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Chromophobe Renal Cell CarcinomaPhase 1/2NCT00126503

Sorafenib Tosylate and Bevacizumab in Treating Patients With Advanced Kidney Cancer

A Phase 1/2 study testing Bevacizumab, Sorafenib Tosylate and Pharmacological Study in people with Chromophobe Renal Cell Carcinoma and Clear Cell Renal Cell Carcinoma, run by National Cancer Institute (NCI) at 5 sites in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial 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. Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
Bevacizumab, Sorafenib Tosylate and Pharmacological Study
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
73 participants
Where
5 sitesUnited States
Study dates
May 2005to Feb 2012
Phase
Phase 1/2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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)
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  • 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)

Who cannot join

  • 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
Show all 22Show fewer
  • 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

Trial locations and contacts

5 sites in 1 country.

5 sites in 1 country

United States5 sites

  • Dana-Farber Cancer Institute

    Boston, Massachusetts, 02115

  • Dana-Farber Harvard Cancer Center

    Boston, Massachusetts, 02115

  • Beth Israel Deaconess Medical Center

    Boston, Massachusetts, 02215

  • Vanderbilt-Ingram Cancer Center

    Nashville, Tennessee, 37232

  • University of Pennsylvania/Abramson Cancer Center

    Philadelphia, Pennsylvania, 19104

Other trials in United States

About this study

Official title: A Phase I/II Trial of BAY 43-9006 in Combination With Bevacizumab in Patients With Advanced Renal Cancer

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.

Read the 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.

II. 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.

IV. 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).

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

VI. 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.

Being tested
Bevacizumab, Sorafenib Tosylate, Pharmacological Study, Laboratory Biomarker Analysis
Medical subject headings
Carcinoma, Renal Cell

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • BevacizumabBiological

    Also called Avastin, rhuMab-VEGF

    Given IV

  • Sorafenib TosylateDrug

    Also called BAY 54-9085, Nexavar, SFN

    Given PO

  • Pharmacological StudyOther

    Also called pharmacological studies

    Correlative studies

  • Laboratory Biomarker AnalysisOther

    Correlative studies

Study groups in NCT00126503
Study groupRoleWhat they receive
Treatment (bevacizumab and sorafenib tosylate)ExperimentalPhase 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.
Receives: Biological: Bevacizumab; Drug: Sorafenib Tosylate; Other: Pharmacological Study; Other: Laboratory Biomarker Analysis

What is being measured

The primary outcome is the main question the study is designed to answer.

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

    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.

    Measured: at 28 days

  2. Maximum Tolerated Dose of Bevacizumab in Combination With BAY 43-9006 (Sorafenib)(Phase I)

    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.

    Measured: at 28 days

  3. Objective Response

    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

    Measured: Every 8 weeks to date of progression

Secondary outcomes (2)

  1. Overall Survival

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

    Measured: on-study to date of expired or last date known alive

  2. Progression-free Survival

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

    Measured: on-study to date of progression or last date known alive without progression

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted4 Aug 2005 (estimated)
  2. Study startMay 2005
  3. Primary completionOct 2011
  4. Study completionFeb 2012

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1/2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
73 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT00126503
Sponsor's protocol ID
NCI-2009-00066
Other IDs
NCI-2009-00066, CDR0000434814, URO 470, 6555, U01CA099177, P30CA068485
Status last verified
Sep 2014
First submitted
2 Aug 2005
Last updated
15 Jan 2015

Questions about this trial

What is this clinical trial studying?

A Phase 1/2 study testing Bevacizumab, Sorafenib Tosylate and Pharmacological Study in people with Chromophobe Renal Cell Carcinoma and Clear Cell Renal Cell Carcinoma, run by National Cancer Institute (NCI) at 5 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 35 inclusion and 22 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 15 Jan 2015. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 5 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this combined phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 28 Jun 2013). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Maximum Tolerated Dose (MTD) of BAY 43-9006 (Sorafenib)in Combination With Bevacizumab (Phase I) (time frame: at 28 days). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT00126503.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 15 Jan 2015.

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