Bevacizumab With or Without Everolimus in Treating Patients With Recurrent or Persistent Ovarian Epithelial Cancer, Fallopian Tube Cancer, or Primary Peritoneal Cancer

Phase 2

Completed

Conditions: Recurrent Fallopian Tube Carcinoma
Recurrent Ovarian Carcinoma
Recurrent Primary Peritoneal Carcinoma

Interventions: Biological: Bevacizumab
Other: Laboratory Biomarker Analysis
Drug: Everolimus
Other: Placebo

Registration Number: NCT00886691

Lead Sponsor: GOG Foundation

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: Female

Target Recruitment: 150

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
Patients should be free of active infection requiring parenteral antibiotics (with the exception of uncomplicated urinary tract infection [UTI])
Recovery from effects of recent surgery, radiotherapy, or chemotherapy
- Any hormonal therapy directed at the malignant tumor must be discontinued at least one week prior to registration
- Any other prior therapy directed at the malignant tumor, including biological and immunologic agents, must be discontinued at least 3 weeks prior to registration (including small molecules and murine monoclonal antibodies); chimeric or human or humanized monoclonal antibodies (including bevacizumab) or vascular endothelial growth factor (VEGF) receptor fusion protein (including VEGF Trap, aflibercept) must be discontinued for at least 12 weeks prior to registration; no investigational therapy within 30 days prior to the first date of study treatment
Prior therapy:
- Patients must have had one prior platinum-based chemotherapeutic regimen for management of primary disease containing carboplatin, cisplatin, or another organoplatinum compound' this initial treatment may have included intraperitoneal therapy, consolidation, non-cytotoxic agents or extended therapy administered after surgical or non-surgical assessment
- Patients are allowed to receive, but are not required to receive, two additional cytotoxic regimens for management of recurrent or persistent disease, with no more than 1 non-platinum, non-taxane regimen
- Patients are allowed to receive, but are not required to receive, biologic (non-cytotoxic) therapy as part of their primary treatment regimen; patients must have NOT received any non-cytotoxic therapy for management of recurrent or persistent disease
- Patients who have received only one prior cytotoxic regimen (platinum-based regimen for management of primary disease), must have a platinum-free interval of less than 12 months, or have progressed during platinum-based therapy, or have persistent disease after a platinum-based therapy
- For the purposes of this study, poly (adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitors will be considered ?cytotoxic,? and prior treatment with PARP inhibitors for primary or recurrent disease WILL be allowed (either alone or in combination with chemotherapy)
Absolute neutrophil count (ANC) greater than or equal to 1,500/mcl
Platelets greater than or equal to 100,000/mcl
Creatinine less than or equal to 1.5 x institutional upper limit normal (ULN)
Bilirubin less than or equal to 1.5 x ULN
Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) less than or equal to 3 x ULN
Alkaline phosphatase less than or equal to 2.5 x ULN
Prothrombin time (PT) such that international normalized ratio (INR) is less than or equal to 1.5 x ULN (or an in-range INR, usually between 2 and 3, if a patient is on a stable dose of therapeutic warfarin for management of deep vein thrombosis including pulmonary embolism)
Partial thromboplastin time (PTT) less than or equal to 1.5 times the upper limit of normal
Fasting serum cholesterol less than or equal to 300 mg/dL OR less than or equal to 7.75 mmol/L AND
Fasting triglycerides less than or equal to 300 mg/dL or 3.42 mmol/L
Urine protein creatinine (UPC) ratio must be < 1.0 gm; if UPC ratio >= 1, collection of 24-hour urine measurement of urine protein is recommended; UPC ratio of spot urine is an estimation of the 24-hour urine protein excretion?a UPC ratio of 1 is roughly equivalent to a 24-hour urine protein of 1 gm
Patients of childbearing potential must have a negative serum pregnancy test prior to the study entry and be practicing an effective form of contraception
Patients must have signed an approved informed consent and authorization permitting the release of personal health information
Patients must meet pre-entry requirements
Patients with clinically significant cardiovascular disease; this includes:
- Uncontrolled hypertension, defined as systolic > 150 mm Hg or diastolic > 90 mm Hg
- Myocardial infarction or unstable angina within 6 months prior to registration
- New York Heart Association (NYHA) class II or greater congestive heart failure
- Serious cardiac arrhythmia requiring medication; this does not include asymptomatic, atrial fibrillation with controlled ventricular rate
- Patients who have received prior treatment with an anthracycline (including doxorubicin and or liposomal doxorubicin) and have an ejection fraction < 50%
- Common Terminology Criteria for Adverse Events (CTCAE) grade 2 or greater peripheral vascular disease (at least brief [< 24 hours (hrs)] episodes of ischemia managed non-surgically and without permanent deficit)

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
Patients with medical history or conditions not otherwise previously specified which in the opinion of the investigator should exclude participation in this study; the investigator can consult the Study Chair or Study Co-Chairs for uncertainty in this regard
Patients who are pregnant or nursing
Patients with active hepatitis B or C
- Laboratory confirmation to exclude hepatitis B and C is required in any patient considered at high risk for hepatitis B or C; risk factors can include:
  - You currently live in (or have lived in) Asia, Africa, Central and South America, Eastern Europe, Spain, Portugal, and Greece
  - Known or suspected past hepatitis B infection
  - Known or suspected past hepatitis C infection (including past interferon ?curative? treatment)
  - Blood transfusion(s) prior to 1990
  - Current or prior IV drug use
  - Current or prior dialysis
  - Household contact with hepatitis B or hepatitis C infected person(s)
  - Current or prior high-risk sexual activity
  - Body piercing or tattoos
  - Mother known to have hepatitis B
  - History suggestive of hepatitis B infection, e.g., dark urine, jaundice, right upper quadrant pain

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arm I (bevacizumab and everolimus)	Bevacizumab	Patients receive bevacizumab IV over 30-90 minutes on days 1 and 15 and everolimus PO QD on days 1-28.
Arm II (bevacizumab and placebo)	Bevacizumab	Patients receive bevacizumab as in Arm I and placebo PO QD on days 1-28.
Arm II (bevacizumab and placebo)	Laboratory Biomarker Analysis	Patients receive bevacizumab as in Arm I and placebo PO QD on days 1-28.
Arm I (bevacizumab and everolimus)	Laboratory Biomarker Analysis	Patients receive bevacizumab IV over 30-90 minutes on days 1 and 15 and everolimus PO QD on days 1-28.
Arm II (bevacizumab and placebo)	Placebo	Patients receive bevacizumab as in Arm I and placebo PO QD on days 1-28.
Arm I (bevacizumab and everolimus)	Everolimus	Patients receive bevacizumab IV over 30-90 minutes on days 1 and 15 and everolimus PO QD on days 1-28.

Primary Outcome Measures

Name	Time	Method
Progression-free Survival	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 Outcome Measures

Name	Time	Method
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	Progression-free survival and overall survival broken down by measurable disease status
The Proportion of Patients With Measurable Disease Who Have Objective Tumor Responses by Treatment.	Up to approximately 4 years and 6 months	Complete and Partial Tumor Response by RECIST 1.0
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.	Number of participants with a grade of 3 or higher during the treatment period.
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.	Response as evaluated by CA-125 levels.A CA 125 test measures the amount of the protein CA 125 (cancer antigen 125) in blood.CA 125 is a tumor marker recommended for clinical use in the diagnosis and management of ovarian cancer. CA-125 responses were assessed with Rustin criteria. Initial values had to be 2x ULN (upper limit of normal) within 2 weeks of starting therapy to be considered evaluable.Patient were evaluated by using best overall response while receiving study therapy.

Trial Locations

Locations (45): Oklahoma Cancer Specialists and Research Institute-Tulsa
🇺🇸
Tulsa, Oklahoma, United States
Cleveland Clinic Cancer Center/Fairview Hospital
🇺🇸
Cleveland, Ohio, United States
Riverside Methodist Hospital
🇺🇸
Columbus, Ohio, United States
Iowa-Wide Oncology Research Coalition NCORP
🇺🇸
Des Moines, Iowa, United States
Medical Oncology and Hematology Associates-Laurel
🇺🇸
Des Moines, Iowa, United States
University of Iowa/Holden Comprehensive Cancer Center
🇺🇸
Iowa City, Iowa, United States
Baylor All Saints Medical Center at Fort Worth
🇺🇸
Fort Worth, Texas, United States
Baystate Medical Center
🇺🇸
Springfield, Massachusetts, United States
Carolinas Medical Center/Levine Cancer Institute
🇺🇸
Charlotte, North Carolina, United States
Hillcrest Hospital Cancer Center
🇺🇸
Mayfield Heights, Ohio, United States
Carle Cancer Center
🇺🇸
Urbana, Illinois, United States
CoxHealth South Hospital
🇺🇸
Springfield, Missouri, United States
Cooper Hospital University Medical Center
🇺🇸
Camden, New Jersey, United States
Iowa Methodist Medical Center
🇺🇸
Des Moines, Iowa, United States
Reading Hospital
🇺🇸
West Reading, Pennsylvania, United States
Iowa Lutheran Hospital
🇺🇸
Des Moines, Iowa, United States
Rush University Medical Center
🇺🇸
Chicago, Illinois, United States
University of Pennsylvania/Abramson Cancer Center
🇺🇸
Philadelphia, Pennsylvania, United States
Mercy Hospital Springfield
🇺🇸
Springfield, Missouri, United States
Memorial Sloan Kettering Cancer Center
🇺🇸
New York, New York, United States
UC Irvine Health/Chao Family Comprehensive Cancer Center
🇺🇸
Orange, California, United States
Providence Saint Joseph Medical Center/Disney Family Cancer Center
🇺🇸
Burbank, California, United States
Sudarshan K Sharma MD Limited-Gynecologic Oncology
🇺🇸
Hinsdale, Illinois, United States
McFarland Clinic PC - Ames
🇺🇸
Ames, Iowa, United States
MetroHealth Medical Center
🇺🇸
Cleveland, Ohio, United States
Case Western Reserve University
🇺🇸
Cleveland, Ohio, United States
Cleveland Clinic Foundation
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Cleveland, Ohio, United States
UH Seidman Cancer Center at Lake Health Mentor Campus
🇺🇸
Mentor, Ohio, United States
University of Wisconsin Hospital and Clinics
🇺🇸
Madison, Wisconsin, United States
Women and Infants Hospital
🇺🇸
Providence, Rhode Island, United States
Cedars Sinai Medical Center
🇺🇸
Los Angeles, California, United States
Medical Oncology and Hematology Associates-Des Moines
🇺🇸
Des Moines, Iowa, United States
Mercy Medical Center - Des Moines
🇺🇸
Des Moines, Iowa, United States
Jefferson Abington Hospital
🇺🇸
Abington, Pennsylvania, United States
Gynecologic Oncology Group of Arizona
🇺🇸
Phoenix, Arizona, United States
University of Colorado Hospital
🇺🇸
Aurora, Colorado, United States
Indiana University/Melvin and Bren Simon Cancer Center
🇺🇸
Indianapolis, Indiana, United States
Saint Vincent Hospital and Health Care Center
🇺🇸
Indianapolis, Indiana, United States
Saint Joseph Mercy Hospital
🇺🇸
Ann Arbor, Michigan, United States
Nebraska Methodist Hospital
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Omaha, Nebraska, United States
Duke University Medical Center
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Durham, North Carolina, United States
University of Oklahoma Health Sciences Center
🇺🇸
Oklahoma City, Oklahoma, United States
LDS Hospital
🇺🇸
Salt Lake City, Utah, United States
The Hospital of Central Connecticut
🇺🇸
New Britain, Connecticut, United States
AnMed Health Cancer Center
🇺🇸
Anderson, South Carolina, United States