, is also permitted 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 who require heparin other than low-molecular weight heparin 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, not on a proton pump inhibitor Malabsorption syndrome Subjects with any condition that may increase the risk of gastrointestinal bleeding or gastrointestinal perforation, including Active peptic ulcer disease, not on a proton pump inhibitor 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 hemoptysis in excess of 2.5 mL (1/2 teaspoon ) within 8 weeks prior to first dose of study drug History of serious or non-healing wound, ulcer, or bone fracture Human immunodeficiency virus (HIV)-positive subjects on combination antiretroviral therapy are ineligible Subjects with severe hepatic impairment Bilirubin > 3 x ULN, regardless of any level of ALT

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I (pazopanib hydrochloride)<br>Patients receive pazopanib hydrochloride PO QD. Treatment continues for 14 days in the absence of disease progression or unacceptable toxicity. | Drug: Doxorubicin Hydrochloride<br>* Given IV<br>* Other names: Rubex;Radiation: External Beam Radiation Therapy<br>* Undergo external beam radiation therapy<br>* Other names: external-beam radiation;Drug: Ifosfamide<br>* Given IV<br>* Other names: Z-4942;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Pazopanib Hydrochloride<br>* Given PO<br>* Other names: Votrient;Other: Pharmacological Study<br>* Correlative studies<br>Procedure: Therapeutic Conventional Surgery<br>* Undergo surgery<br>|
| Placebo Comparator: Arm II (placebo)<br>Patients receive placebo PO QD. Treatment continues for 14 days in the absence of disease progression or unacceptable toxicity. | Drug: Doxorubicin Hydrochloride<br>* Given IV<br>* Other names: Rubex;Radiation: External Beam Radiation Therapy<br>* Undergo external beam radiation therapy<br>* Other names: external-beam radiation;Drug: Ifosfamide<br>* Given IV<br>* Other names: Z-4942;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Other: Pharmacological Study<br>* Correlative studies<br>Other: Placebo<br>* Given PO<br>* Other names: sham therapy;Procedure: Therapeutic Conventional Surgery<br>* Undergo surgery<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Maximum SUV of Tumors Measured by FDG-PET Pre- and Post Receipt of Pazopanib Versus Placebo | Change in maximum SUV (standardized uptake value) of tumors measured by FDG-PET. Comparison conducted using a two-sided Wilcoxon rank sum test. | From baseline to 15 days | 
| Change in Maximum SUV of Tumors Measured by FDG-PET Post Receipt of 2 Courses of Preoperative Chemotherapy | Change in maximum SUV of tumors measured by FDG-PET. Comparison conducted using a two-sided Wilcoxon rank sum test. | From baseline to 8 weeks | 
| Tumor Response by RECIST Criteria | RECIST measurements will be performed on serial MRIs to evaluate the correlation with FDG-PET. The longest diameter (LD) of the target lesions will be measured and reported as the baseline LD. The baseline LD will be used as reference to further characterize the objective tumor response of the measurable dimension of the disease.Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Progression (PD), a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions | At 15 days | 
| Tumor Response by RECIST Criteria | RECIST measurements will be performed on serial MRIs to evaluate the correlation with FDG-PET. The longest diameter (LD) of the target lesions will be measured and reported as the baseline LD. The baseline LD will be used as reference to further characterize the objective tumor response of the measurable dimension of the disease.Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Progression (PD), a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions | At 8 weeks | 
| Pharmacokinetic Profile of Pazopanib | Trough plasma pazopanib concentration measured during the 14 day run-in period on days 10 through 14. | Up to 14 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Levels of VEGF and Soluble VEGFR2 Assessed by ELISA on Plasma and Tumor Extracts | Plasma will be collected for measurement of VEGF and soluble VEGFR2 (sVEGFR2) at baseline, after the 14 day Run-in period of pazopanib, after completion of neoadjuvant chemotherapy and approximately every 3 months thereafter until completion of pazopanib maintenance therapy, when indicated. Quantitative enzyme-linked immunosorbent assays (ELISA) for VEGF and sVEGFR2 will be performed on plasma and tumor extracts. Plasma will also be collected for micro RNA at baseline, after the 14 day Run-in period of pazopanib, following neoadjuvant chemotherapy and every 3 months thereafter until completion of pazopanib maintenance therapy, when indicated. | At baseline and after 14 days | 
| Overall Survival | Defined as the interval of time from randomization until death from any cause. | Up to 3 years | 
| Number of Participants With Pathologic Response at the Time of Surgery as Measured by % Tumor Viability ( >= 95% Necrosis) | Estimate the amount of viable tumor, and report the percentage of necrosis. Analysis was only completed on a subset of participants. | An expected average of 12 weeks | 
| Progression Free Survival | Defined as the duration of time from randomization to progressive disease (per RECIST), local recurrence, distant metastatic disease (exclusive of stage IV subjects), or death, whichever occurs first. | Up to 3 years |