Sequential Angiogenic Blockade for the Treatment of Recurrent Mullerian Malignancies
|ClinicalTrials.gov Identifier: NCT00856180|
Recruitment Status : Completed
First Posted : March 5, 2009
Results First Posted : May 17, 2016
Last Update Posted : July 17, 2017
|Condition or disease||Intervention/treatment||Phase|
|Ovarian Cancer Peritoneal Cancer Fallopian Tube Cancer||Drug: Bevacizumab Drug: Cyclophosphamide||Phase 2|
- 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
- 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
- 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
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.
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||20 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||Pilot Study of Sequential Angiogenic Blockade for the Treatment of Recurrent Mullerian Malignancies|
|Study Start Date :||February 2009|
|Actual Primary Completion Date :||April 2010|
|Actual Study Completion Date :||January 2014|
Experimental: Bevacizumab then Cyclophosphamide with Bevacizumab
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.
Other Name: AvastinDrug: Cyclophosphamide
Other Name: cytoxan
- Therapy Completion Rate [ Time Frame: Serologic and radiologic disease assessments occurred every 2 cycles/6 weeks on treatment. Median treatment duration for this study cohort was 7.5 months (range 0.7-20.7). ]The therapy completion rate is defined as the proportion of participants who completed at least 3 months/4 cycles of therapy. Participants were treated until disease progression on the combination regimen or unacceptable toxicity. Clinical response was evaluated based on RECIST 1.0 criteria for measurable disease (MD) participants and Gynecologic Cancer Intergroup (GCIG) CA-125 (Rustin) criteria for non-MD participants. Per RECIST 1.0 for target lesions, PD is at least a 20% increase in sum LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or appearance of new lesions. For non-target lesions, PD is the appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions. Serologic PD is rise in CA-125 or previously normal CA125 that rises to >/=2xULN documented, both requiring 2nd confirmation.
- Grade 3-5 Gastrointestinal Perforation [ Time Frame: Assessed each cycle/3 weeks throughout treatment from time of first dose and up to day 30 post-treatment. Median treatment duration for this study cohort was 7.5 months (range 0.7-20.7). ]All grade 3-5 gastrointestinal perforation events based on CTCAEv3 as reported on case report forms.
- Clinical Benefit Response Rate [ Time Frame: Radiologic disease assessments occurred every 2 cycles/6 weeks on treatment. Median treatment duration for this study cohort was 7.5 months (range 0.7-20.7). ]Clinical benefit response rate is defined as the proportion of participants who achieve confirmed stable disease (SD) or better on treatment based on RECIST 1.0 criteria. Per RECIST 1.0 for target lesions, complete response (CR) is disappearance of all target lesions and partial response (PR) is at least a 30% decrease in the sum of longest diameter (LD) of target lesions, taking as reference baseline sum LD. Progressive disease (PD) is at least a 20% increase in sum LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started. SD is neither PR nor PD. For non-target lesions, PD is the appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions.
- Progression-Free Survival (PFS) [ Time Frame: Radiologic disease assessments occurred every 2 cycles/6 weeks on treatment and every 3 months in follow-up until PD, death or lost to follow-up. Median treatment duration was 7.5 months (range 0.7-20.7) and survival follow-up 23 months.. ]PFS estimated using Kaplan-Meier methods is defined as the duration of time from the start of bevacizumab alone to documented disease progression (PD) requiring removal from the study or death. If participant ultimately received both bevacizumab and cyclophosphamide then it was the time until PD on both agents. Per RECIST 1.0 for target lesions, PD is at least a 20% increase in sum LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or appearance of new lesions. For non-target lesions, PD is the appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions. Serologic PD is rise in CA-125 or previously normal CA-125 that rises to >/=2xULN documented, both requiring 2nd confirmation. Participants who were event-free were censored at the date of their last disease evaluation.
- Overall Survival (OS) [ Time Frame: Participants were followed long-term for survival every 3 months from the end of treatment until death or lost to follow-up. Median follow-up was 23 months in this study cohort. ]OS estimated using Kaplan-Meier methods is defined as the time from study entry to death or date last known alive.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00856180
|United States, Massachusetts|
|Massachusetts General Hospital|
|Boston, Massachusetts, United States, 02114|
|Dana-Farber Cancer Institute|
|Boston, Massachusetts, United States, 02115|
|Principal Investigator:||Ursula Matulonis, MD||Dana-Farber Cancer Institute|