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

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.

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.

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