A Phase I/II Trial of BAY 43-9006 in Combination With Bevacizumab in Patients With Advanced Renal Cancer
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 73
- 试验地点
- 5
- 主要终点
- Objective Response
研究概览
简要总结
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.
详细描述
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)
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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)
排除标准
- •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
研究组 & 干预措施
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.
干预措施: Bevacizumab (Biological)
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.
干预措施: Sorafenib Tosylate (Drug)
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.
干预措施: Pharmacological Study (Other)
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.
干预措施: Laboratory Biomarker Analysis (Other)
结局指标
主要结局
Objective Response
时间窗: 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
Maximum Tolerated Dose of Bevacizumab in Combination With BAY 43-9006 (Sorafenib)(Phase I)
时间窗: 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.
Maximum Tolerated Dose (MTD) of BAY 43-9006 (Sorafenib)in Combination With Bevacizumab (Phase I)
时间窗: 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.
次要结局
- Progression-free Survival(on-study to date of progression or last date known alive without progression)
- Overall Survival(on-study to date of expired or last date known alive)