Study of Bevacizumab/Doxil in Treatment of Platinum-Resistant/Refractory Ovarian Cancer (CA)

Study Overview
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Brief Summary
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The purpose of this research study is to test the safety, tolerability, and effectiveness of two chemotherapy drugs, pegylated liposomal doxorubicin (Doxil) and bevacizumab (Avastin). How Doxil is metabolized and excreted from the body will also be studied.

Detailed Description
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Avastin: Avastin is a humanized monoclonal antibody (a type of protein that is normally made by the immune system to help defend the body from infection and cancer). Avastin has been approved for the treatment of colorectal cancer and lung cancer. Avastin is investigational for the treatment of ovarian cancer and has not been approved by the United States Food and Drug Administration (FDA) for this use. Avastin is thought to work by attaching to a protein called vascular endothelial growth factor (VEGF) to block its action. VEGF plays a role in the formation of both normal and abnormal blood vessels. It is present in normal tissues, but is produced in excess by most solid cancers (tumors). In cancer, VEGF helps blood vessels bring nutrients to tumor cells, allowing the tumor cells to grow. In laboratory studies with human cancer cells grown in animals, Avastin has been shown to prevent or slow the growth of different types of cancer cells by blocking the effects of VEGF. Doxorubicin: Doxorubicin is a type of antibiotic that is only used in cancer chemotherapy. It slows or stops the growth of cancer. Doxorubicin has been approved by the FDA to treat cancers of the head, neck, cervix, vagina, testes, prostate, uterus and Ewing's tumor.

Official Title
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Phase II Study of Bevacizumab and Doxil in the Treatment of Platinum-Resistant or Refractory Ovarian Cancer

Conditions
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Ovarian Cancer

Intervention / Treatment
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* Drug: Doxil
* Drug: Avastin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must be platinum resistant Patients will be included in the study based on the following criteria: No prior anthracycline use PS less or equal 2 Lab values within certain limits (ANC greater 1000, platelets greater 100,000; ALT, AST 2 time ULN, creatinine less 2.0) No more than 3 prior chemotherapy regimens, only 2 of which can have included platinum-containing regimens Use of effective means of contraception in subjects of child-bearing potential Exclusion Criteria: Disease-Specific Exclusions: Evidence of complete or partial bowel obstruction Need for IV hydration or TPN Greater 2 prior abdominal surgeries History of gastrointestinal perforation Gastrointestinal perforation due to any other cause within the last 6 months General Medical Exclusions: Inability to comply with study and/or follow-up procedures Life expectancy of less than 12 weeks 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 Avastin-Specific Exclusions Inadequately controlled hypertension (defined as systolic blood pressure 150 and/or diastolic blood pressure greater 100 mmHg on antihypertensive medications) Any prior history of hypertensive crisis or hypertensive encephalopathy New York Heart Association (NYHA) Grade II or greater congestive heart failure (see Appendix E) History of myocardial infarction or unstable angina within 6 months prior to study enrollment History of stroke or transient ischemic attack within 6 months prior to study enrollment Known CNS disease Significant vascular disease (e.g., aortic aneurysm, aortic dissection) Symptomatic peripheral vascular disease Evidence of bleeding diathesis or coagulopathy Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to study enrollment 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 study enrollment History of abdominal fistula, or intra-abdominal abscess within 6 months prior to study enrollment Serious, non-healing wound, ulcer, or bone fracture Proteinuria at screening as demonstrated by either: Urine protein:creatinine (UPC) ratio 1.0 at screening OR Urine dipstick for proteinuria greater or equal 2plus (patients discovered to have greater or equal 2+ proteinuria on dipstick urinalysis at baseline should undergo a 24 hour urine collection and must demonstrate less or equal 1g of protein in 24 hours to be eligible) Known hypersensitivity to any component of Avastin Pregnant (positive pregnancy test) or lactating. No effective means of contraception (men and women) in subjects of child-bearing potential

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Single Arm: Doxil and Avastin<br>Patients receive both agents, doxil and Avastin. | Drug: Doxil<br>* Open label study of Doxil given as 30 mg/m2 every three weeks by itself in cycle 1<br>* Other names: Doxorubicin;Drug: Avastin<br>* First agent (Doxil) will be following by Avastin 15 mg/kg on cycle 2 and every cycle thereafter until disease progression<br>* Other names: Bevacizumab;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) by RECIST Criteria | Tumor response is evaluated according to Response Evaluation Criteria in Solid Tumors (RECIST) (version 1.0). Target lesions are assessed by hysical exam and/or computerized tomography (CT): Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Stable Disease (SD), neither sufficient decrease in the sum of the longest diameter of target lesions to qualify for PR nor sufficient increase in the sum of the longest diameter of target lesions to qualify for Progressive Disease; Progressive Disease (PD), 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 | Up to 25 months | 
| Progression Free Survival (PFS) by GCIC Criteria | Using GCIC criteria, progression is defined as CA-125 levels greater than, or equal to, 2 times the upper limit of a reference range on 2 occasions and at least 1 week apart. | Up to 25 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | The time from treatment initiation to death by any cause | 4 years | 
| Overall Response Rate (ORR) by RECIST | ORR is the sum of the percentages of patients achieving complete and partial responses. Tumor response is evaluated according to Response Evaluation Criteria in Solid Tumors (RECIST) (version 1.0) | 3 years | 
| Clinical Benefit Rate (by RECIST) | Clinical Benefit Rate (CBR) is the sum of the percentages of patients achieving complete response, partial response, and stable disease. Tumor response is evaluated according to Response Evaluation Criteria in Solid Tumors (RECIST) (version 1.0). Target lesions are assessed by physical exam and/or computerized tomography (CT): Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Stable Disease (SD), neither sufficient decrease in the sum of the longest diameter of target lesions to qualify for PR nor sufficient increase in the sum of the longest diameter of target lesions to qualify for Progressive Disease; Progressive Disease (PD), 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 | 3 years | 
| Overall Response Rate (ORR) by GCIC Criteria | A response according to GCIC criteria has occurred if there is at least a 50% reduction in CA 125 levels from a pretreatment sample. The response must be confirmed and maintained for at least 28 days. Patients can be evaluated according to CA-125 only if they have a pretreatment sample that is at least twice the upper limit of normal and within 2 weeks prior to starting treatment. | 3 years |