Clinical trial NCT00856180
Conditions: Ovarian Cancer Peritoneal Cancer Fallopian Tube Cancer
Keywords: avastin bevacizumab cyclophosphamide cytoxan mullerian malignancies
Sponsor: Dana-Farber Cancer Institute
Start date: 2009-02-01; Completion date: 2014-01-01
Enrollment: 20 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The goals of this study were to evaluate the efficacy and safety of sequentially blocking the angiogenesis pathway via known antiangiogenic mechanisms, first with bevacizumab and then addition of oral cyclophosphamide upon progression of cancer through bevacizumab. The drugs used in this study were chosen because of their known antiangiogenic properties, tolerability, and anti-ovarian cancer effects.

Detailed description:
OBJECTIVES:

Primary

* Assess the efficacy of a sequential antiangiogenic blockade regimen of bevacizumab then cyclophosphamide with bevacizumab at disease progression in patients with recurrent ovarian cancer as measured by the proportion of patients who remain on study at three months (4 cycles)
* Assess the safety profile with respect to gastrointestinal perforations

Secondary

* Assess other toxicity/ safety profile of this metronomic antiangiogenic approach
* Assess preliminary response rate and proportion of patients on study at 6 months
* Assess progression-free survival, time to progression and overall survival

Correlative

* Determine if biological correlates of angiogenesis are altered by the addition of sequential therapy
* Determine if changes in biological markers are correlated with clinical state of cancer
* Determine whether biomarkers of angiogenesis can predict and measure response
* Determine whether oncogenic mutations predict response
* Determine whether hypertension and urinary biomarkers such as varying levels of albuminuria predict response to bevacizumab
* Determine patient risk factors for hypertension and proteinuria as toxicities of bevacizumab

STATISTICAL DESIGN:

This study used a two-stage design to evaluate safety and efficacy of sequential antiangiogenic blockade with a regimen of bevacizumab then cyclophosphamide added at disease progression. Safety was measured by the incidence of grade 3-5 gastrointestinal perforation (GIP) during the first 3 months of therapy and efficacy by completion of at least 3 months of therapy. The sample size was determined based on efficacy with the null and alternative therapy completion rate of 50% and 80%, respectively. If 6 or more patients enrolled in the stage one cohort (n=9 patients) completed at least 3 months of therapy then accrual would proceed to stage two (n=11 patients) if there were fewer than 2 cases of grade 3-5 GIP. There was 0.75 probability of stopping the trial at stage one if the true therapy completion rate was 50%. If 13 or fewer patients remained on therapy for at least 3 months by the end of stage two, this regimen would be deemed ineffective. The power to reject the null hypothesis with a one-sided binomial test was 87% assuming 5% significance.

Arms: arm 1: Patients were given a regimen of sequential antiangiogenic blockade and disease assessed serologically and radiologically every 2 cycles/6 weeks. Patients started with bevacizumab 15 mg/kg IV every 3 weeks until they experienced progressive disease (PD) \[RECIST 1.0 or Rustin criteria\] or significant toxicity. If clinically stable as assessed by their treating physician, patients then received cyclophosphamide 50 mg orally (PO) daily continuously with bevacizumab treatment. If second PD occurred, patients discontinued the combination treatment.
Interventions: intervention 1: Bevacizumab intervention 2: Cyclophosphamide
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents: