Sorafenib Tosylate and Bevacizumab in Treating Patients With Advanced Kidney Cancer

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT00126503
First received: August 2, 2005
Last updated: May 9, 2014
Last verified: March 2014

August 2, 2005
May 9, 2014
May 2005
March 2012   (final data collection date for primary outcome measure)
  • Maximum Tolerated Dose (MTD) of BAY 43-9006 (Sorafenib)in Combination With Bevacizumab (Phase I) [ Time Frame: at 28 days ] [ Designated as safety issue: Yes ]
    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.
  • Maximum Tolerated Dose of Bevacizumab in Combination With BAY 43-9006 (Sorafenib)(Phase I) [ Time Frame: at 28 days ] [ Designated as safety issue: Yes ]
    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.
  • Objective Response [ Time Frame: Every 8 weeks to date of progression ] [ Designated as safety issue: No ]
    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
Not Provided
Complete list of historical versions of study NCT00126503 on ClinicalTrials.gov Archive Site
  • Overall Survival [ Time Frame: on-study to date of expired or last date known alive ] [ Designated as safety issue: No ]
    Months from date on-study to expired or last date known alive
  • Progression-free Survival [ Time Frame: on-study to date of progression or last date known alive without progression ] [ Designated as safety issue: No ]
    Duration of months of progression-free survival (PFS). Determined by months to progressive disease or to last date known alive without progressive disease.
Not Provided
Not Provided
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Sorafenib Tosylate and Bevacizumab in Treating Patients With Advanced Kidney Cancer
A Phase I/II Trial of BAY 43-9006 in Combination With Bevacizumab in Patients With Advanced Renal 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 in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. 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. This phase I/II trial is studying 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.

PRIMARY OBJECTIVES:

I. To determine the tolerability and maximum tolerated dose of Sorafenib when given orally in combination with Bevacizumab in patients with 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: VHL mutation status and 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 MAP kinase, Akt and 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, MEK, Erk, Erk phosphorylation, Akt phosphorylation status and Raf subcellular localization.
  2. VEGFR1 (flk1) and VEGFR 2 (flt1/KDR) status and tissue VEGF
  3. Tumor cell apoptosis - Ki-67, TUNEL staining, and expression levels of 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 DCE- 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 MTD dose level of Sorafenib and bevacizumab representing the recommended phase II dose (RPTD) schedule (200mg QD Sorafenib and 5 mg/kg IV Q 2weeks 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, bFGF, IL-8 etc) and association of findings with response, response duration and prediction of relapse.

OUTLINE: This is an open-label, multicenter, 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.]

Interventional
Phase 1
Phase 2
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
  • Clear Cell Renal Cell Carcinoma
  • Recurrent Renal Cell Cancer
  • Stage IV Renal Cell Cancer
  • Biological: bevacizumab
    Given IV
    Other Names:
    • anti-VEGF humanized monoclonal antibody
    • anti-VEGF monoclonal antibody
    • Avastin
    • rhuMAb VEGF
  • Drug: sorafenib tosylate
    Given PO
    Other Names:
    • BAY 43-9006
    • BAY 43-9006 Tosylate Salt
    • BAY 54-9085
    • Nexavar
    • SFN
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.

Interventions:
  • Biological: bevacizumab
  • Drug: sorafenib tosylate
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Active, not recruiting
73
Not Provided
March 2012   (final data collection date for primary outcome measure)

Inclusion Criteria:

  • Histologically or cytologically confirmed renal cell carcinoma (RCC) of 1 of the following types:

    • Clear cell
    • Papillary (phase I only)
    • Chromophobe (phase I only)
    • Sarcomatoid (phase I only) [Note: Clear cell RCC with < 25% of any other histology (e.g., papillary, chromophobe, or oncocytic) required for enrollment in the phase II portion of the study]
  • Advanced disease
  • Measurable disease not curable by standard therapy (for patients in the phase I portion of the study only)
  • Measurable disseminated disease that is not curable by standard radiotherapy or surgery (for patients in the phase II portion of the study only)
  • Has undergone prior nephrectomy, unless 1 of the following is true (phase II):

    • Primary tumor =< 5 cm
    • Extensive liver metastases (i.e., > 30% of liver parenchyma) OR multiple bone metastases (i.e., > 5) OR extensive extrarenal tumor or unresectable local/regional tumor extension making nephrectomy a clinically questionable and unreasonable procedure
  • Tumor tissue block available (for patients in the phase II portion of the study only)
  • No history or clinical evidence of CNS disease, including primary brain tumor (history of meningioma allowed), or brain metastasis
  • Patients with a history of brain metastasis that have been resected or have had radiosurgery with no progression for man than 6 months are eligible
  • Performance status:

    • ECOG 0-1
  • Life expectancy:

    • More than 3 months
  • Hematopoietic:

    • Hemoglobin >= 9.0 g/dL (transfusion allowed)
    • WBC >= 3,000/mm3
    • Absolute granulocyte count >= 1,200/mm3
    • Platelet count >= 100,000/mm3
    • No history of bleeding diathesis or coagulopathy
  • Hepatic:

    • Bilirubin =< 1.5 times upper limit of normal (ULN)
    • AST and ALT =< 2.5 times ULN
    • INR =< 1.5
    • aPTT =< 1.3 times ULN
  • Renal:

    • Creatinine =< 1.5 times ULN (2.0 times ULN for patients in the phase II portion of the study) OR
    • Creatinine clearance >= 40 mL/min
    • Urine protein < 1+ by dipstick OR =< 1,000 mg by 24-hour urine collection
  • No uncontrolled hypertension
  • Blood pressure must be =< 150/90 mm Hg on a stable antihypertensive regimen
  • No myocardial infarction within the past 6 months
  • No unstable angina pectoris within the past 6 months
  • No New York Heart Association grade II-IV congestive heart failure
  • No peripheral vascular disease >= grade 2 within the past year
  • No history of stroke
  • No other clinically significant cardiovascular disease
  • Negative pregnancy test
  • Fertile patients must use effective contraception prior to, during, and for >= 3 months after completion of study treatment
  • No condition that would preclude ability to swallow pills
  • No other malignancy within the past 3 years with the exception of non-melanoma skin cancer, melanoma in situ, cervical cancer, ductal carcinoma in situ, or lobular carcinoma in situ (for patients in the phase II portion of the study only)
  • No prior malignancy that does not have a very likely cure rate (i.e., approximately 75% or greater) (for patients in the phase II portion of the study only)
  • No history of allergic reaction attributed to Chinese hamster ovary cell products, other recombinant human antibodies, or compounds of similar chemical or biological composition to sorafenib
  • No psychiatric illness or social situation that would preclude study compliance
  • No serious non-healing wound, ulcer, or bone fracture
  • No history or clinical evidence of uncontrolled seizures
  • No significant traumatic injury within the past 28 days
  • No ongoing or active infection requiring parenteral antibiotics
  • No other uncontrolled illness
  • No history of seizures unless controlled with standard medical therapy
  • More than 4 weeks since prior immunotherapy
  • More than 8 weeks since prior monoclonal antibodies
  • No more than 1 prior vaccine or cytokine-based immunotherapy regimen for stage IV disease (for patients in the phase II portion of the study only)
  • No prior vascular endothelial growth factor (VEGF) or VEGF signaling inhibitors
  • No prior bevacizumab or sorafenib
  • No other prior antiangiogenic therapy (e.g., SU011248, ZD6474, or VEGF Trap)
  • Prior thalidomide or interferon alfa as adjuvant therapy or for treatment of stage IV disease allowed
  • No concurrent prophylactic granulocyte or platelet colony-stimulating factors
  • More than 4 weeks since prior chemotherapy
  • No prior chemotherapy regimen for stage IV disease (for patients in the phase II portion of the study only)
  • Prior immunotherapy is not considered chemotherapy
  • At least 2 weeks since prior radiotherapy and recovered
  • More than 4 weeks since prior major surgical procedure or open biopsy
  • No concurrent major surgery
  • No prior MAP kinase pathway inhibitors (for patients in the phase II portion of the study only)
  • No prior experimental therapy for advanced RCC (for patients in the phase II portion of the study only)
  • No concurrent or recent (within 7 days of starting study drugs) use of full-dose anticoagulants or thrombolytic agents
  • Concurrent anticoagulants to maintain patency of preexisting, permanent indwelling IV catheters allowed
  • Concurrent warfarin allowed provided INR =< 1.5
  • No concurrent P450 enzyme-inducing antiepileptic drugs (e.g., phenytoin, carbamazepine, phenobarbital, rifampin, or Hypericum perforatum [St. John's wort])
  • No concurrent combination anti-retroviral therapy for HIV-positive patients
  • Not pregnant
  • No nursing during and for >= 3 months after completion of study treatment
Both
18 Years and older
No
Contact information is only displayed when the study is recruiting subjects
United States
 
NCT00126503
NCI-2009-00066, NCI-2009-00066, CDR0000434814, URO 470, 6555, U01CA099177, P30CA068485
Not Provided
National Cancer Institute (NCI)
National Cancer Institute (NCI)
Not Provided
Principal Investigator: Jeffrey Sosman Vanderbilt-Ingram Cancer Center
National Cancer Institute (NCI)
March 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP