Symptoms and General Pathology

All Conditions

Neoplasms

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Gland and Hormone Related Diseases

Rare Diseases

Recurrence

Ovarian Neoplasms

Carcinoma, Ovarian Epithelial

Fallopian Tube Neoplasms

Adnexal Diseases

Genital Diseases, Female

Genital Diseases

Urogenital Diseases

Female Urogenital Diseases

Pregnancy Complications

Female Urogenital Diseases and Pregnancy Complications

Genital Neoplasms, Female

Urogenital Neoplasms

Fallopian Tube Diseases

Ovarian Cancer

Ovarian Epithelial Cancer

Fallopian Tube Cancer

Antineoplastic Agents

All Drugs and Chemicals

Antirheumatic Agents

Bevacizumab

Cyclophosphamide

Angiogenesis Inhibitors

Immunosuppressive Agents

Immunologic Factors

Antineoplastic Agents, Alkylating

Alkylating Agents

Antineoplastic Agents, Immunological

Growth Inhibitors

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.

Ursula Matulonis, MD

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.

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.

Sequential Angiogenic Blockade for the Treatment of Recurrent Mullerian Malignancies

Pilot Study of Sequential Angiogenic Blockade for the Treatment of Recurrent Mullerian Malignancies

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.

All grade 3-5 gastrointestinal perforation events based on CTCAEv3 as reported on case report forms.

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.

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.

OS estimated using Kaplan-Meier methods is defined as the time from study entry to death or date last known alive.

Massachusetts General Hospital

Brigham and Women's Hospital

Genentech, Inc.

Dana-Farber Cancer Institute

Medical Oncologist

Maximum grade toxicity by type was first calculated. Serious AEs were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher per CTCAEv3. Other AEs were defined as events with treatment-attribution of possible, probable or definite and grades 1 or 2 per CTCAEv3.

Patients were given a regimen of sequential antiangiogenic blockade and disease assessed serologically and radiologically every 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.

Bevacizumab Then Cyclophosphamide With Bevacizumab

Age, Continuous

Sex: Female, Male

United States

Region of Enrollment

Ursula A. Matulonis, MD

The analysis dataset is comprised of all treated participants.

Therapy Completion Rate

Grade 3-5 Gastrointestinal Perforation

At baseline, participants were classified as platinum sensitive or platinum resistant. Platinum sensitive is defined as having had a \>6 month interval since last receiving platinum therapy prior to disease recurrence.

Platinum Sensitive

At baseline, participants were classified as platinum sensitive or platinum resistant. Platinum resisistant is defined as having had a \</=6 month interval since last receiving platinum therapy prior to disease recurrence.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Sequential Angiogenic Blockade for the Treatment of Recurrent Mullerian Malignancies	NCT00856180	Ovarian Cancer Peritoneal Canc... Fallopian Tube ...	Bevacizumab Cyclophosphamid...	18 Years -	Dana-Farber Cancer Institute
Sequential Angiogenic Blockade for the Treatment of Recurrent Mullerian Malignancies	NCT00856180	Ovarian Cancer Peritoneal Canc... Fallopian Tube ...	Bevacizumab Cyclophosphamid...	18 Years -	Dana-Farber Cancer Institute
Sequential Angiogenic Blockade for the Treatment of Recurrent Mullerian Malignancies	NCT00856180	Ovarian Cancer Peritoneal Canc... Fallopian Tube ...	Bevacizumab Cyclophosphamid...	18 Years -	Dana-Farber Cancer Institute

Spots Global Cancer Trial Database for mullerian malignancies