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.
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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
DOUBLE
Enrollment
23
Given IV
Undergo external beam radiation therapy
Given IV
Correlative studies
Given PO
Correlative studies
Given PO
Undergo surgery
Fred Hutch/University of Washington Cancer Consortium
Seattle, Washington, United States
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.
Time frame: 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.
Time frame: 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
Time frame: 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
Time frame: At 8 weeks
Pharmacokinetic Profile of Pazopanib
Trough plasma pazopanib concentration measured during the 14 day run-in period on days 10 through 14.
Time frame: Up to 14 days
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.
Time frame: At baseline and after 14 days
Overall Survival
Defined as the interval of time from randomization until death from any cause.
Time frame: 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.
Time frame: 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.
Time frame: Up to 3 years
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