Sequential Angiogenic Blockade for the Treatment of Recurrent Mullerian Malignancies

This study has been completed.
Sponsor:
Collaborators:
Massachusetts General Hospital
Brigham and Women's Hospital
Genentech, Inc.
Information provided by (Responsible Party):
Ursula A. Matulonis, MD, Dana-Farber Cancer Institute
ClinicalTrials.gov Identifier:
NCT00856180
First received: February 25, 2009
Last updated: April 13, 2016
Last verified: March 2016
  Purpose
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.

Condition Intervention Phase
Ovarian Cancer
Peritoneal Cancer
Fallopian Tube Cancer
Drug: Bevacizumab
Drug: Cyclophosphamide
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Pilot Study of Sequential Angiogenic Blockade for the Treatment of Recurrent Mullerian Malignancies

Resource links provided by NLM:


Further study details as provided by Dana-Farber Cancer Institute:

Primary Outcome Measures:
  • 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). ] [ Designated as safety issue: No ]
    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). ] [ Designated as safety issue: Yes ]
    All grade 3-5 gastrointestinal perforation events based on CTCAEv3 as reported on case report forms.


Secondary Outcome Measures:
  • 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). ] [ Designated as safety issue: No ]
    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.. ] [ Designated as safety issue: No ]
    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. ] [ Designated as safety issue: No ]
    OS estimated using Kaplan-Meier methods is defined as the time from study entry to death or date last known alive.


Enrollment: 20
Study Start Date: February 2009
Study Completion Date: January 2014
Primary Completion Date: April 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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.
Drug: Bevacizumab
Other Name: Avastin
Drug: Cyclophosphamide
Other Name: cytoxan

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.

  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Histologically confirmed diagnosis of epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube cancer.
  • Recurrent cancer and have received and failed a previous platinum-based chemotherapy regimen.
  • Up to 2 prior lines of chemotherapy in the recurrent setting (either platinum-based or non-platinum regimens). Biologic therapies count as a prior line but hormonal therapies do not count.
  • Platinum-resistant or platinum-sensitive recurrence.
  • Must be able to take oral medications and have no evidence of bowel obstruction or partial bowel obstruction
  • Measurable disease by either RECIST or Rustin criteria
  • No chemotherapy, radiation therapy, nor biologic therapy within the last three weeks prior to initiating therapy
  • ECOG score of 0 or 1
  • Life expectancy of 12 weeks or greater
  • 18 years of age or older
  • Laboratory values as outlined in the protocol
  • Patients with treated limited stage basal cell or squamous cell carcinoma of the skin or carcinoma in situ of the breast or cervix are eligible. Subjects with stage I or II cancer treated with curative intent and no evidence of recurrent disease are also eligible.
  • No evidence of preexisting hypertension. If patient has hypertension, it must be controlled medically (less than 150/90) prior to starting bevacizumab
  • Normal blood coagulation parameters
  • No prior treatment with any other antiangiogenic agents or cyclophosphamide
  • For patients who have received prior doxorubicin or pegylated doxorubicin, LVEF must be 50% or greater.

Exclusion Criteria:

  • Current, recent (within 4 weeks of the first study infusion), or planned participation in an experimental drug study other than a Genentech-sponsored bevacizumab cancer study
  • Active malignancy, other than superficial basal cell and superficial squamous (skin) cell, or carcinoma in situ of the cervix within last five years
  • Uncontrolled diarrhea
  • Prior history of hypertensive crisis or hypertensive encephalopathy
  • NYHA Grade II or greater congestive heart failure
  • History of myocardial infarction or unstable angina within 6 months prior to Day 1
  • History of stroke or transient ischemic attack within 6 months prior to day 1
  • Known CNS disease, except for treated brain metastasis
  • Treated brain metastases are defined as having no evidence of progression or hemorrhage after treatment and no ongoing requirement for dexamethasone, as ascertained by clinical examination and brain imaging (MRI or CT) during the screening period. Anticonvulsants (stable dose) are allowed. Treatment for brain metastases may include whole brain radiotherapy (WBRT), radiosurgery (RS: Gamma Knife, LINAC, or equivalent) or a combination as deemed appropriate by the treating physician. Patients with CNS metastases treated by neurosurgical resection or brain biopsy performed within 3 months prior to day 1 will be excluded.
  • Significant vascular disease within 6 months prior to day 1
  • History of hemoptysis within 1 month prior to day 1
  • Evidence of bleeding diathesis or significant coagulopathy (in the absence of therapeutic anticoagulation)
  • Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to day 1 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 Day 1
  • History of abdominal fistula or gastrointestinal perforation within 6 months prior to Day 1
  • Serious, non-healing wound, active ulcer, or untreated bone fracture
  • Proteinuria as demonstrated by a UPC ratio of 1.0 or greater at screening
  • Known hypersensitivity to any component of bevacizumab
  • Pregnancy (positive pregnancy test) or lactation. Use of effective means of contraception (men and women) in subjects of child-bearing potential
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00856180

Locations
United States, Massachusetts
Massachusetts General Hospital
Boston, Massachusetts, United States, 02114
Dana-Farber Cancer Institute
Boston, Massachusetts, United States, 02115
Sponsors and Collaborators
Dana-Farber Cancer Institute
Massachusetts General Hospital
Brigham and Women's Hospital
Genentech, Inc.
Investigators
Principal Investigator: Ursula Matulonis, MD Dana-Farber Cancer Institute
  More Information

Publications:
Responsible Party: Ursula A. Matulonis, MD, Medical Oncologist, Dana-Farber Cancer Institute
ClinicalTrials.gov Identifier: NCT00856180     History of Changes
Other Study ID Numbers: 08-148 
Study First Received: February 25, 2009
Results First Received: April 13, 2016
Last Updated: April 13, 2016
Health Authority: United States: Institutional Review Board
Individual Participant Data  
Plan to Share IPD: No

Keywords provided by Dana-Farber Cancer Institute:
avastin
bevacizumab
cyclophosphamide
cytoxan
mullerian malignancies

Additional relevant MeSH terms:
Fallopian Tube Neoplasms
Genital Neoplasms, Female
Urogenital Neoplasms
Neoplasms by Site
Neoplasms
Fallopian Tube Diseases
Adnexal Diseases
Genital Diseases, Female
Bevacizumab
Cyclophosphamide
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Physiological Effects of Drugs
Growth Inhibitors
Antineoplastic Agents
Immunosuppressive Agents
Immunologic Factors
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Myeloablative Agonists

ClinicalTrials.gov processed this record on July 26, 2016