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

http://www.clinicaltrials.gov/ct/show/NCT00095459?order=3

SUMMARY:

This study will determine the optimum doses of BAY 43-9006 (Sorafenib) and bevacizumab (Avastin) that can be used safely in combination in patients with various solid tumor cancers. It will examine the effects, good and bad, of the drugs and see how it affects the cancer by measuring amounts of proteins in the tumor before starting treatment and at various times during treatment.
Patients 18 years of age and older with a solid tumor cancer that has spread beyond the primary site and for whom standard treatments are not beneficial may be eligible for this study. Participants are assigned to one of two treatment groups. Treatment is given in 28-day cycles. Group 1 receives both BAY 43-9006 and bevacizumab from the start of treatment. Group 2 receives either BAY 43-9006 or bevacizumab for the first 28-day treatment cycle and then both drugs for subsequent cycles. BAY 43-9006 is taken by mouth every day twice a day; bevacizumab is given by vein every 2 weeks. In addition to drug therapy, patients undergo the following tests and procedures:
  • Physical examination, blood tests (including research blood samples), and urine tests every 2 weeks for the first 8 weeks and then every 4 weeks while on treatment.
  • You may be admitted to the hospital for 2 days after your first dose of bevacizumab to monitor your blood pressure closely
  • Blood pressure checks daily during the first 4 weeks and then as needed (at home with a machine that we lend you) (Group 1 only)
  • Blood pressure checks once a week during the first 8 weeks. (Group 2 only)
  • Multiple measurements of blood levels of BAY 43-9006. (Group 2 only). This is done early in the study to see how the body handles the drug. It is repeated after 4 weeks in patients who began the study with BAY 43-9006 alone and added bevacizumab after 4 weeks. Patients are admitted to the hospital for this test.
  • CT scans or other imaging tests every 8 weeks to evaluate the tumor's response to treatment. CT is an x-ray test that provides detailed pictures of the inside of the body. It can be done from different angles, providing a 3-dimensional picture of the part of the body being studied. (Group 1 only)
  • Positron emission tomography (PET) before starting treatment, approximately 2 weeks into therapy, and after 2 weeks of combined therapy to look at how different parts of the body use glucose (a sugar nutrient). Because rapidly growing cells, such as tumors, use more sugar than normal cells do, this test can be used to detect cancer. For the test, the patient is injected with a sugar solution in which a radioactive tracer has been attached to the sugar molecule. A special camera detects the radiation emitted by the solution, and the resulting images show how much sugar is being used in various parts of the body. (Group 2 only)
  • Dynamic, contrast-enhanced MRI (DCE-MRI) before starting treatment, after 2 weeks of treatment, and after 2 weeks of combined therapy. MRI uses a powerful magnet and radio waves instead of X-rays to produce accurate, detailed pictures of organs and tissues. This test uses MRI with a special non-radioactive dye to examine blood flow in a certain part of the body. (Group 2 only)
  • Tumor biopsy before starting treatment, after 2 weeks of treatment, and after 2 weeks of combined therapy. For the biopsy, a small piece of tissue is collected for analysis using either a small bore needle under CT guidance or by direct visualization using a laparoscope. For the needle biopsy, a needle is inserted through the skin and guided by CT into the tumor mass. For the laparoscopy, the patient is sedated or asleep and small lighted tubes are inserted into small holes made in the skin. The tumor is located and tissue withdrawn. (Group 2 only)

Treatment continues until the study doctor determines that the medication is not beneficial, that the side effects are too bad, or the patient wishes to withdraw from the study.

Neoplasms
Drug: Bevacizumab
Drug: BAY 43-9006
Phase I

MedlinePlus related topics: Cancer; Cancer Alternative Therapy

Study Type: Interventional

Study Design: Treatment, Safety

Official Title: A Phase I Trial of BAY 43-9006 (Sorafenib) and Bevacizumab in Refractory Solid Tumors with Biologic and Proteomic Analysis

Further Study Details:

Expected Total Enrollment: 38

Study start: November 2, 2004

Despite the developments with signal transduction and angiogenesis inhibitors, these drugs have produced clinically mixed results. While these targeted drugs have activity in certain tumors, they are only rarely effective as single agents particularly in solid tumors. It has become evident that for certain tumor types, inhibition of multiple targets may be necessary for more significant clinical effects. BAY 43-9006 (Sorafenib) and bevacizumab are agents which inhibit two pathways that are commonly activated in human solid tumors: The Ras-Raf-MAPK and VEGF pathways, respectively. Given the significant interactions of these signaling pathways in both tumor cells and endothelial cells attenuation of both the Ras-Raf-MAPK and VEGF pathways may provide synergistic antitumor activity. Recent understanding of signaling events suggest that it is possible to alter regulation of more than one pathway related to outside-in signaling with more than additive effect. The goals of this phase I trial are to determine combination of BAY 43-9006 and bevacizumab that can be safely administered while affecting biological signaling cascades and to evaluate downstream signaling effects. To achieve these goals, we will accrue patients in a traditional phase I dose-escalation scheme with cohort expansion once the MTD is determined. A series of correlative studies will be done during treatment to measure biological and clinical effects of this drug combination. These studies will include analyses of tissue and blood samples as well as correlative imaging studies.

ELIGIBILITY

Genders Eligible for Study: Both

Criteria

ELIGIBILITY CRITERIA:

Patients must have a solid tumor malignancy that is metastatic or unresectable and for which standard curative therapies do not exist or are no longer effective.

Patients must have histological documentation of cancer confirmed in the Laboratory of Pathology/NCI.

Patients must be off prior chemotherapy, radiation therapy, hormonal therapy, or biological therapy for at least 4 weeks. Patients who were receiving mitomycin C, nitrosoureas, or carboplatin must be 6 weeks from the last administration of chemotherapy. Patients with prostate cancer must continue to receive LHRH agonist (unless orchiectomy has been performed). Patients should not be receiving complementary/alternative therapy while on study. Furthermore, complementary therapy should be stopped at least 7 days prior to enrollment. Any patient who has undergone therapy with a monoclonal antibody must be at least 8 weeks from the last treatment.

All patients enrolling in cohort 2 must have at least one lesion amenable to biopsy. This determination will be made by a member of the interventional radiology team or surgical associate investigator and an associate investigator. This requirement is not necessary for patients in cohort 1.

  • Age greater than or equal to18 years.
  • ECOG performance status 0 or 1.
  • Life expectancy of greater than 3 months.
  • Patients must have adequate organ and marrow function as defined below:
  • 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 X institutional upper limits of normal
  • AST(SGOT) and ALT(SGPT) less than or equal to 2.5 X 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 1.25 x institutional upper limits of normal
  • Prothrombin Time (PT) OR INR less than 1.25 x institutional upper limits of normal
  • Amylase and Lipase within institutional limits of normal
  • Patients must have recovered from toxicity related to prior therapy to at least CTEP grade 1 (defined by CTC 3.0)
  • Women of child-bearing potential and men must agree to use adequate contraception (abstinence; hormonal or barrier method of birth control) for the study and at least 2 months after completion. Pregnant women will not be eligible for study.
  • Ability to understand and the willingness to sign a written informed consent document.

EXCLUSION CRITERIA:

  • 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. Urine dipstick proteinuria of 1+ 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.
  • 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.
Special Instructions: Currently Not Provided
Keywords:
Raf-Kinase Inhibitor
Combinatorial Therapy
Pathway Profiling
Angiogenesis
VEGFR
Recruitment Keyword(s):
Cancer
Solid Tumor
Metastatic Uresectable Solid Tumors
Condition(s):
Neoplasms
Investigational Drug(s):
Bevacizumab
BAY 43-9006
Investigational Device(s):
None
Intervention(s):
None
Supporting Site:
N/A
Contact(s):
Patient Recruitment and Public Liaison Office
Building 61
10 Cloister Court
Bethesda, Maryland 20892-4754
Toll Free: 1-800-411-1222
TTY: 301-594-9774 (local),1-866-411-1010 (toll free)
Fax: 301-480-9793

*** POSTED APRIL 8, 2005 ***