Paclitaxel + Bevacizumab (Avastin) for the Treatment of Metastatic or Unresectable Angiosarcoma

Study Overview
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Brief Summary
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This is an open-label, single-arm, multi-center, Phase 2 study with Paclitaxel in combination with Bevacizumab in patients with Unresectable or Metastatic Angiosarcoma. The study aims to determine the safety and effectiveness of combining two drugs Paclitaxel and Bevacizumab in the treatment of Angiosarcoma that cannot be removed by surgery, or has spread to other parts of your body. The primary objective is to evaluate 4month non progression rate. The secondary objective is to evaluate overall response rate after 3rd and 6th cycle, median duration of response, 6th and 12th month survival, toxicity of Paclitaxel and Bevacizumab combination, toxicity of maintenance Bevacizumab and to collect paraffin-embedded tumor blocks for angiogenesis markers and tissue microarray.

Detailed Description
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Regimen A versus B was chosen at the discretion of the treating physician. Both groups were analyzed together as far as outcome. Patients were to receive paclitaxel 200 mg/m2 intravenously over 3 hours every 21 days (Regimen A) or pactlitaxel 90 mg/m2 weekly x 3 of a 28 day cycle (Regimen B) followed by bevacizumab 15 mg/kg intravenously over (cycle 1: 90 min; cycle 2: 60 min; cycles 3-6: 30 min) every 21 days x 6 cycles. Maintenance bevacizumab (MB) started after the completion of combination of paclitaxel and bevacizumab and it was given at a dose of 15 mg/kg intravenously once every 21 days for a maximum of 8 cycles. Patients were allowed to receive growth factors. Dose reductions were done based on hematologic and non-hematologic toxicities.

Official Title
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Paclitaxel in Combination With Bevacizumab (Avastin) for the Treatment of Metastatic or Unresectable Angiosarcoma

Conditions
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Angiosarcomas, Soft Tissue Sarcoma

Intervention / Treatment
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* Drug: Bevacizumab
* Drug: Paclitaxel


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA Baseline measurements and evaluations must be obtained within 4 weeks of registration to the study. Abnormal PET scans will not constitute evaluable disease, unless verified by computed tomography (CT) scan or other appropriate imaging At least 1 objective measurable disease parameter by Response Evaluation Criteria In Solid Tumors (RECIST) criteria Unresectable locally advanced or metastatic angiosarcoma ≤ 2 prior chemotherapeutic regimens for angiosarcoma No prior paclitaxel, docetaxel, or bevacizumab for angiosarcoma (previous paclitaxel or docetaxel allowed if not given for angiosarcoma and more than 12 months has elapsed since last dose) No evidence of other active malignancies other than carcinomas in-situ of the cervix or basal cell carcinoma of the skin within 6 months prior to registration If history of deep venous thrombosis or pulmonary embolism, receiving a stable dose of anticoagulation therapy for at least 2 weeks prior to registration Within 7 days prior to registration, use of any anti-platelet drugs, such as ticlopidine, clopidogrel, and cilostazol. The use of aspirin or other nonsteroidal anti-inflammatory drugs (NSAID) is allowed ECOG performance status 0 to 2 Patients must have adequate organ function as evidenced by the following laboratory studies (within 2 weeks prior to registration): Serum creatinine ≤ 2.0 mg/dL Total bilirubin ≤ 2.0 x upper limit of normal (ULN). If documented hepatic involvement, can be ≤ 3 x ULN Serum glutamic oxaloacetic transaminase (SGOT) or Aspartate aminotransferase (AST) < 2 x ULN. If documented hepatic involvement, can be ≤ 5 x ULN Absolute neutrophil count ≥ 1500/mm3 and platelet count > 100,000/mm3 Platelets ≤ 1.5 x ULN International normalized ratio (INR) ≤ 1.5 x ULN Partial thromboplastin time (PTT) ≤ 1.5 x ULN Left ventricular ejection fraction ≥ 50% ≥ 18 years Women of childbearing potential must have a negative human chorionic gonadotropin (hCG) pregnancy test within 2 weeks prior to registration EXCLUSION CRITERIA Life expectancy < 12 weeks Current, recent (within 4 weeks of the first infusion of this study), or planned participation in an another experimental drug study Inadequately-controlled hypertension (defined as systolic blood pressure > 150 mmHg and/or diastolic blood pressure > 100 mmHg) History of hypertensive crisis or hypertensive encephalopathy New York Heart Association (NYHA) Grade II or greater congestive heart failure History of myocardial infarction or unstable angina within 6 months prior to Day 1 History of stroke or transient ischemic attack within 6 months prior to Day 1 Known central nervous system (CNS) disease, except for treated brain metastasis. Treated brain metastases are defined as having no evidence of progression or hemorrhage after treatment and no ongoing requirement for dexamethasone, as ascertained by clinical examination and brain imaging (MRI or CT) during the screening period. Anticonvulsants (stable dose) are allowed. Treatment for brain metastases may include whole brain radiotherapy (WBRT), radiosurgery (RS; Gamma Knife, LINAC, or equivalent) or a combination as deemed appropriate by the treating physician. Patients with CNS metastases treated by neurosurgical resection or brain biopsy performed within 3 months prior to Day 1 will be excluded. Significant vascular disease (eg, aortic aneurysm, requiring surgical repair or recent peripheral arterial thrombosis) within 6 months prior to Day 1 History of hemoptysis (≥ 1/2 teaspoon of bright red blood per episode) within 1 month prior to Day 1 Evidence of bleeding diathesis or significant coagulopathy (in the absence of therapeutic anticoagulation) Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to Day 1 or anticipation of need for major surgical procedure during the course of the study Core biopsy or other minor surgical procedure, excluding placement of a vascular access device, within 7 days prior to Day 1 History of abdominal fistula or gastrointestinal perforation within 6 months prior to Day 1 Serious, non-healing wound, active ulcer, or untreated bone fracture Proteinuria as demonstrated by a urine protein: creatinine ratio (UPC) ratio ≥ 1.0 at screening Known hypersensitivity to any component of bevacizumab Active infection requiring parental antibiotics Known human immunodeficiency virus (HIV) infection Pregnant or breast feeding Inability to comply with study and/or follow-up procedures

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: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Regimen A / Treatment 1<br>Participants were to receive paclitaxel 200 mg/m² intravenously over 3 hours every 21 days followed by bevacizumab 15 mg/kg intravenously over (cycle 1: 90 min; cycle 2: 60 min; cycles 3 to 6: 30 min) every 21 days x 6 cycles. Maintenance bevacizumab (MB), 15 mg/kg once every 21 days intravenously for a maximum of 8 cycles, was initiated after the completion of paclitaxel + bevacizumab combination. | Drug: Bevacizumab<br>* 15 mg/kg, IV every 21 days x 6 cycles.<br>* Other names: Avastin;Drug: Paclitaxel<br>* Regimen A / Treatment 1: 200 mg/m² IV over 3 hours every 21 days. Regimen B / Treatment 2: 90 mg/m² weekly x 3 of a 28-day cycle<br>* Other names: Abraxane;|
| Experimental: Regimen B / Treatment 2<br>Patients were to receive paclitaxel 90 mg/m² weekly x 3 of a 28-day cycle followed by bevacizumab 15 mg/kg intravenously over (cycle 1: 90 min; cycle 2: 60 min; cycles 3 to 6: 30 min) every 21 days x 6 cycles. Maintenance bevacizumab (MB), 15 mg/kg once every 21 days intravenously for a maximum of 8 cycles, was initiated after the completion of paclitaxel + bevacizumab combination. | Drug: Bevacizumab<br>* 15 mg/kg, IV every 21 days x 6 cycles.<br>* Other names: Avastin;Drug: Paclitaxel<br>* Regimen A / Treatment 1: 200 mg/m² IV over 3 hours every 21 days. Regimen B / Treatment 2: 90 mg/m² weekly x 3 of a 28-day cycle<br>* Other names: Abraxane;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival (PFS) | The primary objective of this study was to evaluate progression-free survival (PFS or non-progression rate) through 4 months from start of treatment. Progression is defined as ≥ 20% increase in the sum of the longest diameter of target lesions, as compared to the baseline measurements, and/or the appearance of one or more new lesion(s). | 4 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate After 3 Cycles | Response was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) Criteria, per protocol. Overall response rate (ORR) is the sum of the Complete Response (CR) + Partial Response (PR) rates. The ORR for participants after 3 cycles of treatment (12 weeks) is expressed as the number and proportion of subjects. RECIST Criteria CR = Disappearance of all target lesions PR = ≥ 30% decrease in the sum of the longest diameter of target lesions Progressive disease (PD) = 20% increase in the sum of the longest diameter of target lesions, and/or the appearance of one or more new lesion(s), Stable disease (SD) = Small changes that do not meet any of the above criteria | 12 weeks | 
| Overall Response Rate After 6th Cycle | Response was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) Criteria, per protocol. Overall response rate (ORR) is the sum of the Complete Response (CR) + Partial Response (PR) rates. The ORR for participants after 6 cycles of treatment (24 weeks) is expressed as the number and proportion of subjects. RECIST Criteria CR = Disappearance of all target lesions PR = ≥ 30% decrease in the sum of the longest diameter of target lesions Progressive disease (PD) = 20% increase in the sum of the longest diameter of target lesions, and/or the appearance of one or more new lesion(s), Stable disease (SD) = Small changes that do not meet any of the above criteria | 6 Cycles | 
| Overall Survival (OS) at 6 Months | Assessed as the number of subjects known to remain alive 6 months after study entry | 6 months | 
| Overall Survival (OS) at 12 Months | Assessed as the number of subjects known to remain alive 12 months after study entry | 12 months |