Phase II Study of Doxorubicin and Avastin® in Sarcoma.

Phase II Study of Doxorubicin and Avastin® for Patients With Advanced Soft-tissue Sarcomas.

This research is being done to find out if adding a drug called Avastin to an already approved regimen used for soft-tissue sarcoma, Doxorubicin, will improve overall survival, and slow disease progression. The study will also evaluate the overall safety of combining these drugs. It is not known if combining these drugs will improve outcome. Avastin has been approved for the treatment of metastatic carcinoma of the colon or rectum. It is not approved for the treatment of soft-tissue sarcoma when added to Doxorubicin.

The rationale for this trial is to improve the efficacy of prototypical anti-sarcoma chemotherapeutic regimen Doxorubicin when combined with Avastin®. Soft tissue sarcomas are highly vascular tumors and are therefore ideally suited to trials combining angiogenic inhibitors with chemotherapy. Several studies have revealed correlations between prognosis and surrogates for angiogenesis, including microvessel density, and circulating VEGF and basic fibroblast growth factor (bFGF). The aim of this study is to evaluate the safety and efficacy of Avastin® in combination with Doxorubicin for the treatment of advanced soft-tissue sarcomas.

Inclusion Criteria:

1. Pathologically confirmed intermediate or high grade locally advanced or metastatic soft tissue sarcoma.
2. The presence of measurable disease
3. Normal renal function (spot dipstick <2** or urine protein: creatinine ratio >1.0
4. Normal Hepatic function (total bilirubin within JOHC normal limits, transaminases (AST and ALT <3 times upper limit of normal
5. Hematologic parameters as defined as ANC >1500/mm³ and Platelets > 100,000/mm³.
6. Performance status 0-1 on ECOG scale
7. Use of effective means of contraception (men and women) in subjects of child-bearing age
8. No prior use of mesna, adriamycin, ifosfamide or Avastin®.
9. Baseline ECHO or MUGA with LVEF > or = 50-60%.
10. Age ≥ 18

Exclusion Criteria:

1. Major surgery within 28 days
2. History of proteinuria > 1+
3. Current, recent (within 4 weeks of the first infusion of this study), or planned participation in an experimental drug study other than a Genentech-sponsored Avastin® cancer study
4. Inadequately controlled hypertension (defined as systolic blood pressure >150 and/or diastolic blood pressure > 100 mmHg on antihypertensive medications)
5. Any prior history of hypertensive crisis or hypertensive encephalopathy
6. New York Heart Association (NYHA) Grade II or greater congestive heart failure (see Appendix E)
7. History of myocardial infarction or unstable angina within 6 months prior to study enrollment
8. History of stroke or transient ischemic attack within 6 months prior to study enrollment
9. Symptomatic peripheral vascular disease
10. Significant vascular disease (e.g., aortic aneurysm, aortic dissection)
11. Evidence of bleeding diathesis or coagulopathy
12. Current or recent (within 10 days of enrollment) use of aspirin (>325 mg/day) or chronic use of other NSAIDs
13. Current, ongoing treatment with full-dose warfarin or its equivalent (i.e., unfractionated and/or low molecular weight heparin).
14. Known central nervous system or brain metastases
15. Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to Day 0, anticipation of need for major surgical procedure during the course of the study
16. Core biopsy or other minor surgical procedure, excluding placement of a vascular access device, within 7 days prior to study enrollment
17. Pregnant (positive pregnancy test) or lactating
18. Proteinuria :creatinine (UPC) ratio ≥ 1.0 at screening or Urine dipstick for proteinuria ≥ 2+ (patients discovered to have ≥2+ proteinuria on dipstick urinalysis at baseline should undergo a 24 hour urine collection and must demonstrate ≤ 1g of protein in 24 hours to be eligible).
19. History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to Day 0
20. Serious, non-healing wound, ulcer, or bone fracture
21. Known hypersensitivity to any component of Avastin®
22. Inability to comply with study and/or follow-up procedures