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

Efficacity of Paclitaxel in association or not with Bevacizumab in treatment of angiosarcoma

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

Eligibility Criteria:
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