Efficacity of Weekly Paclitaxel in Association or Not With Bevacizumab in Metastatic or Locally Advanced Angiosarcomas

Study Overview
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Brief Summary
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Efficacity of Paclitaxel in association or not with Bevacizumab in treatment of angiosarcoma

Detailed Description
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Randomization is stratified : angiosarcoma in irradiated region : yes / no visceral angiosarcoma : yes / no All patient will received a maximum of 6 cycles of weekly Paclitaxel (Arm A and B) in association or not with Bevacizumab (ArmB). 1 cycle = 28 days Treatment by Bevacizumab is to continue beyond the 6th cycle, until disease progression or unacceptable toxicity Arm A and B: Day 1, D8 and D15 Paclitaxel : 90 mg/m², IV weekly with premedication Arm B : Day 1 and D15 Bevacizumab : 10 mg/kg and then, Bevacizumab : 15 mg/kg/3 weeks until disease progression or unacceptable toxicity

Official Title
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Phase II Study, Multicenter, Randomized, Stratified, Evaluating the Efficacity of Weekly Paclitaxel, With or Without Bevacizumab in the Treatment of Metastatic or Locally Advanced Angiosarcomas Not Accessible to Surgery Treatment.

Conditions
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Angiosarcoma

Intervention / Treatment
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* Drug: Paclitaxel
* Drug: Bevacizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Angiosarcoma histologically proven Metastatic or locally advanced and not accessible to surgery treatment Measurable tumor with at least 1 measurable lesion, according to RECIST For angiosarcoma in irradiated region, absence of clinical arguments of progression of the tumor prior treated by radiation At least 28 days since the previous treatment (systemic or major surgery) Performance Status (ECOG) ≤ 1 Man or woman >= 18 years Polynuclear neutrophils >1500/mm3, platelets > 100 000/ mm3, Hemoglobin > 9.0 g/dl Total bilirubin ≤ 1.5 x USL, AST and ALT ≤ 2.5 x USL (or ≤ 5 if hepatic metastasis ) Serum creatinin ≤ 1.5 x USL or clearance calculated > 50 ml/mn (Cockcroft formulae) Absence of hematuria on dipstick Proteinuria on dipstick <2+, if >2, the 24 hours proteinuria must be < 1g Albumin > 35 g/l and lymphocytes > 700/mm3 attesting a life expectancy > 3 months Normal cardiac function : LVEF ≥ 50% Normal coagulation test : INR ≤ 1.5 and TCA ≤ 1.5 x USL within 7 days before inclusion Systolic BP ≤ 150 mmHg and diastolic BP ≤ 100 mmHg Negative pregnancy test for women of reproductive potential(within 7 days before treatment start) Effective contraceptive methods for male and female (if applicable) during the period of treatment and until the 6 months after the last administration of Bevacizumab Adequate central veinous access Patient covered by government health insurance Informed consent form signed by the patient Exclusion Criteria: Patients that have received more than 2 regimens of chemotherapy whatever the indication Kaposi's sarcoma, hemangio-endothelioma, hemangio-pericytoma (Malignant solitary fibrous tumor) Surgery (except the diagnostic biopsy) or radiotherapy within the past 4 weeks before inclusion, except antalgic radiotherapy Uncontrolled, active peptic ulcer, Other malignant evolutive tumor Previous thrombotic or hemorrhagic disorders Clinically significant cardiovascular disease (stroke within 6 months prior inclusion, unstable angina, heart failure, myocardial infarction, arrhythmia requiring treatment) Anticoagulant treatment for curative aim within 10 days before beginning of treatment (oral or parenteral administration), aspirin > 325 mg/day, or Plavix or a thrombolytic (thrombolytics for preventive use is permitted) or anti-platelet (dipyridamol, ticlopidine, clodiprogel, cilostazol) Chronic treatment(more than 15 days) by every AINS including aspirin > 325 mg/j Currently active bacterial or fungus infection (grade > 2 CTCAE v4.02) Known HIV1, HIV2, hepatitis B or hepatitis C infections Presence of known meningeal or brain metastasis Epilepsy requiring the use of anti-epileptic Previous organ transplant Peripheral stem cell transplantation within 4 months prior to inclusion in the study Using of drugs affecting the biological response, for example G-CSF, within the 3 weeks before inclusion Kidney dialysis patient Clinically significant neuropathy (grade> 2 CTCAE V4.02) Any circumstance that could jeopardise compliance or proper follow-up during the trial Pregnant or nursing women. Women should not breastfeed for at least 6 months after the last administration of Bevacizumab Constitutional or acquired coagulopathy Uncontrolled hypertension (SBP> 150 mmHg or DBP> 100 mmHg) Known hypersensitivity to paclitaxel or to one of its excipients (Cremophor EL, to Bevacizumab components, to products of Chinese hamster ovary cells (CHO) or other recombinant human or humanized antibodies Patients unable to undergo trail medical follow-up for geographical, social or psychological reasons Patient refusal of ambulatory care

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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Arm A : Paclitaxel<br>administration of paclitaxel drug during cycle of 28 days (6 cycles Max) + blood sample on day 1, 8, 15, 29 and 57 | Drug: Paclitaxel<br>* Day 1, 8 and 15 : Paclitaxel 90 mg/m², IV over 1h, during 6 cycles (1 cycle = 28 days)<br>* Other names: Taxol;|
| Other: Arm B : Paclitaxel + Bevacizumab<br>administration of paclitaxel drug during per cycle of 28 days (6 cycles Max) + Bevacizumab every two weeks during paclitaxel cycles then every 3 weeks during P cycles until disease progression or inacceptable toxicity + blood sample on day 1, 8, 15, 29 and 57 | Drug: Paclitaxel<br>* Day 1, 8 and 15 : Paclitaxel 90 mg/m², IV over 1h, during 6 cycles (1 cycle = 28 days)<br>* Other names: Taxol;Drug: Bevacizumab<br>* Bevacizumab until progression or inacceptable toxicity : During the cycles of chemotherapy : Day 1 and D15 : 10 mg/kg,IV After 6 cycles of chemotherapy : 15 mg/kg, IV<br>* Other names: Avastin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression free rate after 6 months of treatment | Stable disease, complete response and partial response according to RECIST 1.1 | after 6 months of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective response at 3, 6, 9 months of treatment | Stable disease, complete response and partial response according to RECIST 1.1 | at 3, 6, 9 months of treatment | 
| Median progression-free rate | Median time for both cohort between : date of inclusion date of clinical or radiological progression | an average time period of 1 year | 
| Global median survival | Median time for both cohort between : date of inclusion date of death whatever the cause | an average time period of 18 months | 
| Tolerance | According to NCI-CTCAE v4.0 | during the study | 
| Correlation between efficacity and serum expression of anti angiogenic factors | Blood samples at different times | Day 1, 8, 15, 29 and 57 | 
| Correlation between efficacity and beta-tubuline III expression in tissue | Paraffin blocks | At baseline | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Angiosarcoma, Paclitaxel, bevacizumab