- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT00856180
Sequential Angiogenic Blockade for the Treatment of Recurrent Mullerian Malignancies
Pilot Study of Sequential Angiogenic Blockade for the Treatment of Recurrent Mullerian Malignancies
Study Overview
Status
Conditions
Intervention / Treatment
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 Type
Enrollment (Actual)
Phase
- Phase 2
Contacts and Locations
Study Locations
-
-
Massachusetts
-
Boston, Massachusetts, United States, 02115
- Dana-Farber Cancer Institute
-
Boston, Massachusetts, United States, 02114
- Massachusetts General Hospital
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
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
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: N/A
- Interventional Model: Single Group Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
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 Names:
Other Names:
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
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.
|
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).
|
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.
|
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).
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
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.
|
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).
|
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.
|
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..
|
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.
|
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.
|
Collaborators and Investigators
Sponsor
Investigators
- Principal Investigator: Ursula Matulonis, MD, Dana-Farber Cancer Institute
Publications and helpful links
Study record dates
Study Major Dates
Study Start
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Urogenital Neoplasms
- Neoplasms by Site
- Genital Neoplasms, Female
- Adnexal Diseases
- Fallopian Tube Diseases
- Neoplasms
- Fallopian Tube Neoplasms
- Physiological Effects of Drugs
- Molecular Mechanisms of Pharmacological Action
- Antirheumatic Agents
- Antineoplastic Agents
- Immunosuppressive Agents
- Immunologic Factors
- Antineoplastic Agents, Alkylating
- Alkylating Agents
- Myeloablative Agonists
- Antineoplastic Agents, Immunological
- Angiogenesis Inhibitors
- Angiogenesis Modulating Agents
- Growth Substances
- Growth Inhibitors
- Cyclophosphamide
- Bevacizumab
Other Study ID Numbers
- 08-148
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
Clinical Trials on Ovarian Cancer
-
Roswell Park Cancer InstituteCompletedFallopian Tube Carcinoma | Primary Peritoneal Carcinoma | Stage IIA Ovarian Cancer | Stage IIB Ovarian Cancer | Stage IIC Ovarian Cancer | Stage IIIA Ovarian Cancer | Stage IIIB Ovarian Cancer | Stage IIIC Ovarian Cancer | Stage IV Ovarian Cancer | Stage IA Ovarian Cancer | Stage IB Ovarian Cancer | Stage IC... and other conditionsUnited States
-
City of Hope Medical CenterNational Cancer Institute (NCI)CompletedCancer Survivor | Stage IIIA Ovarian Epithelial Cancer | Stage IIIB Ovarian Epithelial Cancer | Stage IIIC Ovarian Epithelial Cancer | Stage IIA Ovarian Epithelial Cancer | Stage IIB Ovarian Epithelial Cancer | Stage IIC Ovarian Epithelial Cancer | Stage IA Ovarian Epithelial Cancer | Stage IB Ovarian... and other conditionsUnited States
-
Massachusetts General HospitalJohns Hopkins University; M.D. Anderson Cancer Center; National Cancer Institute... and other collaboratorsRecruitingOvarian Neoplasms | Fallopian Tube Neoplasms | Stage III Ovarian Cancer AJCC v8 | Stage IIIA Ovarian Cancer AJCC v8 | Stage IIIA1 Ovarian Cancer AJCC v8 | Stage IIIA2 Ovarian Cancer AJCC v8 | Stage IIIB Ovarian Cancer AJCC v8 | Stage IIIC Ovarian Cancer AJCC v8 | Stage IV Ovarian Cancer AJCC v8 | Stage... and other conditionsUnited States
-
Gynecologic Oncology GroupNational Cancer Institute (NCI)CompletedOvarian Clear Cell Cystadenocarcinoma | Ovarian Endometrioid Adenocarcinoma | Ovarian Seromucinous Carcinoma | Ovarian Serous Cystadenocarcinoma | Stage IV Ovarian Germ Cell Tumor | Ovarian Sarcoma | Malignant Ovarian Epithelial Tumor | Ovarian Carcinosarcoma | Ovarian Brenner Tumor | Ovarian Mucinous... and other conditionsUnited States
-
Gynecologic Oncology GroupNational Cancer Institute (NCI)CompletedStage IIA Fallopian Tube Cancer | Stage IIA Ovarian Cancer | Stage IIB Fallopian Tube Cancer | Stage IIB Ovarian Cancer | Stage IIC Fallopian Tube Cancer | Stage IIC Ovarian Cancer | Stage IIIA Fallopian Tube Cancer | Stage IIIA Ovarian Cancer | Stage IIIA Primary Peritoneal Cancer | Stage IIIB Fallopian... and other conditionsUnited States
-
University of WashingtonNational Cancer Institute (NCI)CompletedCaregiver | Stage IIIA Ovarian Cancer | Stage IIIB Ovarian Cancer | Stage IIIC Ovarian Cancer | Stage IV Ovarian CancerUnited States
-
Sidney Kimmel Cancer Center at Thomas Jefferson...CompletedStage I Breast Cancer | Stage I Uterine Corpus Cancer | Stage II Uterine Corpus Cancer | Stage III Uterine Corpus Cancer | Stage II Breast Cancer | Stage IIIA Breast Cancer | Stage IIIB Breast Cancer | Stage IA Breast Cancer | Stage IB Breast Cancer | Stage IIA Breast Cancer | Stage IIB Breast Cancer | Stage... and other conditionsUnited States
-
Eve RodlerNot yet recruitingBreast Cancer | Ovarian Cancer | Breast Neoplasm | Breast Carcinoma | Breast Cancer Stage IV | Breast Cancer Stage I | Breast Cancer Stage II | Invasive Breast Cancer | Cancer, Breast | Breast Cancer Stage III | Ovary Cancer | Malignant Tumor of Breast | Ovarian Cancer Stage IIIC | Ovarian Cancer Stage IV | Ovarian Cancer... and other conditionsUnited States
-
Gynecologic Oncology GroupNational Cancer Institute (NCI)RecruitingStage IIIA Ovarian Cancer | Stage IIIB Ovarian Cancer | Stage IIIC Ovarian Cancer | Stage IV Ovarian CancerUnited States
-
Centre Leon BerardCancer Côte d'or registry; Cancer Calvados registryUnknownOvarian Epithelial CancerFrance
Clinical Trials on Cyclophosphamide
-
Children's Hospital Los AngelesLucile Packard Children's HospitalTerminatedMetabolic Diseases | Stem Cell Transplantation | Chronic Granulomatous Disease | Bone Marrow Transplantation | Thalassemia | Wiskott-Aldrich Syndrome | Genetic Diseases | Peripheral Blood Stem Cell Transplantation | Pediatrics | Diamond-Blackfan Anemia | Allogeneic Transplantation | Combined Immune Deficiency | X-linked Lymphoproliferative Disease
-
Medical College of WisconsinNational Cancer Institute (NCI); National Heart, Lung, and Blood Institute... and other collaboratorsCompletedAnemia, AplasticUnited States
-
Columbia UniversityUnknownSevere Combined Immunodeficiency | Fanconi Anemia | Bone Marrow Failure | OsteopetrosisUnited States
-
National Cancer Institute, NaplesImmatics Biotechnologies GmbH; CureVac; European Commission -FP7-Health-2013-Innovation-1CompletedHepatocellular CarcinomaBelgium, Germany, Italy, Spain, United Kingdom
-
Centre Oscar LambretCompleted
-
Mahidol UniversityTerminatedRenal Insufficiency | InfectionThailand
-
Eisai Inc.CompletedBreast Cancer | Ovarian Cancer | Prostate Cancer | Colon Cancer | Renal CancerUnited States
-
Baylor Research InstituteCompletedMalignant Melanoma Stage IVUnited States
-
University of Turin, ItalyUnknown
-
Merck KGaA, Darmstadt, GermanyCompleted