Sorafenib and Bevacizumab to Treat Ovarian, Fallopian and Peritoneal Cancer

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )
ClinicalTrials.gov Identifier:
NCT00436215
First received: February 15, 2007
Last updated: September 6, 2014
Last verified: February 2014
  Purpose

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 effectiveness 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 at different treatment intervals.

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 (MRI and PET) are done before treatment, 3 days after beginning treatment, and 6 weeks into therapy.
  • 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.

Condition Intervention Phase
Peritoneal Cancer
Drug: Sorafenib
Biological: Bevacizumab
Genetic: proteomic profiling
Other: laboratory biomarker analysis
Procedure: dynamic contract-enhanced magnetic resonance imaging
Procedure: needle biopsy
Procedure: positron emission tomography
Radiation: fludeoxyglucose F 18
Phase 2

Study Type: Interventional
Study Design: Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase II Study of Sorafenib and Bevacizumab in Epithelial Ovarian, Fallopian, and Peritoneal Cancer

Resource links provided by NLM:


Further study details as provided by National Institutes of Health Clinical Center (CC):

Primary Outcome Measures:
  • Clinical response rate. [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Progression-free survival after 6 or more courses of treatment. [ Designated as safety issue: No ]
  • Toxicity [ Designated as safety issue: Yes ]
  • Biological markers [ Designated as safety issue: No ]

Enrollment: 55
Study Start Date: December 2006
Study Completion Date: September 2014
Primary Completion Date: September 2014 (Final data collection date for primary outcome measure)
Intervention Details:
    Drug: Sorafenib
    N/A
    Biological: Bevacizumab
    N/A
    Genetic: proteomic profiling
    N/A
    Other: laboratory biomarker analysis
    N/A
    Procedure: dynamic contract-enhanced magnetic resonance imaging
    N/A
    Procedure: needle biopsy
    N/A
    Procedure: positron emission tomography
    N/A
    Radiation: fludeoxyglucose F 18
    N/A
Detailed Description:

Background:

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Sorafenib is an inhibitor of wild-type and mutant B-Raf and c-Raf kinase isoforms in vitro, but it also inhibits p38, c-kit, VEGFR-2 and PDGFR-Beta affecting tumor growth as well as possibly promoting apoptosis by events downstream of c-Raf.

Bevacizumab is a humanized IgG1 monoclonal antibody (MAb) that binds all biologically active isoforms of human 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 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. DCE-MRI and 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 RECIST criteria.

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

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria
  • 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, 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 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
  • AST(SGOT) and ALT(SGPT)< TAB> 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)/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 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), 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 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 CT or 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 (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.

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 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).

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00436215

Locations
United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, United States, 20892
Sponsors and Collaborators
Investigators
Principal Investigator: Christina M Annunziata, M.D. National Cancer Institute (NCI)
  More Information

Additional Information:
Publications:
Responsible Party: National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )
ClinicalTrials.gov Identifier: NCT00436215     History of Changes
Other Study ID Numbers: 070058, 07-C-0058
Study First Received: February 15, 2007
Last Updated: September 6, 2014
Health Authority: United States: Federal Government

Keywords provided by National Institutes of Health Clinical Center (CC):
Angiogenesis
VEGF
Gynecological
Carcinoma
Raf-kinase
Sorafenib
Bevacizumab
Ovarian Cancer
Fallopian Cancer
Peritoneal Cancer
Fallopian Tube Cancer

Additional relevant MeSH terms:
Peritoneal Neoplasms
Abdominal Neoplasms
Digestive System Diseases
Digestive System Neoplasms
Neoplasms
Neoplasms by Site
Peritoneal Diseases
Bevacizumab
Fluorodeoxyglucose F18
Sorafenib
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Antineoplastic Agents
Diagnostic Uses of Chemicals
Enzyme Inhibitors
Growth Inhibitors
Growth Substances
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Physiological Effects of Drugs
Protein Kinase Inhibitors
Radiopharmaceuticals
Therapeutic Uses

ClinicalTrials.gov processed this record on October 23, 2014