Ignite Creation Date:
2025-12-24 @ 7:24 PM
Ignite Modification Date:
2025-12-29 @ 5:32 PM
Study NCT ID:
NCT00126503
Status:
COMPLETED
Last Update Posted:
2015-01-15
First Post:
2005-08-02
Is NOT Gene Therapy:
True
Has Adverse Events:
True
Brief Title:
Sorafenib Tosylate and Bevacizumab in Treating Patients With Advanced Kidney Cancer
Sponsor:
National Cancer Institute (NCI)
Organization:
Study Overview
Official Title:
A Phase I/II Trial of BAY 43-9006 in Combination With Bevacizumab in Patients With Advanced Renal Cancer
Status:
COMPLETED
Status Verified Date:
2014-09
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
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.
Detailed Description:
PRIMARY OBJECTIVES:
I. 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:
I. 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).
V. 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.
I. 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:
I. 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).
V. 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.
Study Oversight
Has Oversight DMC:
Is a FDA Regulated Drug?:
Is a FDA Regulated Device?:
Is an Unapproved Device?:
Is a PPSD?:
Is a US Export?:
Is an FDA AA801 Violation?:
Secondary ID Infos
| Secondary ID | Type | Domain | Link | View |
|---|---|---|---|---|
| NCI-2009-00066 | REGISTRY | CTRP (Clinical Trial Reporting Program) | View | |
| CDR0000434814 | None | None | View | |
| URO 470 | OTHER | Vanderbilt-Ingram Cancer Center | View | |
| 6555 | OTHER | CTEP | View | |
| U01CA099177 | NIH | None | https://reporter.nih.gov/quic… | View |
| P30CA068485 | NIH | None | https://reporter.nih.gov/quic… | View |