A Phase II Randomized, Double-Blinded Evaluation of Oral Everolimus (RAD001) Plus Bevacizumab vs. Oral Placebo Plus Bevacizumab in the Treatment of Recurrent or Persistent Epithelial Ovarian, Fallopian Tube or Primary Peritoneal Cancer
Overview
- Phase
- Phase 2
- Intervention
- Bevacizumab
- Conditions
- Recurrent Fallopian Tube Carcinoma
- Sponsor
- GOG Foundation
- Enrollment
- 150
- Locations
- 45
- Primary Endpoint
- Progression-free Survival
- Status
- Completed
- Last Updated
- 4 years ago
Overview
Brief Summary
This randomized phase II trial studies how well bevacizumab with or without everolimus works in treating patients with recurrent or persistent ovarian epithelial cancer, fallopian tube cancer, or primary peritoneal cancer. Monoclonal antibodies, such as bevacizumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Everolimus may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Bevacizumab and everolimus may also stop the growth of tumor cells by blocking blood flow to the tumor. It is not yet known whether bevacizumab is more effective when given together with or without everolimus in treating ovarian epithelial cancer, fallopian tube cancer, or primary peritoneal cancer.
Detailed Description
PRIMARY OBJECTIVES: I. To estimate the progression-free survival hazard ratio of the combination of oral everolimus (RAD001) and bevacizumab compared to oral placebo and bevacizumab in patients with persistent or recurrent ovarian, fallopian tube, or primary peritoneal cancer. SECONDARY OBJECTIVES: I. To determine the nature and degree of toxicity of oral everolimus (or placebo) plus bevacizumab. II. To characterize and compare progression-free survival and overall survival in patients with measurable disease (Response Evaluation Criteria in Solid Tumors \[RECIST\] criteria) and patients with detectable (non-measurable) disease. III. To estimate the proportion of patients with measurable disease who have objective tumor responses by treatment. IV. To provide descriptive information about cancer antigen (CA)-125 responses by regimen and where possible by objective tumor responses. OUTLINE: Patients are randomized to 1 of 2 treatment arms. ARM I: Patients receive bevacizumab intravenously (IV) over 30-90 minutes on days 1 and 15 and everolimus orally (PO) once daily (QD) on days 1-28. ARM II: Patients receive bevacizumab as in Arm I and placebo PO QD on days 1-28. In both arms, courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed every 3 months for 2 years and then every 6 months for 3 years.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Patients must have recurrent or persistent epithelial ovarian, fallopian tube, or primary peritoneal carcinoma; histologic documentation of the original primary tumor is required via the pathology report
- •Patients must have measurable disease or detectable (non-measurable) disease:
- •Measurable disease is defined as at least one lesion that can be accurately measured in at least one dimension (longest dimension to be recorded); each lesion must be greater than or equal to 10 mm when measured by computed tomography (CT), magnetic resonance imaging (MRI) or caliper measurement by clinical exam; or greater than or equal to 20 mm when measured by chest x-ray; lymph nodes must be greater than or equal to 15 mm in short axis when measured by CT or MRI
- •Detectable disease in a patient is defined as one who does not have measurable disease but has at least one of the following conditions:
- •Baseline values of CA-125 at least 2 x upper limit of normal (ULN)
- •Ascites and/or pleural effusion attributed to tumor
- •Solid and/or cystic abnormalities on radiographic imaging that do not meet RECIST 1.1 definitions for target lesions
- •Patients in the measurable disease cohort must have at least one ?target lesion? to be used to assess response on this protocol as defined by RECIST 1.1; tumors within a previously irradiated field will be designated as ?non-target? lesions unless progression is documented or a biopsy is obtained to confirm persistence at least 90 days following completion of radiation therapy
- •Patients must not be eligible for a higher priority Gynecologic Oncology Group (GOG) protocol, if one exists; in general, this would refer to any active GOG phase III protocol or Rare Tumor Protocol for the same patient population
- •Patients who have had one prior treatment must have a GOG performance status of 0, 1, or 2; patients who have had two or three prior treatments must have a GOG performance status of 0 or 1
Exclusion Criteria
- •Patients who have received prior everolimus or any other mammalian target of rapamycin (mTOR) inhibitor
- •Patients with other invasive malignancies, with the exception of non-melanoma skin cancer and other specific malignancies, are excluded if there is any evidence of other malignancy being present within the last three years; patients are also excluded if their previous cancer treatment contraindicates this protocol therapy
- •Patients who have received prior radiotherapy to any portion of the abdominal cavity or pelvis OTHER THAN for the treatment of ovarian, fallopian tube or primary peritoneal cancer within the last three years are excluded; prior radiation for localized cancer of the breast, head and neck, or skin is permitted, provided that it was completed more than three years prior to registration, and the patient remains free of recurrent or metastatic disease
- •Patients who have received prior chemotherapy for any abdominal or pelvic tumor OTHER THAN for the treatment of ovarian, fallopian tube or primary peritoneal cancer within the last three years are excluded; patients may have received prior adjuvant chemotherapy for localized breast cancer, provided that it was completed more than three years prior to registration, and the patient remains free of recurrent or metastatic disease
- •Patients with serious non-healing wound, ulcer, or bone fracture; this includes history of abdominal fistula, gastrointestinal perforation or intra-abdominal abscess within 28 days prior to the first date of study treatment
- •Patients with active bleeding or pathologic conditions that carry high risk of bleeding, such as known bleeding disorder, coagulopathy, or tumor involving major vessels
- •Patients with history or evidence upon physical examination of central nervous system (CNS) disease, including primary brain tumor, seizures not controlled with standard medical therapy, any brain metastases, or history of cerebrovascular accident (CVA, stroke), transient ischemic attack (TIA) or subarachnoid hemorrhage within six months prior to the first date of study treatment
- •Known hypersensitivity to murine or chimeric antibodies
- •Major surgery within 28 days prior to the first date of study treatment
- •Patients with clinical symptoms or signs of gastrointestinal obstruction and patients who require parenteral hydration and/or nutrition
Arms & Interventions
Arm I (bevacizumab and everolimus)
Patients receive bevacizumab IV over 30-90 minutes on days 1 and 15 and everolimus PO QD on days 1-28.
Intervention: Bevacizumab
Arm I (bevacizumab and everolimus)
Patients receive bevacizumab IV over 30-90 minutes on days 1 and 15 and everolimus PO QD on days 1-28.
Intervention: Everolimus
Arm I (bevacizumab and everolimus)
Patients receive bevacizumab IV over 30-90 minutes on days 1 and 15 and everolimus PO QD on days 1-28.
Intervention: Laboratory Biomarker Analysis
Arm II (bevacizumab and placebo)
Patients receive bevacizumab as in Arm I and placebo PO QD on days 1-28.
Intervention: Bevacizumab
Arm II (bevacizumab and placebo)
Patients receive bevacizumab as in Arm I and placebo PO QD on days 1-28.
Intervention: Laboratory Biomarker Analysis
Arm II (bevacizumab and placebo)
Patients receive bevacizumab as in Arm I and placebo PO QD on days 1-28.
Intervention: Placebo
Outcomes
Primary Outcomes
Progression-free Survival
Time Frame: Duration of time from start of treatment to time of progression, approximately 4 years and 6 months.
The time from randomization until disease progression, death, or date of last contact. Endpoints are progression or death. Patients who are not observed with an endpoint are censored. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) as an 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.
Secondary Outcomes
- Characterize and Compare Progression-free Survival and Overall Survival in Patients With Measurable Disease (RECIST Criteria) and Patients With Detectable (Non-measurable) Disease(Continued until disease progression, assessed up to approximately 4 years and 6 months)
- The Proportion of Patients With Measurable Disease Who Have Objective Tumor Responses by Treatment.(Up to approximately 4 years and 6 months)
- Incidence of Adverse Events as Assessed by Common Terminology Criteria for Adverse Events Version 4.0 (CTCAE v4.0)(All Adverse Events (AEs) and Serious Adverse Events (SAEs) occurring during treatment and up to 30 days after stopping the study treatment, approximately 4 years and 6 months.)
- Percentage of Participants With at Least One Cancer Antigen 125 (CA-125) Response(Prior to each cycle of treatment. Then follow-up every three months for 2 years , then every 6 months for 3 years. Duration was approximately 4 years and 6 months.)