Brief Title
Sequential Angiogenic Blockade for the Treatment of Recurrent Mullerian Malignancies
Official Title
Pilot Study of Sequential Angiogenic Blockade for the Treatment of Recurrent Mullerian Malignancies
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.
Study Phase
Phase 2
Study Type
Interventional
Primary Outcome
Therapy Completion Rate
Secondary Outcome
Clinical Benefit Response Rate
Condition
Ovarian Cancer
Intervention
Bevacizumab
Study Arms / Comparison Groups
Bevacizumab then Cyclophosphamide with Bevacizumab
Description: 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.
Publications
* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.
Recruitment Information
Recruitment Status
Drug
Estimated Enrollment
20
Start Date
February 2009
Completion Date
January 2014
Primary Completion Date
April 2010
Eligibility 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
Gender
All
Ages
18 Years - N/A
Accepts Healthy Volunteers
No
Contacts
Ursula Matulonis, MD, ,
Location Countries
United States
Location Countries
United States
Administrative Informations
NCT ID
NCT00856180
Organization ID
08-148
Responsible Party
Principal Investigator
Study Sponsor
Dana-Farber Cancer Institute
Collaborators
Massachusetts General Hospital
Study Sponsor
Ursula Matulonis, MD, Principal Investigator, Dana-Farber Cancer Institute
Verification Date
August 2018