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Sorafenib Tosylate and Bevacizumab in Treating Patients With Advanced Kidney Cancer

Sponsor
National Cancer Institute (NCI) (NIH)
Overall Status
Completed
CT.gov ID
NCT00126503
Collaborator
(none)
73
Enrollment
5
Locations
1
Arm
81.1
Duration (Months)
14.6
Patients Per Site
0.2
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This phase I/II trial studies the side effects and best dose of sorafenib tosylate and bevacizumab and to see how well they work in treating patients with advanced kidney cancer. Sorafenib tosylate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as bevacizumab, can block tumor growth by targeting certain cells. Bevacizumab and sorafenib tosylate may also stop the growth of tumor cells by blocking blood flow to the tumor. Giving sorafenib tosylate together with bevacizumab may kill more tumor cells.

Condition or Disease Intervention/Treatment Phase
  • Biological: Bevacizumab
  • Drug: Sorafenib Tosylate
  • Other: Pharmacological Study
  • Other: Laboratory Biomarker Analysis
 Phase 1/Phase 2

Detailed Description

PRIMARY OBJECTIVES:
  1. To determine the tolerability and maximum tolerated dose of Sorafenib (sorafenib tosylate) when given orally in combination with Bevacizumab in patients with renal cell carcinoma (RCC). (Phase I) II. To estimate the objective response rate of advanced RCC receiving the combination therapy of Bevacizumab and Sorafenib. (Phase II) III. To estimate the progression-free survival of advanced renal cell carcinoma patients to Sorafenib (sorafenib tosylate) in combination with Bevacizumab. (Phase II)
SECONDARY OBJECTIVES:

  1. To obtain fixed tissue in the form of paraffin blocks or unstained slides for evaluation of the following: von Hippel-Lindau tumor suppressor, E3 ubiquitin protein ligase (VHL) mutation status and phosphatase and tensin homolog (PTEN) mutation and/or expression status; VHL downstream proteins; Apoptosis and proliferation status; Microvascular density, and if able to process; kinase status- phosphorylation, inactive for mitogen-activated protein (MAP) kinase, v-akt murine thymoma viral oncogene homolog 1 (Akt) and kinase insert domain receptor (KDR) if feasible.

  2. In situations where fresh tumor may be obtained prior to and/or following therapy (4 weeks)

  1. Assess tumor baseline and changes in signal transduction - Raf-1 proto-oncogene, serine/threonine kinase (Raf), mitogen-activated protein kinase kinase (MEK), mitogen-activated protein kinase 1 (Erk), Erk phosphorylation, Akt phosphorylation status and Raf subcellular localization.

  2. fms-related tyrosine kinase 1 (VEGFR1) (flk1) and kinase insert domain receptor (VEGFR2) (flt1/KDR) status and tissue vascular endothelial growth factor (VEGF).

  3. Tumor cell apoptosis - marker of proliferation Ki-67 (Ki-67), transferase dUTP nick end labeling (TUNEL) staining, and expression levels of BH3 interacting domain death agonist (BH3) domain containing proteins.

  4. Tumor blood vessel characteristics - microvessel density, fraction of immature tumor blood vessels, endothelial cell apoptosis.

  5. Presence of VHL downstream proteins III. To relate changes in tumor perfusion and vascular permeability on serial arterial spin labeled (ASL) and dynamic contrast-enhanced (DCE)-magnetic resonance imaging (MRI) to clinical outcome and anti-tumor effects.

  1. Evaluate the pharmacokinetics of Sorafenib (alone and in combination) and bevacizumab in patients enrolled on the maximum tolerated dose (MTD) dose level of Sorafenib and bevacizumab representing the recommended phase II dose (RPTD) schedule (200mg once daily [QD] Sorafenib and 5 mg/kg intravenously [IV] Q 2 weeks of bevacizumab).

  2. To determine the steady-state trough plasma concentration of Sorafenib and trough concentration of Bevacizumab and relate to toxicity and correlative endpoints.

  3. Serial analysis of circulating angiogenic cytokines (i.e. VEGF, angiopoeitin 2, basic fibroblast growth factor [bFGF], interleukin [IL]-8 etc) and association of findings with response, response duration and prediction of relapse.

OUTLINE: This phase I dose-escalation study followed by a phase II study.

PHASE I: Patients receive sorafenib tosylate orally (PO) twice daily on days 1-28 and bevacizumab intravenously (IV) over 30-90 minutes on days 1 and 15.

Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of sorafenib tosylate and bevacizumab until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 6 patients experience dose-limiting toxicity. An additional 6 patients are treated at the MTD.

PHASE II: Patients receive sorafenib tosylate PO once daily on days 1-28 and bevacizumab IV over 90 minutes on days 1 and 15 at the MTD in the absence of disease progression or unacceptable toxicity*.

[Note: *Patients may remain on protocol if only 1 of the drugs is stopped.]

After completion of study treatment, patients are followed up every 3 months for 2 years and then every 6 months thereafter.

Study Design

Study Type:
Interventional
Actual Enrollment :
73 participants
Allocation:
N/A
Intervention Model:
Single Group Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Phase I/II Trial of BAY 43-9006 in Combination With Bevacizumab in Patients With Advanced Renal Cancer
Study Start Date :
May 1, 2005
Actual Primary Completion Date :
Oct 1, 2011
Actual Study Completion Date :
Feb 1, 2012

Arms and Interventions

Arm Intervention/Treatment
Experimental: Treatment (bevacizumab and sorafenib tosylate)

Phase I: Patients receive sorafenib PO twice daily on days 1-28 and bevacizumab IV over 30-90 minutes on days 1 and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of sorafenib and bevacizumab until the MTD is determined. The MTD is defined as the dose preceding that at which 2 of 6 patients experience dose-limiting toxicity. An additional 6 patients are treated at the MTD. Phase II: Patients receive sorafenib PO once daily on days 1-28 and bevacizumab IV over 90 minutes on days 1 and 15 at the MTD in the absence of disease progression or unacceptable toxicity.

Biological: Bevacizumab
Given IV
Other Names:
  • Avastin
  • rhuMab-VEGF

    • Drug: Sorafenib Tosylate
    Given PO
    Other Names:
  • BAY 54-9085
  • Nexavar
  • SFN

    • Other: Pharmacological Study
    Correlative studies
    Other Names:
  • pharmacological studies

    • Other: Laboratory Biomarker Analysis
    Correlative studies

    Outcome Measures

    Primary Outcome Measures

    1. Maximum Tolerated Dose (MTD) of BAY 43-9006 (Sorafenib)in Combination With Bevacizumab (Phase I) [at 28 days]

      The highest dose in milligrams (mg) of BAY 43-9006 (Sorafenib) in combination with Bevacizumab while maintaining tolerability. Cohorts of 3-6 patients received escalating doses of sorafenib and bevacizumab until the maximum tolerated dose (MTD) was achieved. The MTD is defined as the dose preceding that at which 2 or more of 6 patients experience dose-limiting toxicity during the initial cycle of therapy. DLTs include absolute neutrophil count (ANC) < 500/mm3 for > 7 days, ANC < 1000/mm3 with fever > 101 degrees Fahrenheit, platelet count < 50,000 mm3, and non-hematologic toxicity Common Toxicity Criteria (CTC) >= Grade 3.

    2. Maximum Tolerated Dose of Bevacizumab in Combination With BAY 43-9006 (Sorafenib)(Phase I) [at 28 days]

      The highest dose in milligrams (mg) of Bevacizumab in combination with BAY 43-9006 (Sorafenib) while maintaining tolerability. Cohorts of 3-6 patients received escalating doses of sorafenib and bevacizumab until the maximum tolerated dose (MTD) was achieved. The MTD is defined as the dose preceding that at which 2 or more of 6 patients experience dose-limiting toxicity during the initial cycle of therapy. DLTs include absolute neutrophil count (ANC) < 500/mm3 for > 7 days, ANC < 1000/mm3 with fever > 101 degrees Fahrenheit, platelet count < 50,000 mm3, and non-hematologic toxicity Common Toxicity Criteria (CTC) >= Grade 3.

    3. Objective Response [Every 8 weeks to date of progression]

      Objective response as determined by RECIST v. 1.0 (measurable lesions: complete response (CR) disappearance of target lesions, partial response (PR) > 30% decrease in the sum of the longest diameter (LD) of target lesions, progressive disease (PD) > 20% increase in the sum of the LD of target lesions or appearance of new lesions, stable disease (SD) neither sufficient decrease nor increase of the sum of smallest sum of the LD of target lesions)or last date known alive

    Secondary Outcome Measures

    1. Overall Survival [on-study to date of expired or last date known alive]

      Months from date on-study to expired or last date known alive

    2. Progression-free Survival [on-study to date of progression or last date known alive without progression]

      Duration of months of progression-free survival (PFS). Determined by months to progressive disease or to last date known alive without progressive disease.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:

    • PHASE I ELIGIBILITY CRITERIA

    • Patients must have histological or cytological confirmation of renal cell carcinoma (clear cell, papillary, chromophobe, or sarcomatoid) not curable by standard approaches; tumor must be measurable by Response Evaluation Criteria In Solid Tumors (RECIST) criteria; nephrectomy prior to enrollment is not required

    • Patients may not have had prior therapy with inhibitors of the mitogen-activated protein (MAP) kinase pathway or inhibitors of VEGF and/or its receptor signaling (VEGFR2)

    • Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

    • Life expectancy of greater than 3 months

    • Hemoglobin (Hgb) >= 9.0gm/dl (transfusions allowed prior to enrollment)

    • White Blood Count >= 3,000/mm^3

    • Absolute Granulocyte Count >= 1,200/mm^3

    • Platelet Count >= 100,000/mm^3

    • Serum creatinine =< 1.5 x upper limit of normal (ULN) or serum creatinine clearance (CrCl) >= 40ml/min (neither drug is cleared by the kidney)

    • Total Bilirubin =< 1.5 x ULN

    • Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 2.5 x ULN

    • International normalized ratio (INR) =< 1.5 and activated partial thromboplastin time (aPTT) that is not greater than 1.3 times the ULN

    • Urine Dipstick must show less then 1+ protein in urine or the patient will require 24 hour urine collection with total protein =< 1000 mg/24 hour

    • Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; should a woman become pregnant while participating in this study, she should inform her treating physician immediately

    • Ability to understand and the willingness to sign a written informed consent document

    • PHASE II ELIGIBILITY CRITERIA

    • Patients enrolled on the phase II portion of the study will be required to have predominantly clear cell variant of renal cell carcinoma with less than 25% of any other histology (papillary or chromophobe or oncocytic); there must be histologic confirmation by treating center of either primary or metastatic lesion; patients must be willing to consent for obtaining tumor tissue blocks or unstained slides from prior biopsy or surgery; patients who participated in the Phase I part of the protocol will not be part of the accrual to the Phase II cohort

    • Patients enrolled on the phase II portion of the study will be required to have measurable disseminated disease that is not curable by standard radiation therapy or surgery

    • Previous nephrectomy is required with the following exceptions:

    • Primary tumor =< 5cm or

    • Extensive liver (> 30% of liver parenchymal) or multiple (> 5) bone metastases, or extensive extrarenal tumor or unresectable local/regional tumor extension making nephrectomy a clinically questionable and unreasonable procedure

    • For the phase II study, patients will be allowed no more than one prior regimen containing a vaccine or cytokine based immunotherapy or chemotherapy for advanced disease

    • Hgb >= 9.0gm/dl (transfusions allowed prior to enrollment)

    • White Blood Count >= 3,000/mm^3 (phase II)

    • Absolute Granulocyte Count >= 1,200/mm^3 (phase II)

    • Platelet Count >= 100,000/mm^3 (phase II)

    • Serum creatinine =< 1.5 x upper limit of normal (ULN) or serum creatinine clearance (CrCl) >= 40ml/min (neither drug is cleared by the kidney) (phase II)

    • Total Bilirubin =< 1.5 x ULN (phase II)

    • AST/ALT =< 2.5 x ULN

    • INR =< 1.5

    • Urine Dipstick must show less then 1+ protein in urine or the patient will require 24 hour urine collection with total protein =< 1000 mg/24 hour (phase II)

    • No prior malignancy diagnosed within the past 3 years with the exception of non-melanoma skin cancers, melanoma in situ, carcinoma in situ of the cervix, ductal carcinoma in situ, and lobular carcinoma in situ; any prior malignancy must have a very likely cure rate (75% or greater)

    • Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; should a woman become pregnant while participating in this study, she should inform her treating physician immediately (phase II)

    • Ability to understand and the willingness to sign a written informed consent document (phase II)

    Exclusion Criteria:

    • History or clinical evidence of central nervous system (CNS) disease, including primary brain tumor (participants with a history of meningioma are not excluded), seizures not controlled with standard medical therapy, any brain metastasis, or history of stroke within the prior 12 months; patients who have had a history of brain metastasis that have been resected or have had radiosurgery with no progression for more than 6 months are eligible if the Principle Investigator from the coordinating center is consulted and agrees

    • Patients entered onto the phase II study may not have received more than one chemotherapy or immunotherapy regimen for Stage IV disease

    • Patients may not have received chemotherapy or immunotherapy within 4 weeks of initiating treatment; patients will not have received a regimen containing a monoclonal antibody within 8 weeks of initiating treatment; toxicities from radiation must have resolved and a minimum of two weeks must pass prior to enrollment

    • Patients may not have had prior anti-angiogenic therapy including, Sunitinib, VEGF Trap; prior Temsirilomus, Everolimus, Bevacizumab and Sorafenib will not be allowed; thalidomide or interferon (IFN) alpha are allowed either for adjuvant therapy or stage IV disease

    • History of allergic reactions attributed to Chinese hamster ovary cell products, other recombinant human antibodies, or compounds of similar chemical or biologic composition to Sorafenib

    • History of bleeding diathesis or coagulopathy

    • A condition that impairs patient's ability to swallow pills will make patient ineligible

    • No major surgical procedure, open biopsy or significant traumatic injury within 28 days prior to initiation of therapy on trial

    • Anticipation of the need for major surgery during the course of the study

    • Current or recent use (within 7 days of starting the study drugs) of full-dose of anticoagulants (except as required to maintain patency of preexisting, permanent indwelling IV catheters or for deep vein thrombosis [DVT] prophylaxis, for subjects receiving warfarin, INR should be =< 1.5) or thrombolytic agent

    • Patients with uncontrolled hypertension; blood pressure must be =< 150/90 mmHg at the time of enrollment on a stable antihypertensive regimen

    • Patients with clinically significant cardiovascular disease within 1 year prior to study entry

    • Uncontrolled hypertension

    • Myocardial infarction or unstable angina < 6 months prior to registration

    • New York heart association grade II or greater congestive heart failure, serious cardiac arrhythmia requiring medication (participants with controlled atrial arrhythmias are not excluded), unstable angina pectoris

    • Grade II or greater peripheral vascular disease

    • Serious, non-healing wound, ulcer, or bone fracture

    • Significant proteinuria (> 1000 mg protein/24 hours ) at baseline; subjects discovered to have >= 1+ proteinuria on dipstick should undergo a 24-hour urine collection, which should contain < 1000 mg protein/ 24 hours to be allowed participation in the study

    • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection requiring parental antibiotics, or psychiatric illness/social situations that would limit compliance with study requirements

    • Patients taking cytochrome P450 enzyme-inducing antiepileptic drugs will be excluded (phenytoin, carbamazepine, Phenobarbital, rifampin, and St.John's Wort)

    • Pregnant and lactating women are excluded from the study; breastfeeding should be discontinued while receiving therapy

    • Human immunodeficiency virus (HIV)-positive patients receiving combination anti-retroviral therapy are excluded from the study

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Dana-Farber Cancer Institute Boston Massachusetts United States 02115
    2 Dana-Farber Harvard Cancer Center Boston Massachusetts United States 02115
    3 Beth Israel Deaconess Medical Center Boston Massachusetts United States 02215
    4 University of Pennsylvania/Abramson Cancer Center Philadelphia Pennsylvania United States 19104
    5 Vanderbilt-Ingram Cancer Center Nashville Tennessee United States 37232

    Sponsors and Collaborators

    • National Cancer Institute (NCI)

    Investigators

    • Principal Investigator: Jeffrey Sosman, Vanderbilt-Ingram Cancer Center

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    National Cancer Institute (NCI)
    ClinicalTrials.gov Identifier:
    NCT00126503
    Other Study ID Numbers:
    • NCI-2009-00066
    • NCI-2009-00066
    • CDR0000434814
    • URO 470
    • 6555
    • U01CA099177
    • P30CA068485
    First Posted:
    Aug 4, 2005
    Last Update Posted:
    Jan 15, 2015
    Last Verified:
    Sep 1, 2014
    Additional relevant MeSH terms:
    Carcinoma
    Carcinoma, Renal Cell
    Bevacizumab
    Sorafenib

    Study Results

    Participant Flow

    Recruitment Details This Phase I/II study was open 5/2005 through 12/2010.
    Pre-assignment Detail 73 patients consented, 4 of whom were determined to be ineligible.
    Arm/Group Title Phase I Phase II
    Arm/Group Description Sorafenib will be taken orally twice daily beginning on day 1 and continued for 28 days which will be defined as a cycle. Bevacizumab will be administered once every 14 days (with up to a 3 day window before or after 14 days to allow for unforeseen scheduling problems) beginning on day 1. Sorafenib will be taken orally once daily at 200 mg beginning on day -14 and continued for 28 days per cycle. There is no planned interruption. Bevacizumab 5mg/kg IV will be administered every 14 days (+/- 3 days) beginning on day 1.
    Period Title: Overall Study
    STARTED 48 21
    COMPLETED 1 0
    NOT COMPLETED 47 21

    Baseline Characteristics

    Arm/Group Title Phase I Phase II Total
    Arm/Group Description Sorafenib will be taken orally twice daily beginning on day 1 and continued for 28 days which will be defined as a cycle. Bevacizumab will be administered once every 14 days (with up to a 3 day window before or after 14 days to allow for unforeseen scheduling problems) beginning on day 1. Sorafenib will be taken orally once daily at 200 mg beginning on day -14 and continued for 28 days per cycle. There is no planned interruption. Bevacizumab 5mg/kg IV will be administered every 14 days (+/- 3 days) beginning on day 1. Total of all reporting groups
    Overall Participants 48 21 69
    Age (Count of Participants)
    <=18 years
    0
    0%
    0
    0%
    0
    0%
    Between 18 and 65 years
    35
    72.9%
    19
    90.5%
    54
    78.3%
    >=65 years
    13
    27.1%
    2
    9.5%
    15
    21.7%
    Age (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    65
    (1)
    58
    (1)
    62
    (1)
    Sex: Female, Male (Count of Participants)
    Female
    8
    16.7%
    7
    33.3%
    15
    21.7%
    Male
    40
    83.3%
    14
    66.7%
    54
    78.3%
    Region of Enrollment (participants) [Number]
    United States
    48
    100%
    21
    100%
    69
    100%

    Outcome Measures

    1. Primary Outcome
    Title Maximum Tolerated Dose (MTD) of BAY 43-9006 (Sorafenib)in Combination With Bevacizumab (Phase I)
    Description The highest dose in milligrams (mg) of BAY 43-9006 (Sorafenib) in combination with Bevacizumab while maintaining tolerability. Cohorts of 3-6 patients received escalating doses of sorafenib and bevacizumab until the maximum tolerated dose (MTD) was achieved. The MTD is defined as the dose preceding that at which 2 or more of 6 patients experience dose-limiting toxicity during the initial cycle of therapy. DLTs include absolute neutrophil count (ANC) < 500/mm3 for > 7 days, ANC < 1000/mm3 with fever > 101 degrees Fahrenheit, platelet count < 50,000 mm3, and non-hematologic toxicity Common Toxicity Criteria (CTC) >= Grade 3.
    Time Frame at 28 days

    Outcome Measure Data

    Analysis Population Description
    Patients enrolled to determine the safety of BAY 43-9006 (Sorafenib) in combination with Bevacizumab
    Arm/Group Title Phase I
    Arm/Group Description Sorafenib will be taken orally twice daily beginning on day 1 and continued for 28 days which will be defined as a cycle. Bevacizumab will be administered once every 14 days (with up to a 3-day window before or after 14 days to allow for unforeseen scheduling problems) beginning on day 1.
    Measure Participants 48
    Number [mg]
    200
    2. Secondary Outcome
    Title Overall Survival
    Description Months from date on-study to expired or last date known alive
    Time Frame on-study to date of expired or last date known alive

    Outcome Measure Data

    Analysis Population Description
    All treated patients available for determination of overall survival. No patients in the Phase I cohort moved to the Phase II cohort. No Phase II patients were in the Phase I cohort.
    Arm/Group Title Phase I Phase II
    Arm/Group Description The highest dose in milligrams (mg) of BAY 43-9006 (Sorafenib) in combination with Bevacizumab while maintaining tolerability. The highest dose in milligrams/kilograms of body weight mg/kg of Bevacizumab in combination with BAY 43-9006 (Sorafenib) while maintaining tolerability. Sorafenib will be taken orally once daily at 200 mg beginning on day -14 and continued for 28 days per cycle. There is no planned interruption. Bevacizumab 5mg/kg IV will be administered every 14 days (+/- 3 days) beginning on day 1.
    Measure Participants 48 21
    Median (Full Range) [months]
    24
    25
    3. Secondary Outcome
    Title Progression-free Survival
    Description Duration of months of progression-free survival (PFS). Determined by months to progressive disease or to last date known alive without progressive disease.
    Time Frame on-study to date of progression or last date known alive without progression

    Outcome Measure Data

    Analysis Population Description
    All patients who underwent treatment. No patients in the Phase I cohort moved to the Phase II cohort. No Phase II patients were in the Phase I cohort.
    Arm/Group Title Phase I Phase II
    Arm/Group Description The highest dose in milligrams (mg) of BAY 43-9006 (Sorafenib) in combination with Bevacizumab while maintaining tolerability. The highest dose in milligrams/kilograms of body weight mg/kg of Bevacizumab in combination with BAY 43-9006 (Sorafenib) while maintaining tolerability. Sorafenib will be taken orally once daily at 200 mg beginning on day -14 and continued for 28 days per cycle. There is no planned interruption. Bevacizumab 5mg/kg IV will be administered every 14 days (+/- 3 days) beginning on day 1.
    Measure Participants 48 21
    Median (Full Range) [months]
    11
    15
    4. Primary Outcome
    Title Maximum Tolerated Dose of Bevacizumab in Combination With BAY 43-9006 (Sorafenib)(Phase I)
    Description The highest dose in milligrams (mg) of Bevacizumab in combination with BAY 43-9006 (Sorafenib) while maintaining tolerability. Cohorts of 3-6 patients received escalating doses of sorafenib and bevacizumab until the maximum tolerated dose (MTD) was achieved. The MTD is defined as the dose preceding that at which 2 or more of 6 patients experience dose-limiting toxicity during the initial cycle of therapy. DLTs include absolute neutrophil count (ANC) < 500/mm3 for > 7 days, ANC < 1000/mm3 with fever > 101 degrees Fahrenheit, platelet count < 50,000 mm3, and non-hematologic toxicity Common Toxicity Criteria (CTC) >= Grade 3.
    Time Frame at 28 days

    Outcome Measure Data

    Analysis Population Description
    Patients enrolled to determine the safety of BAY 43-9006 (Sorafenib) in combination with Bevacizumab
    Arm/Group Title Phase I
    Arm/Group Description Sorafenib will be taken orally twice daily beginning on day 1 and continued for 28 days which will be defined as a cycle. Bevacizumab will be administered once every 14 days (with up to a 3 day window before or after 14 days to allow for unforeseen scheduling problems) beginning on day 1.
    Measure Participants 48
    Number [mg/kg]
    5
    5. Primary Outcome
    Title Objective Response
    Description Objective response as determined by RECIST v. 1.0 (measurable lesions: complete response (CR) disappearance of target lesions, partial response (PR) > 30% decrease in the sum of the longest diameter (LD) of target lesions, progressive disease (PD) > 20% increase in the sum of the LD of target lesions or appearance of new lesions, stable disease (SD) neither sufficient decrease nor increase of the sum of smallest sum of the LD of target lesions)or last date known alive
    Time Frame Every 8 weeks to date of progression

    Outcome Measure Data

    Analysis Population Description
    Patients available for measurement of response to treatment with regimen. 7 Phase I and 4 Phase II patients were not available for measurement of response, respectively: disease progression (5, 2), complicating disease (1, 0), death on-study (1, 0), toxicity (0, 1), and alternative treatment (0, 1). All were counted as clinical progression.
    Arm/Group Title Phase I Phase II
    Arm/Group Description The highest dose in milligrams (mg) of BAY 43-9006 (Sorafenib) in combination with Bevacizumab while maintaining tolerability. The highest dose in milligrams/kilograms of body weight mg/kg of Bevacizumab in combination with BAY 43-9006 (Sorafenib) while maintaining tolerability. No Phase I patients moved to the Phase II cohort. Sorafenib will be taken orally once daily at 200 mg beginning on day -14 and continued for 28 days per cycle. There is no planned interruption. Bevacizumab 5mg/kg IV will be administered every 14 days (+/- 3 days) beginning on day 1. No Phase II patients were in the Phase I cohort.
    Measure Participants 41 17
    Complete Response
    0
    0%
    0
    0%
    Partial Response
    23
    47.9%
    3
    14.3%
    Progressive Disease
    2
    4.2%
    0
    0%
    Stable Disease
    16
    33.3%
    14
    66.7%

    Adverse Events

    Time Frame
    Adverse Event Reporting Description
    Arm/Group Title Phase I Phase II
    Arm/Group Description Sorafenib will be taken orally twice daily beginning on day 1 and continued for 28 days which will be defined as a cycle. Bevacizumab will be administered once every 14 days (with up to a 3 day window before or after 14 days to allow for unforeseen scheduling problems) beginning on day 1. Sorafenib will be taken orally once daily at 200 mg beginning on day -14 and continued for 28 days per cycle. There is no planned interruption. Bevacizumab 5mg/kg IV will be administered every 14 days (+/- 3 days) beginning on day 1.
    All Cause Mortality
    Phase I Phase II
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total / (NaN) / (NaN)
    Serious Adverse Events
    Phase I Phase II
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 17/48 (35.4%) 8/21 (38.1%)
    Cardiac disorders
    Cardiac ischemia/infarction 3/48 (6.3%) 3 1/21 (4.8%) 1
    Supraventricular and nodal arrhythmia-atrial fibrillation 1/48 (2.1%) 2 0/21 (0%) 0
    Cardiac General-other 1/48 (2.1%) 1 0/21 (0%) 0
    Supraventricular and nodal arrhythmia-atrial flutter 1/48 (2.1%) 1 0/21 (0%) 0
    Gastrointestinal disorders
    Pain-abdomen NOS 3/48 (6.3%) 3 1/21 (4.8%) 1
    Obstruction, GI-gallbladder 0/48 (0%) 0 1/21 (4.8%) 1
    Nausea 0/48 (0%) 0 1/21 (4.8%) 1
    Vomiting 0/48 (0%) 0 1/21 (4.8%) 1
    Perforation, GI-colon 0/48 (0%) 0 1/21 (4.8%) 1
    stricture/stenosis (including anastomotic), GI-jejunum 1/48 (2.1%) 1 0/21 (0%) 0
    Diarrhea 1/48 (2.1%) 1 0/21 (0%) 0
    Oral mucositis 3/48 (6.3%) 3 0/21 (0%) 0
    General disorders
    Edema-limb 1/48 (2.1%) 1 0/21 (0%) 0
    Death not associated with CTCAE term-Disease progression NOS 2/48 (4.2%) 2 0/21 (0%) 0
    Wound complication, non-infectious 0/48 (0%) 0 1/21 (4.8%) 1
    Fatigue 2/48 (4.2%) 2 0/21 (0%) 0
    Fever (in the absence of neutropenia, where neutropenia is defined as ANC < 1.0 x 10e9/L) 0/48 (0%) 0 1/21 (4.8%) 1
    Infections and infestations
    Infection with unknown ANC-pancreas 1/48 (2.1%) 1 0/21 (0%) 0
    Infection with unknown ANC-lung (pneumonia) 1/48 (2.1%) 1 0/21 (0%) 0
    Infection-Other 1/48 (2.1%) 1 0/21 (0%) 0
    Infection with Grade 1 or 2 neutrophils (ANC < 1.0 x 10e9/L)-skin (cellulitis) 2/48 (4.2%) 2 1/21 (4.8%) 1
    Infection with normal ANC or Grade 1 or 2 neutrophils-bone (osteomyelitis) 0/48 (0%) 0 1/21 (4.8%) 1
    Investigations
    weight loss 1/48 (2.1%) 1 0/21 (0%) 0
    Metabolism and nutrition disorders
    Hypokalemia 1/48 (2.1%) 1 0/21 (0%) 0
    Hypoglycemia 1/48 (2.1%) 1 0/21 (0%) 0
    Hypercalcemia 1/48 (2.1%) 1 0/21 (0%) 0
    Hyperbilirubinemia 0/48 (0%) 0 1/21 (4.8%) 1
    Dehydration 0/48 (0%) 0 1/21 (4.8%) 1
    Hyperkalemia 0/48 (0%) 0 1/21 (4.8%) 1
    Hyponatremia 0/48 (0%) 0 1/21 (4.8%) 1
    Musculoskeletal and connective tissue disorders
    Pain-chest wall 1/48 (2.1%) 1 0/21 (0%) 0
    Musculoskeletal/soft tissue-Other 2/48 (4.2%) 2 0/21 (0%) 0
    Pain-joint 1/48 (2.1%) 1 0/21 (0%) 0
    Fracture 2/48 (4.2%) 2 0/21 (0%) 0
    Pain-back 1/48 (2.1%) 1 0/21 (0%) 0
    Nervous system disorders
    CNS cerebrovascular ischemia 1/48 (2.1%) 1 0/21 (0%) 0
    Neuropathy - sensory 1/48 (2.1%) 1 0/21 (0%) 0
    Somnomolence/depressed level of consciousness 1/48 (2.1%) 1 0/21 (0%) 0
    Renal and urinary disorders
    Proteinuria 1/48 (2.1%) 1 0/21 (0%) 0
    Hyperuricemia 1/48 (2.1%) 1 0/21 (0%) 0
    Renal failure 0/48 (0%) 0 2/21 (9.5%) 2
    Respiratory, thoracic and mediastinal disorders
    Hemorrhage, pulmonary/upper respiratory-nose 1/48 (2.1%) 1 0/21 (0%) 0
    Dyspnea 1/48 (2.1%) 1 1/21 (4.8%) 1
    Skin and subcutaneous tissue disorders
    palmar-plantar paresthesia 10/48 (20.8%) 10 0/21 (0%) 0
    Vascular disorders
    Vascular-other 1/48 (2.1%) 1 0/21 (0%) 0
    Thrombosis/thrombus/embolism 1/48 (2.1%) 1 0/21 (0%) 0
    Hypertension 10/48 (20.8%) 10 1/21 (4.8%) 1
    Other (Not Including Serious) Adverse Events
    Phase I Phase II
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 48/48 (100%) 21/21 (100%)
    Blood and lymphatic system disorders
    Leukocytes (total WBC) 0/48 (0%) 0 1/21 (4.8%) 4
    Lymphopenia 0/48 (0%) 0 3/21 (14.3%) 4
    Cardiac disorders
    Palpitations 0/48 (0%) 0 1/21 (4.8%) 1
    Left ventricular systolic dysfunction 0/48 (0%) 0 1/21 (4.8%) 1
    Supraventricular and nodal arrhythmia-atrial tachycardia/paroxysmal atrial tachycardia 0/48 (0%) 0 1/21 (4.8%) 2
    Ear and labyrinth disorders
    Otitis, middle ear (non-infectious) 0/48 (0%) 0 1/21 (4.8%) 1
    Infection with normal ANC or Grade 1 or 2 neutrophils-external ear 0/48 (0%) 0 1/21 (4.8%) 1
    Endocrine disorders
    Thyroid function, low (hypothyroidism) 0/48 (0%) 0 3/21 (14.3%) 3
    Endocrine other 0/48 (0%) 0 1/21 (4.8%) 1
    Eye disorders
    Dry eye syndrome 4/48 (8.3%) 8 0/21 (0%) 0
    Ocular/visual-Other 0/48 (0%) 0 2/21 (9.5%) 2
    Vision-blurred vision 8/48 (16.7%) 9 1/21 (4.8%) 1
    Vision-flashing lights/floaters 0/48 (0%) 0 3/21 (14.3%) 3
    Watery eye (epiphora, tearing) 3/48 (6.3%) 4 0/21 (0%) 0
    Infection with normal ANC or Grade 1 or 2 neutrophils-Eye NOS 0/48 (0%) 0 1/21 (4.8%) 1
    Occular surface disease 0/48 (0%) 0 1/21 (4.8%) 1
    Gastrointestinal disorders
    Anorexia 28/48 (58.3%) 72 10/21 (47.6%) 11
    Colitis 0/48 (0%) 0 1/21 (4.8%) 1
    constipation 22/48 (45.8%) 38 8/21 (38.1%) 12
    Dental-teeth 0/48 (0%) 0 2/21 (9.5%) 4
    Diarrhea 33/48 (68.8%) 171 9/21 (42.9%) 29
    Distension/bloating, abdominal 4/48 (8.3%) 10 0/21 (0%) 0
    Dry mouth/salivary gland (xerostomia) 5/48 (10.4%) 8 4/21 (19%) 4
    Dysphagia 7/48 (14.6%) 12 3/21 (14.3%) 4
    Esophagitis 0/48 (0%) 0 1/21 (4.8%) 1
    fistula-GI anus 0/48 (0%) 0 1/21 (4.8%) 1
    Flatulence 18/48 (37.5%) 32 4/21 (19%) 5
    Gastrointestinal-Other 8/48 (16.7%) 14 1/21 (4.8%) 1
    Heartburn, dyspepsia 21/48 (43.8%) 41 6/21 (28.6%) 9
    Hemorrhage, GI-lower GI NOS 0/48 (0%) 0 1/21 (4.8%) 1
    Hemorrhage, GI oral cavity 4/48 (8.3%) 6 4/21 (19%) 4
    Hemorrhage, GI rectum 4/48 (8.3%) 4 2/21 (9.5%) 2
    Hemorrhoids 9/48 (18.8%) 11 1/21 (4.8%) 1
    Mucositis/stomatitis-anus/rectum (functional/symptomatic) 3/48 (6.3%) 13 1/21 (4.8%) 1
    Mucositis/stomatitis-oral cavity (clinical exam) 23/48 (47.9%) 43 9/21 (42.9%) 10
    Nausea 25/48 (52.1%) 57 9/21 (42.9%) 23
    Pain-stomach 6/48 (12.5%) 10 0/21 (0%) 0
    Vomiting 16/48 (33.3%) 28 5/21 (23.8%) 9
    Chelitis 0/48 (0%) 0 1/21 (4.8%) 1
    Infection with unknown ANC-stomach 0/48 (0%) 0 1/21 (4.8%) 1
    Leak (including anastomatic)-GI-rectum 0/48 (0%) 0 1/21 (4.8%) 1
    General disorders
    Constitutional symptoms Other 3/48 (6.3%) 5 1/21 (4.8%) 1
    Edema head and neck 3/48 (6.3%) 4 1/21 (4.8%) 1
    Edema limb 7/48 (14.6%) 13 6/21 (28.6%) 6
    Fatigue 38/48 (79.2%) 140 13/21 (61.9%) 37
    Fever (in the absence of neutropenia, with neutropenia defined as ANC < 1.0 x 10e9/L 3/48 (6.3%) 3 2/21 (9.5%) 3
    Flu-like syndrome 3/48 (6.3%) 6 2/21 (9.5%) 2
    Pain-abdomen NOS 17/48 (35.4%) 35 6/21 (28.6%) 11
    Pain-anus/rectum 4/48 (8.3%) 5 0/21 (0%) 0
    Pain-back 17/48 (35.4%) 30 8/21 (38.1%) 17
    Pain-bone 4/48 (8.3%) 7 1/21 (4.8%) 2
    Pain-chest/thorax 6/48 (12.5%) 6 4/21 (19%) 7
    Pain-dental/periodontal 4/48 (8.3%) 9 0/21 (0%) 0
    Pain-oral cavity/gums 8/48 (16.7%) 12 1/21 (4.8%) 1
    Pain-Other/NOS 10/48 (20.8%) 14 4/21 (19%) 8
    Pain-pelvis 0/48 (0%) 0 1/21 (4.8%) 2
    Pain-sinus 4/48 (8.3%) 9 3/21 (14.3%) 3
    Rigor, chills 9/48 (18.8%) 13 6/21 (28.6%) 7
    Pain-neck 6/48 (12.5%) 6 3/21 (14.3%) 3
    Tumor pain 3/48 (6.3%) 8 0/21 (0%) 0
    Pain-chest wall 3/48 (6.3%) 3 0/21 (0%) 0
    Immune system disorders
    allergic reaction/hypersensivity 0/48 (0%) 0 1/21 (4.8%) 1
    allergic rhinitis 18/48 (37.5%) 33 10/21 (47.6%) 10
    Infections and infestations
    Hemoglobin 9/48 (18.8%) 30 3/21 (14.3%) 9
    Infection-Other 0/48 (0%) 0 2/21 (9.5%) 3
    Infection with normal ANC or Grade 1 or 2 neutrophils-cellulitis 3/48 (6.3%) 3 0/21 (0%) 0
    Infection with unknown ANC-cellulitis 0/48 (0%) 0 1/21 (4.8%) 1
    Infection with unknown ANC-soft tissue 0/48 (0%) 0 2/21 (9.5%) 2
    Infection with unknown ANC-wound 0/48 (0%) 0 1/21 (4.8%) 1
    Infection with normal ANC or Grade 1 or 2 neutrophils-sinus 0/48 (0%) 0 2/21 (9.5%) 2
    Mucositis/stomatitis (functional/symptomatic)-Oral cavity 0/48 (0%) 0 7/21 (33.3%) 10
    Injury, poisoning and procedural complications
    Burn 0/48 (0%) 0 2/21 (9.5%) 2
    Investigations
    ALT/SGPT (serum glutamine pyruvic transminase) 11/48 (22.9%) 28 4/21 (19%) 9
    AST, SGOT (serum glutamine oxaloacetic transminase) 11/48 (22.9%) 30 4/21 (19%) 9
    Hypercalcemia 0/48 (0%) 0 1/21 (4.8%) 1
    Platelets 4/48 (8.3%) 18 1/21 (4.8%) 5
    Weight loss 26/48 (54.2%) 67 9/21 (42.9%) 19
    Alkaline phosphatase 4/48 (8.3%) 6 1/21 (4.8%) 1
    Bicarbonate, serum-low 0/48 (0%) 0 2/21 (9.5%) 6
    Hyperbilirubinemia 3/48 (6.3%) 3 1/21 (4.8%) 2
    Hypophosphatemia 11/48 (22.9%) 54 5/21 (23.8%) 9
    Partial prothrombin time (PTT) 0/48 (0%) 0 1/21 (4.8%) 1
    Triglyceride, serum-high 0/48 (0%) 0 1/21 (4.8%) 2
    Metabolism and nutrition disorders
    Creatinine 9/48 (18.8%) 24 2/21 (9.5%) 5
    Dehydration 3/48 (6.3%) 4 0/21 (0%) 0
    Hypercholesterolemia 0/48 (0%) 0 1/21 (4.8%) 3
    Hyperglycemia 11/48 (22.9%) 26 4/21 (19%) 40
    Hyperkalemia 5/48 (10.4%) 9 1/21 (4.8%) 2
    Hypocalcemia 5/48 (10.4%) 8 1/21 (4.8%) 1
    Hypoglycemia 3/48 (6.3%) 8 2/21 (9.5%) 5
    Hypokalemia 5/48 (10.4%) 8 4/21 (19%) 9
    Hyponatremia 11/48 (22.9%) 22 3/21 (14.3%) 24
    Metabolic/laboratory-Other 0/48 (0%) 0 2/21 (9.5%) 2
    Obesity 4/48 (8.3%) 8 3/21 (14.3%) 4
    Hypoalbuminemia 0/48 (0%) 0 4/21 (19%) 15
    Weight gain 4/48 (8.3%) 5 0/21 (0%) 0
    Musculoskeletal and connective tissue disorders
    Extemity-lower (gait/walking) 0/48 (0%) 0 1/21 (4.8%) 1
    Muscle weakness, generalized or specific area-upper extremity/whole body/generalized 3/48 (6.3%) 3 1/21 (4.8%) 1
    Musculoskeletal/soft tissue-Other 5/48 (10.4%) 7 0/21 (0%) 0
    Pain-joint 17/48 (35.4%) 35 6/21 (28.6%) 16
    Arthritis (non-septic) 0/48 (0%) 0 1/21 (4.8%) 1
    Pain-extremity. limb 16/48 (33.3%) 31 8/21 (38.1%) 20
    Pain-buttock 0/48 (0%) 0 1/21 (4.8%) 1
    Pain-muscle 10/48 (20.8%) 11 3/21 (14.3%) 3
    Myositis 0/48 (0%) 0 1/21 (4.8%) 1
    Nervous system disorders
    Dizziness 11/48 (22.9%) 19 5/21 (23.8%) 5
    Memory impairment 5/48 (10.4%) 6 1/21 (4.8%) 1
    Neurology-Other 0/48 (0%) 0 1/21 (4.8%) 2
    Neuropathy - sensory 15/48 (31.3%) 42 5/21 (23.8%) 7
    Pain-Head/headache 26/48 (54.2%) 53 13/21 (61.9%) 20
    Syncope/fainting 0/48 (0%) 0 1/21 (4.8%) 1
    Taste alteration (dysgeusia) 14/48 (29.2%) 26 5/21 (23.8%) 6
    Extrapyramidal/involuntary movement/restlessnes 0/48 (0%) 0 1/21 (4.8%) 1
    Seizure 0/48 (0%) 0 1/21 (4.8%) 1
    Psychiatric disorders
    Insomnia 11/48 (22.9%) 13 6/21 (28.6%) 6
    Mood alteration-agitation 0/48 (0%) 0 1/21 (4.8%) 1
    Mood alteration-anxiety 10/48 (20.8%) 12 2/21 (9.5%) 2
    Mood alteration-depression 10/48 (20.8%) 11 2/21 (9.5%) 2
    Confusion 3/48 (6.3%) 3 0/21 (0%) 0
    Renal and urinary disorders
    Hemorrhage, GU urinary 0/48 (0%) 0 4/21 (19%) 4
    Proteinuria 11/48 (22.9%) 49 9/21 (42.9%) 56
    Renal/Genitourinary-Other 0/48 (0%) 0 2/21 (9.5%) 2
    Uric acid, serum-high (hyperuricemia) 0/48 (0%) 0 3/21 (14.3%) 3
    Urinary frequency/urgency 5/48 (10.4%) 7 2/21 (9.5%) 4
    Hemoglobinuria 0/48 (0%) 0 2/21 (9.5%) 3
    Reproductive system and breast disorders
    Hemorrhage, GU vaginal 0/48 (0%) 0 1/21 (4.8%) 3
    Pain-breast 3/48 (6.3%) 4 0/21 (0%) 0
    Respiratory, thoracic and mediastinal disorders
    Bronchospasm-wheezing 0/48 (0%) 0 1/21 (4.8%) 1
    Cough 19/48 (39.6%) 30 10/21 (47.6%) 13
    Dyspnea 10/48 (20.8%) 16 4/21 (19%) 6
    Hemorrhage, pulmonary/upper respiratory-nose 15/48 (31.3%) 26 9/21 (42.9%) 13
    Pain-throat, pharynx 10/48 (20.8%) 17 5/21 (23.8%) 11
    Pulmonary\upper respiratory-Other 8/48 (16.7%) 13 4/21 (19%) 6
    Voice changes/dysarthria 33/48 (68.8%) 58 14/21 (66.7%) 21
    Hiccoughs 0/48 (0%) 0 1/21 (4.8%) 2
    Infection with normal ANC or Grade 1 or 2 neutrophils-lung (pneumonia) 0/48 (0%) 0 1/21 (4.8%) 1
    Infection with normal ANC or Grade 1 or 2 neutrophils-upper airway NOS 0/48 (0%) 0 2/21 (9.5%) 2
    pneumonitis/pumonary infiltrates 0/48 (0%) 0 1/21 (4.8%) 1
    Skin and subcutaneous tissue disorders
    Bruising (in absence of Grade 3/4 thromboctyopenia) 4/48 (8.3%) 4 2/21 (9.5%) 2
    Dermatology/Skin-Other 14/48 (29.2%) 31 6/21 (28.6%) 16
    Dry skin 16/48 (33.3%) 26 7/21 (33.3%) 8
    hair loss-scalp or body 5/48 (10.4%) 15 6/21 (28.6%) 6
    Nail changes 5/48 (10.4%) 6 1/21 (4.8%) 1
    Pruritis 10/48 (20.8%) 15 5/21 (23.8%) 7
    Rash/desquamation 18/48 (37.5%) 30 9/21 (42.9%) 15
    Rash acne/actiform 13/48 (27.1%) 17 3/21 (14.3%) 3
    palmar/plantar paresthesia 27/48 (56.3%) 195 17/21 (81%) 41
    Sweating/diphoresis 5/48 (10.4%) 10 3/21 (14.3%) 4
    Hyperpigmentation 0/48 (0%) 0 1/21 (4.8%) 1
    Pain-skin 0/48 (0%) 0 1/21 (4.8%) 1
    Pain-scalp 10/48 (20.8%) 12 1/21 (4.8%) 1
    Telangiectasia 0/48 (0%) 0 1/21 (4.8%) 1
    Vascular disorders
    Flushing 4/48 (8.3%) 5 1/21 (4.8%) 1
    Hypertension 20/48 (41.7%) 54 15/21 (71.4%) 26
    Vascular-other 0/48 (0%) 0 1/21 (4.8%) 1
    Hypotension 3/48 (6.3%) 3 0/21 (0%) 0
    Vessel injury-vein-extremity-limb 0/48 (0%) 0 1/21 (4.8%) 1

    Limitations/Caveats

    To depict results of this Phases I/II study accurately, each phase was entered as an ARM to enable separation of the data by phase. Events reported in the Adverse Event and Serious Adverse Event sections include AEs and SAEs from Phase I and Phase II

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.

    Results Point of Contact

    Name/Title Jeffrey Sosman, MD
    Organization Vanderbilt-Ingram Cancer Center
    Phone 615-936-3048
    Email jeff.sosman@vanderbilt.edu
    Responsible Party:
    National Cancer Institute (NCI)
    ClinicalTrials.gov Identifier:
    NCT00126503
    Other Study ID Numbers:
    • NCI-2009-00066
    • NCI-2009-00066
    • CDR0000434814
    • URO 470
    • 6555
    • U01CA099177
    • P30CA068485
    First Posted:
    Aug 4, 2005
    Last Update Posted:
    Jan 15, 2015
    Last Verified:
    Sep 1, 2014