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
试验速览
- 阶段
- 不适用
- 状态
- 已完成
- 入组人数
- 23
- 试验地点
- 1
- 主要终点
- Change in Maximum SUV of Tumors Measured by FDG-PET Pre- and Post Receipt of Pazopanib Versus Placebo
研究概览
简要总结
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.
详细描述
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:
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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
研究组 & 干预措施
Arm I (pazopanib hydrochloride)
Patients receive pazopanib hydrochloride PO QD. Treatment continues for 14 days in the absence of disease progression or unacceptable toxicity.
干预措施: Doxorubicin Hydrochloride (Drug)
Arm I (pazopanib hydrochloride)
Patients receive pazopanib hydrochloride PO QD. Treatment continues for 14 days in the absence of disease progression or unacceptable toxicity.
干预措施: External Beam Radiation Therapy (Radiation)
Arm I (pazopanib hydrochloride)
Patients receive pazopanib hydrochloride PO QD. Treatment continues for 14 days in the absence of disease progression or unacceptable toxicity.
干预措施: Ifosfamide (Drug)
Arm I (pazopanib hydrochloride)
Patients receive pazopanib hydrochloride PO QD. Treatment continues for 14 days in the absence of disease progression or unacceptable toxicity.
干预措施: Laboratory Biomarker Analysis (Other)
Arm I (pazopanib hydrochloride)
Patients receive pazopanib hydrochloride PO QD. Treatment continues for 14 days in the absence of disease progression or unacceptable toxicity.
干预措施: Pazopanib Hydrochloride (Drug)
Arm I (pazopanib hydrochloride)
Patients receive pazopanib hydrochloride PO QD. Treatment continues for 14 days in the absence of disease progression or unacceptable toxicity.
干预措施: Pharmacological Study (Other)
Arm I (pazopanib hydrochloride)
Patients receive pazopanib hydrochloride PO QD. Treatment continues for 14 days in the absence of disease progression or unacceptable toxicity.
干预措施: Therapeutic Conventional Surgery (Procedure)
Arm II (placebo)
Patients receive placebo PO QD. Treatment continues for 14 days in the absence of disease progression or unacceptable toxicity.
干预措施: Doxorubicin Hydrochloride (Drug)
Arm II (placebo)
Patients receive placebo PO QD. Treatment continues for 14 days in the absence of disease progression or unacceptable toxicity.
干预措施: External Beam Radiation Therapy (Radiation)
Arm II (placebo)
Patients receive placebo PO QD. Treatment continues for 14 days in the absence of disease progression or unacceptable toxicity.
干预措施: Ifosfamide (Drug)
Arm II (placebo)
Patients receive placebo PO QD. Treatment continues for 14 days in the absence of disease progression or unacceptable toxicity.
干预措施: Laboratory Biomarker Analysis (Other)
Arm II (placebo)
Patients receive placebo PO QD. Treatment continues for 14 days in the absence of disease progression or unacceptable toxicity.
干预措施: Pharmacological Study (Other)
Arm II (placebo)
Patients receive placebo PO QD. Treatment continues for 14 days in the absence of disease progression or unacceptable toxicity.
干预措施: Placebo (Other)
Arm II (placebo)
Patients receive placebo PO QD. Treatment continues for 14 days in the absence of disease progression or unacceptable toxicity.
干预措施: Therapeutic Conventional Surgery (Procedure)
结局指标
主要结局
Change in Maximum SUV of Tumors Measured by FDG-PET Pre- and Post Receipt of Pazopanib Versus Placebo
时间窗: From baseline to 15 days
Change in maximum SUV (standardized uptake value) of tumors measured by FDG-PET. Comparison conducted using a two-sided Wilcoxon rank sum test.
Change in Maximum SUV of Tumors Measured by FDG-PET Post Receipt of 2 Courses of Preoperative Chemotherapy
时间窗: From baseline to 8 weeks
Change in maximum SUV of tumors measured by FDG-PET. Comparison conducted using a two-sided Wilcoxon rank sum test.
Pharmacokinetic Profile of Pazopanib
时间窗: Up to 14 days
Trough plasma pazopanib concentration measured during the 14 day run-in period on days 10 through 14.
Tumor Response by RECIST Criteria
时间窗: At 8 weeks
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
次要结局
- Change in Levels of VEGF and Soluble VEGFR2 Assessed by ELISA on Plasma and Tumor Extracts(At baseline and after 14 days)
- Overall Survival(Up to 3 years)
- Number of Participants With Pathologic Response at the Time of Surgery as Measured by % Tumor Viability ( >= 95% Necrosis)(An expected average of 12 weeks)
- Progression Free Survival(Up to 3 years)