Bevacizumab and Low-Dose Cyclophosphamide in Treating Patients With Recurrent Ovarian Epithelial or Primary Peritoneal Cancer

Study Overview
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Brief Summary
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This phase II trial is to see if combining bevacizumab with low-dose cyclophosphamide works in treating patients with ovarian epithelial or primary peritoneal cancer that has come back or spread to other parts of the body. Monoclonal antibodies, such as bevacizumab, can block cancer growth in different ways. Some block the ability of cancer cells to grow and spread. Others find cancer cells and help kill them or deliver cancer-killing substances to them. Drugs used in chemotherapy, such as cyclophosphamide, work in different ways to stop tumor cells from dividing so they stop growing or die. Combining bevacizumab with cyclophosphamide may kill more tumor cells.

Detailed Description
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OBJECTIVES: Primary I. Determine the time to progression in patients with recurrent ovarian epithelial or primary peritoneal cancer treated with bevacizumab and low-dose cyclophosphamide. Secondary I. Determine the response rate in patients treated with this regimen. II. Determine the toxicity of this regimen in these patients. III. Determine molecular correlates for response and outcomes in patients treated with this regimen. OUTLINE: This is a nonrandomized, multicenter study. Patients receive bevacizumab IV over 30-90 minutes on days 1, 8, and 15 for the first course and on days 1 and 15 for all subsequent courses. Patients also receive low-dose oral cyclophosphamide on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. PROJECTED ACCRUAL: A total of 23-55 patients will be accrued for this study within 1-2 years.

Official Title
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Phase II Clinical Trial of Bevacizumab (NSC 704865) and Low Dose Oral Cyclophosphamide in Recurrent Ovarian Cancer, Primary Peritoneal Carcinoma

Conditions
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Primary Peritoneal Carcinoma, Recurrent Ovarian Carcinoma, Stage IV Ovarian Cancer

Intervention / Treatment
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* Biological: Bevacizumab
* Drug: Cyclophosphamide
* Other: Laboratory Biomarker Analysis


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed recurrent or metastatic ovarian epithelial or primary peritoneal cancer Unidimensionally measurable disease Previously irradiated indicator lesions must have progressed after radiotherapy Received a platinum-containing regimen for primary disease No more than 2 prior chemotherapy regimens for recurrent disease Must have received prior platinum-based chemotherapy for recurrent disease if it has been > 12 months since treatment for primary disease (except if hypersensitivity to platinum has developed) Rechallenge with the same platinum-based regimen is considered 1 prior regimen No history or clinical evidence of CNS disease, including primary brain tumor No brain metastases Performance status - SWOG 0-2 At least 3 months Absolute neutrophil count at least 1,500/mm^3 Platelet count at least 100,000/mm^3 No bleeding diathesis No coagulopathy Bilirubin no greater than 1.5 times normal ALT or AST no greater than 3 times upper limit of normal INR less than 1.5 (for patients receiving warfarin) Creatinine no greater than 1.5 times normal No proteinuria (less than 1+) Proteinuria less than 500 mg/24-hour urine collection No prior deep vein thrombosis No prior stroke No clinically significant cardiovascular disease None of the following within the past year: Uncontrolled hypertension New York Heart Association class II-IV congestive heart failure Serious cardiac arrhythmia requiring medication Grade II or greater peripheral vascular disease None of the following within the past 6 months: Unstable angina Myocardial infarction Transient ischemic attack Cerebrovascular accident Other arterial thromboembolic event No clinically significant peripheral artery disease No active infection requiring parenteral antibiotics No known hypersensitivity to Chinese hamster ovary cell products or other recombinant human antibodies Not pregnant or nursing Fertile patients must use effective contraception No serious, non-healing wound, ulcer, or bone fracture No significant traumatic injury within the past 28 days No seizures not controlled with standard medical therapy No other malignancy within the past 5 years except nonmelanoma skin cancer or carcinoma in situ of the cervix All prior invasive malignancies must be in complete remission No other concurrent medical, psychological, or social condition that would preclude study participation No prior antiangiogenesis agents See Disease Characteristics Recovered from prior chemotherapy See Disease Characteristics Recovered from prior radiotherapy More than 28 days since prior major surgical procedure or open biopsy and recovered At least 3 weeks since prior therapy directed at the malignancy No recent or concurrent full-dose anticoagulants or thrombolytic agents Anticoagulants to maintain patency of preexisting, permanent indwelling IV catheters allowed No concurrent chronic daily aspirin (greater than 325 mg/day) or nonsteroidal anti-inflammatory drugs known to inhibit platelet function
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: Treatment (bevacizumab, cyclophosphamide)<br>Patients receive bevacizumab IV over 30-90 minutes on days 1, 8, and 15 for the first course and on days 1 and 15 for all subsequent courses. Patients also receive low-dose oral cyclophosphamide on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. | Biological: Bevacizumab<br>* Given IV<br>* Other names: rhuMab-VEGF;Drug: Cyclophosphamide<br>* Given PO<br>* Other names: WR- 138719;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Median Time to Progression | Time from treatment initiation to disease progresion calculated using the method of Kaplan-Meier. RECIST v1.0 was used to evaluate response. Progression was defined as a 20% or greater increase in the sums of the longest dimensions of target lesions, or the appearance of new lesions within 8 weeks of study entry. | Up to 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response Rate Based on the RECIST | Percentage of patients with a confirmed partial or complete response using RECIST v1.0 criteria. Complete response was defined as the disapperance of all target and nontarget lesions, no evidence of new lesions and normalization of CA-125; Partial response was defined as a 30% or greater reduction in the sum of the longest dimensions of all target lesions and no unequivocal progression of nontarget lesions, lasting at least 4 weeks. | Up to 3 years | 
| Median Overall Survival | Calculated using the method of Kaplan-Meier. | Time from first day of treatment to time of death due to any cause, assessed up to 3 years |