A Phase I/II Trial of BAY 43-9006 in Combination With Bevacizumab in Patients With Advanced RenalCancer

Inclusion Criteria

DISEASE CHARACTERISTICS:

- 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 (for patients in
the phase II portion of the study only):

- 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

PATIENT CHARACTERISTICS:

Age

- 18 and over

Performance status

- ECOG 0-1

Life expectancy

- More than 3 months

Hematopoietic

- Hemoglobin ≥ 9.0 g/dL (transfusion allowed)

- WBC ≥ 3,000/mm^3

- Absolute granulocyte count ≥ 1,200/mm^3

- Platelet count ≥ 100,000/mm^3

- 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

Cardiovascular

- No uncontrolled hypertension

- Blood pressure must be ≤ 150/90 mm Hg on a stable antihypertensive regimen

- No clinically significant cardiovascular disease within 1 year prior to study entry

- 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 serious cardiac arrhythmia requiring medication

- No peripheral vascular disease ≥ grade 2 within the past year

- No history of stroke

- No other clinically significant cardiovascular disease

Other

- Not pregnant

- No nursing during and for ≥ 3 months after completion of study treatment

- 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

PRIOR CONCURRENT THERAPY:

Biologic 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

Chemotherapy

- 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

Endocrine therapy

- Not specified

Radiotherapy

- At least 2 weeks since prior radiotherapy and recovered

Surgery

- See Disease Characteristics

- More than 4 weeks since prior major surgical procedure or open biopsy

- No concurrent major surgery

Other

- 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