BAY 43-9006 (Sorafenib) and Bevacizumab (Avastin) To Treat Solid Tumors

Completed · Phase 1

Conditions studied: Neoplasms

In brief

Background: * BAY 43-9006 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 (k(d)= 1.1nM) * The most common adverse events associated with bevacizumab of any severity include asthenia, pain, headache, hypertension, diarrhea, stomatitis, constipation, epistaxis, dyspnea, dermatitis and proteinuria. * This Phase I trial is open to patients with all solid tumors. Objectives: * Determine the safety and toxicity of the combination of BAY 43-9006 (Sorafenib) and bevacizumab. * Determine estimates of biochemical changes in the Ras-Raf-MAPK and VEGF signal transduction pathways in tumor and stromal cells in response to treatment at the MTD, at least in a pilot fashion, if those changes are statistically significant. Eligibility: * Adults with histologically documented solid tumor malignancy that is metastatic or unresectable and for which standard curative therapies do not exist or are no longer effective. * Patients must be off prior chemotherapy, radiation therapy, hormonal therapy, or biological therapy for at least 4 weeks. * All patients enrolling in cohort 2 must have at least one lesion amenable to biopsy. * ECOG performance status 0 or 1 and adequate organ and marrow function. Design: * Cohort I will receive BAY 43-9006 and bevacizumab together at the start of study in a dose escalation fashion. * Cohort II will be randomized as to which agent they receive for cycle one. Cycles 2 and beyond are treated using both agents. * Tumor biopsies will be obtained from patients in Cohort II before treatment, two weeks into mono-therapy, and two weeks into combinatorial therapy. * DCE-MRI studies will be obtained on patients in Cohort II before treatment, two weeks into monotherapy, four weeks into monotherapy, and two weeks into combinatorial therapy. * FDG-PET studies will be obtained on patients in Cohort II before treatment, two weeks into mono-therapy, and two weeks into combinatorial therapy. * Patients will be evaluated for toxicity in clinic every 2 weeks for Cycles 1 and 2, and then every 4 weeks. * Patients will be evaluated for response every 8 weeks using the RECIST criteria. * Approximately 62 patients will be needed to achieve the objectives of the trial.

Key facts

Study ID

NCT00095459

Run by

National Cancer Institute (NCI)

People needed

57

Starts

2004-11-02

Expected to finish

2012-07-20

Last updated by the study team

2019-12-17

Who can join

Age: 18 and older. Sex: any. Healthy volunteers: not accepted.

You may not qualify if…

• Brain metastases
• Patients who have a history of remote CNS metastases that have undergone "curative therapy" by radiation therapy, gamma knife therapy, or surgery and have remained without recurrence for a period of greater than or equal to 2 years will be considered on a case-by-case basis.
• 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. Screening CNS scans should be required for certain tumor types with relatively high risk of CNS metastases, including but not limited to melanoma, RCC, breast, lung.
• 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.
• 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 BAY 43-9006, bevacizumab, and/or the combination.
• Patients who have been treated with BAY 43-9006 or bevacizumab will be excluded
• Hypertension defined as systolic blood pressure greater than 140 mmHg or diastolic pressure greater than 90 mmHg despite optimal medical management.
• Proteinuria defined as a 24-hour urine protein excretion greater than 1000 mg. Spot urine analysis for protein creatinine ratio (UPC) of 0.5 or greater will require a 24-hour urine to determine eligibility for enrollment.
• Therapeutic anticoagulation with coumadin, heparins, or heparinoids.
• Serious non-healing wounds (including wounds healing by secondary intention), acute or non-healing ulcers, or bone fractures within 3 months of fracture. History of abdominal fistula, gastrointestinal perforation or intra-abdominal abcesses within 28 days will be excluded.
• Evidence of bleeding diathesis
• Impairment of swallowing that would preclude administration of BAY 43-9006.
• History of hemoptysis or surgery within the past 28 days.
• Patients with squamous cell carcinoma of the lungs will be excluded due to risk of fatal pulmonary hemorrhage. If a patient has a history of any type primary lung cancer and hemoptysis, they will be excluded.
• History of high grade varices.
• Use of herbal supplements are not permitted within 14 days of trial commencement and on study. Vitamin supplement (above a typical single multi-vitamin) usage is discouraged unless clearly indicated by an existing medical condition. An Associate or Principal Investigator will have the discretion regarding which vitamin supplements are permitted.
• Patients with known hypersensitivity to Chinese hamster ovary cell products or other recombinant human antibodies.

Where it is running

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

Full record on ClinicalTrials.gov

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