Sorafenib and Bevacizumab in Treating Patients With Advanced Kidney Cancer

• Toxicity (Phase I) [ Time Frame: 30 days after last chemotherapy treatment ] [ Designated as safety issue: Yes ]
• Progression-free survival (Phase II) [ Time Frame: Off-study date ] [ Designated as safety issue: No ]

RATIONALE: Sorafenib 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 may also stop the growth of tumor cells by blocking blood flow to the tumor. Giving sorafenib together with bevacizumab may kill more tumor cells.

PURPOSE: This phase I/II trial is studying the side effects and best dose of sorafenib and bevacizumab and to see how well they work in treating patients with advanced kidney cancer.

OBJECTIVES:

Primary

• Determine the tolerability and maximum tolerated dose of sorafenib and bevacizumab in patients with advanced renal cell cancer. (Phase I)
• Determine the progression-free survival of patients treated with this regimen. (Phase II)
• Determine the median time to progression in patients treated with this regimen. (Phase II)
• Determine the number and percent of patients with stable disease at 6 months after treatment with this regimen. (Phase II)
• Determine the objective response rate and duration of objective response in patients treated with this regimen. (Phase II)
• Determine the number of complete and partial responses in patients treated with this regimen. (Phase II)

Secondary

• Correlate changes in tumor perfusion and vascular permeability by serial dynamic contrast-enhanced MRI or arterial spin labeled MRI with antitumor effects of this regimen and clinical outcome in these patients. (Phase II)
• Determine the effect of this regimen on circulating endothelial cells and progenitors as an indicator of angiogenic effects in these patients. (Phase II)
• Correlate steady-state trough plasma concentrations of these drugs with toxicity and clinical activity in these patients. (Phase II)

OUTLINE: This is an open-label, multicenter, phase I dose-escalation study followed by a phase II study.

• Phase I: Patients receive oral sorafenib 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 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 oral sorafenib 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 therapy, patients are followed every 3 months for 2 years and then every 6 months thereafter.

PROJECTED ACCRUAL: A total of 32-58 patients (12-18 for the phase I portion and 20-40 for the phase II portion) will be accrued for this study within approximately 5-19 months.

• Drug: bevacizumab
  Given through a vein in the arm 1 time every 2 weeks.
• Drug: sorafenib tosylate
  Will be take by mouth twice a day.

• Puzanov I, Flaherty KT, Atkins MB: Final results of a phase I trial of sorafenib and bevacizumab in patients with metastatic renal cell cancer (mRCC). [Abstract] American Association for Cancer Research: Molecular Targets and Cancer Therapeutics, October 22-26, 2007, San Francisco, CA A-19, 2007.
• Sosman JA, Flaherty K, Atkins MB, et al.: A phase I/II trial of sorafenib (S) with bevacizumab (B) in metastatic renal cell cancer (mRCC) patients (Pts). [Abstract] J Clin Oncol 24 (Suppl 18): A-3031, 128s, 2006.

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