Sorafenib and Bevacizumab to Treat Ovarian, Fallopian and Peritoneal Cancer

November 3, 2020 updated by: Christina Annunziata, M.D., National Cancer Institute (NCI)

A Phase II Study of Sorafenib and Bevacizumab in Epithelial Ovarian, Fallopian, and Peritoneal Cancer

Background:

  • Sorafenib and bevacizumab are anti-cancer drugs that work by targeting the blood vessels that allow tumors to grow. Using the two drugs together may more effectively block the formation of blood vessels that feed tumors.
  • Sorafenib and bevacizumab both are approved by the Food and Drug Administration for use in other cancers but have not ovarian cancer. In a preliminary trial of this drug combination, however, tumors in 6 of 14 patients with ovarian cancer shrank.

Objectives:

  • To determine the safety and activity of the combination of sorafenib and bevacizumab for treating patients with ovarian, fallopian and peritoneal cancer.
  • To determine how sorafenib and bevacizumab may affect the cancer by measuring amounts of different proteins in small biopsy samples of tumor taken before starting treatment and after 6 weeks.

Eligibility:

  • Females 18 years of age and older with ovarian, fallopian, or peritoneal cancer whose disease has not responded to standard treatment or for which no standard treatment is available.
  • Patients must have not been previously treated with bevacizumab or must have had their disease worsen while taking bevacizumab-based therapy.

Design:

  • Patients take 200 mg of sorafenib by mouth twice a day Monday through Friday each week and 5 mg/kg of bevacizumab through a vein every 2 weeks.
  • Tumor biopsies and imaging scans (magnetic resonance imaging (MRI) and positron emission tomography (PET) are done before treatment, 3 days after beginning treatment, and 6 weeks into therapy.
  • Computed tomography (CT) or other imaging tests are done every 8 weeks to evaluate response to treatment.
  • History, physical examinations, blood and urine tests are done periodically during treatment for health checks and research purposes.
  • About 74 patients are to be enrolled in the trial.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

Background:

Sorafenib is an inhibitor of wild-type and mutant proto-oncogene BRaf (B-Raf) and proto-oncogene c-Raf (c-Raf) kinase isoforms in vitro, but it also inhibits mitogen-activated protein kinase (p38), proto-oncogene c-kit (c-kit), vascular endothelial growth factor receptor 2 (VEGFR-2) and platelet-derived growth factor (PDGFR)-Beta affecting tumor growth as well as possibly promoting apoptosis by events downstream of c-Raf.

Bevacizumab is a humanized immunoglobulin G 1 (IgG1) monoclonal antibody (MAb) that binds all biologically active isoforms of human vascular endothelial growth factor (vascular endothelial growth factor (VEGF), or VEGF-A) with high affinity (kd = 1.1nM).

Phase I trial of sorafenib and bevacizumab administered concurrently showed activity of the combination in patients with refractory ovarian cancer.

Objectives:

Determine the activity and tolerability of the combination bevacizumab and sorafenib in patients with refractory or recurrent epithelial ovarian, fallopian, or peritoneal cancer in patients who are bevacizumab-naive or bevacizumab-resistant.

Eligibility:

Adults with histologically documented refractory or recurrent epithelial ovarian, fallopian, or peritoneal cancer.

Patients must be off prior chemotherapy, radiation therapy, hormonal therapy, or biological therapy for at least 4 weeks.

Patients must have an Eastern Cooperative Oncology Group (ECOG) of 1 or less.

Patients must have disease that is amenable to biopsy.

Patients must have not been previously treated with bevacizumab or must have progressed on prior bevacizumab-based therapy.

Design:

Patients will be stratified on entrance to the trial based on their previous exposure to bevacizumab to either strata A (bevacizumab-naive patients) or strata B (patients previously treated with bevacizumab).

Patients will receive oral sorafenib 200 mg twice daily 5 out of 7 days each week and intravenous bevacizumab 5 mg/kg every two weeks.

Tumor biopsies will be obtained from patients before treatment and six weeks into therapy. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and fludeoxyglucose 18F-positron emission tomography (FDG-PET) will be obtained from patients before treatment, on day 3 of treatment, and six weeks into therapy.

Patients will be evaluated for response every 8 weeks using the Response Evaluation Criteria in Solid Tumors (RECIST) criteria.

Approximately 74 patients will be needed to achieve the objectives of the trial.

Study Type

Interventional

Enrollment (Actual)

55

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Maryland
      • Bethesda, Maryland, United States, 20892
        • National Institutes of Health Clinical Center, 9000 Rockville Pike

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

  • ELIGIBILITY CRITERIA:

Histopathologically documented recurrent/refractory epithelial ovarian cancer, primary peritoneal cancer or fallopian tube cancer from a previous biopsy verified by the Laboratory of Pathology, National Cancer Institute (NCI).

-Recurrent/refractory disease defined as progression within 6 months of upfront platinum-containing therapy or progression after subsequent therapy in previously relapsed patients.

Disease amenable to percutaneous or skin biopsy as determined by an associate investigator and a member of the interventional team.

Patient willingness to have biopsies performed.

Measurable disease defined as tumor greater than or equal to 1 cm.

Age greater than or equal to 18 years.

Life expectancy of more than 3 months.

Performance status of 0 to 1 according to the Eastern Cooperative Oncology Group (ECOG) criteria.

Adequate organ function as defined below:

Laboratory Test Required value

  • Leukocytes greater than or equal to 3,000/ microliter
  • Absolute neutrophil count greater than or equal to 1,200/ microliter
  • Platelets greater than or equal to 100,000/ microliter
  • Total bilirubin less than or equal to 1.5 times the institutional upper limits of normal
  • Aspartate aminotransferase (AST) serum glutamic oxaloacetic transaminase (SGOT) and alanine aminotransferase (ALT) serum glutamic pyruvic transaminase (SGPT) less than or equal to 2.5 times the institutional upper limit of normal
  • Creatinine less than or equal to 1.5 mg/dL

OR

  • Creatinine clearance greater than or equal to 45 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal.
  • Activated partial thromboplastin time (PTT) less than 1.5 times the institutional upper limits of normal
  • Prothrombin Time (PT)/ International normalized ratio (INR) less than 1.5 times the institutional upper limits of normal
  • Amylase and Lipase Less than institutional upper limits of normal

Patients must have a urine protein/creatinine ratio (UPC) less than 1.0 for enrollment.

No surgery, radiation therapy, chemotherapy, immunotherapy, biotherapy, or hormonal therapy (exception raloxifene for bone health) within four weeks (6 weeks for mitomycin C, carboplatin, or nitrosoureas);

No metabolically active complimentary or alternative therapy for at least 1 week, defined as any ingested or administered chemical substances including herbal medications, but not including acupuncture, hypnosis, meditation, or other non-chemical treatments.

No monoclonal antibody therapy for at least 6 weeks.

Patients must have recovered from any acute toxicity related to prior therapy, including surgery. Toxicity should be less than or equal to grade 1 (as defined by Common Terminology Criteria for Adverse Events (CTCAE v3) or returned to baseline. Peripheral neuropathy less than or equal to grade 2 will be allowed as this patient population has universally been treated with platinum-based chemotherapy with residual neuropathy being a common occurrence.

No other invasive malignancies within the past two years (with the exception of non-melanoma skin cancers, non-invasive bladder cancer, stage I endometrial cancer or cervical cancer synchronous to the ovarian cancer diagnosis and cured by surgical resection).

Ability to understand and sign an informed consent form.

Patients who require hematopoietic growth factor support (e.g. epogen, darbepoetin), Non-steroidal anti-inflammatory drugs (NSAIDs), and other maintenance medications prior to study entry will be allowed to continue their supportive therapies.

Ability to tolerate orally administered medications.

Contraception is not a consideration as these patients have all had surgical removal of their reproductive organs. Pregnant women are excluded from this study because BAY 43-9006 and bevacizumab are agents with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with BAY 43-9006 and/or bevacizumab, breastfeeding should be discontinued if the mother is treated with BAY 43-9006 and/or bevacizumab.

There is no limit on the number of prior regimens with which a patient has been treated.

Patients who have been treated with bevacizumab previously are eligible for the trial if they have progressed while on bevacizumab-based therapy.

-Disease progression on bevacizumab therapy will be defined as documented increase in disease based on imaging while the patient is receiving bevacizumab or within three months of their last dose of bevacizumab.

Patients must be at least 6 weeks from their last dose of bevacizumab prior to being enrolled on study.

Patients who have a healed fistula greater than 28 days prior to enrollment are eligible (refer to section 3.2.15 for patients who have had prior bevacizumab)

EXCLUSION CRITERIA:

Serious non-healing wounds (including wounds healing by secondary intention), acute or non-healing ulcers, or bone fractures within 3 months of enrollment.

Moderate or massive hemoptysis or surgery within 28 days of enrollment.

Ongoing treatment with any other investigational agents.

Brain metastases

  • Patients with central nervous system (CNS) metastases within the past 2 years are ineligible. Patients who have had CNS disease curatively treated and without recurrence for 2 years may be eligible. but any CNS disease that has not undergone curative therapy with radiation, gamma knife, and/or surgical therapy are ineligible.
  • CNS imaging will not be mandated for all patients. However, if there is clinical suspicion of CNS involvement, a contrast computed tomography (CT) or magnetic resonance imaging (MRI) of the brain will be required.
  • Patients with CNS metastases may not be on steroids for the purpose of CNS disease or edema control.
  • Patients with CNS disease must be on an anti-seizure medication and that medication cannot be a CYPP4503A modulating agent.

Thrombotic or embolic events within the past 6 months such as a cerebrovascular accident (including transient ischemic attacks), pulmonary embolism, unstable angina, or myocardial infarction. Fully treated deep vein thrombosis no longer requiring anticoagulation will be allowed.

Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure (American Heart Association (AHA) Class II or worse), unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.

-Patients with evidence of active infection will become eligible for reconsideration 7 days after completing antibiotic therapy.

Human immunodeficiency virus (HIV)-positive patients receiving combination anti-retroviral therapy are excluded from the study because of possible pharmacokinetic interactions with sorafenib, bevacizumab, and/or the combination.

Hypertension defined as systolic blood pressure greater than 150 mmHg or diastolic pressure greater than 90 mmHg despite optimal medical management.

Therapeutic anticoagulation with coumadin, heparins, or heparinoids.

Evidence of a bleeding diathesis.

History of high grade varices or arteriovenous malformations.

Patients previously treated with sorafenib will not be eligible for this trial.

Fistula or bowel obstruction or perforation in the 28 days prior to enrollment.

Patients must not be taking the cytochrome p450 (CYP450) enzyme-inducing drugs phenytoin, carbamazepine, phenobarbital, St. John's wort, or rifampin.

For patients who have been previously treated with bevacizumab, any severe toxicity associated with bevacizumab while the patient was being treated with the agent will make the patient ineligible for the trial. This includes bevacizumab-induced hypertensive crisis, arterial thromboembolic events (including cardiac ischemia or cerebrovascular ischemia or other arterial thrombosis), nephrotic syndrome, gastrointestinal perforation, serious hemorrhage, and fistulas (unless the fistula completely resolved while the patient was still on bevacizumab or it has been surgically corrected).

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

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: BAY 43-9006 + Bevacizumab
BAY 43-9006 (sorafenib) + Bevacizumab
Drug: Bevacizumab
bevacizumab 5 mg/kg intravenous (IV) every two weeks
Other Names:
  • Avastin
Drug: BAY 43-9006
BAY 43-9006 200 mg po (by mouth) twice daily 5 out of 7 days each week (Mon-Fri)
Other Names:
  • sorafenib

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Clinical Response Rate.
Time Frame: patients were followed for a median of 18 weeks (range 1-116 weeks)
Clinical response rate is defined as the percentage of participants with a complete response (CR) or partial response (PR) per the Response Evaluation Criteria in Solid Tumors (RECIST). CR is disappearance of all target lesions. PR is at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD. Progressive disease (PD) is a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. Stable disease (SD) is neither sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started lasting at least 6 months.
patients were followed for a median of 18 weeks (range 1-116 weeks)

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Progression-free Survival
Time Frame: up to 28 months
Progression free survival is defined by the number of weeks between the first day of treatment and the date of cancer progression.
up to 28 months
Number of Participants With Adverse Events
Time Frame: up to 28 months
Here is the number of participants with adverse events. For a detailed list of adverse events, see the adverse event module.
up to 28 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

National Cancer Institute (NCI)

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

December 12, 2006

Primary Completion (Actual)

June 26, 2014

Study Completion (Actual)

September 27, 2014

Study Registration Dates

First Submitted

February 15, 2007

First Submitted That Met QC Criteria

February 15, 2007

First Posted (Estimate)

February 19, 2007

Study Record Updates

Last Update Posted (Actual)

November 23, 2020

Last Update Submitted That Met QC Criteria

November 3, 2020

Last Verified

November 1, 2020

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 070058
  • 07-C-0058

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

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.

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