Determine time-to-progression (TTP) for an escalating dose schedule for subjects with progressive metastatic renal cell carcinoma treated with sorafenib

Sorafenib to be administered as 28-day cycles.

Sorafenib dose escalation by cycle is:

• Cycle 1: 400 mg BID
• Cycle 2: 600 mg BID
• Cycle 3+: 800 mg BID

Within subject dose escalation and maximum dose is dependent on observed tolerability.

Dose escalation only occurs after acceptable tolerability is demonstrated by subject.

Inclusion Criteria:

1. Histologically- or cytologically-confirmed metastatic or unresectable renal cell carcinoma (RCC).
2. must have a component of conventional clear cell renal carcinoma.
3. No more than one prior systemic therapy.
4. No prior vascular endothelial growth factor receptor agents.
5. Prior palliative radiotherapy in metastatic lesion(s) is permitted, provided the subject has at least one measurable and/or evaluable lesion(s) that has not been irradiated.
6. All major surgery of any type and/or radiotherapy must be completed at least 4 weeks prior to Day 1 dosing. Patients must have recovered from surgery and/or radiotherapy toxicity prior to Day 1 dosing.
7. Measureable disease by RECIST criteria
8. Karnofsky performance status at least 70% or ECOG not more than 2
9. Ability to give written informed consent
10. At least 18 years old
11. Negative pregnancy test within 7 days of Day 1 dosing (female subjects of childbearing potential)
12. Sexually active fertile subjects must agree to use an accepted method of contraception during the course of the study for 3 months thereafter.
13. ANC at least 1,500/uL
14. Platelet count at least 100,000/uL
15. AST/ALT not more than 2.5 times the upper limit of normal (ULN)
16. Alkaline phosphatase not more than 2.5 x ULN
17. Serum bilirubin not more than 1.5 x ULN
18. Amylase/Lipase within normal range
19. Urinalysis not more than 1+ protein
20. Serum creatinine not more than 1.5 x ULN
21. No active ischemia by ECG
22. Echocardiogram or MUGA ejection fraction at least 40%

Exclusion Criteria:

1. Ongoing hemoptysis
2. Cerebrovascular accident within 12 months
3. Peripheral vascular disease with claudication on less than 1 block
4. History of clinically significant bleeding
5. Malignancy with true papillary/sarcomatoid features without any clear cell component
6. Chromophobe
7. Oncocytoma
8. Collecting duct tumors
9. Transitional cell carcinoma
10. Deep venous thrombosis or pulmonary embolus within one year of consent
11. Ongoing need for full-dose oral or parenteral anticoagulation. Low dose coumadin (1 mg) for maintenance of catheter patency or daily prophylactic aspirin is allowed
12. Subjects with evidence of current central nervous system (CNS) metastases
13. MRI or CT scan of the brain (with contrast, if possible) within 28 days prior to Day 1 dosing
14. Significant cardiovascular disease defined as congestive heart failure (New York Heart Association Class II, II or IV)
15. Angina pectoris requiring nitrate therapy
16. Myocardial infarction within the last 6 months
17. Uncontrolled hypertension (defined as blood pressure at least 160 mmHg systolic or at least 90 mmHg diastolic on medication)
18. Ongoing requirement for systemic corticosteroid therapy (except replacement therapy for adrenal insufficiency). Topical and/or inhaled steroids are allowed.
19. Uncontrolled psychiatric disorder
20. Delayed healing of wounds, ulcers, and/or bone fractures
21. Prior malignancy (EXCEPTIONS: adequately-treated basal cell or squamous cell skin cancer or any other cancer for which chemotherapy has been completed > 5 years ago and from which the patient has been disease-free for > 5 years)
22. Pregnant
23. Currently lactating
24. Currently using St John's Wort (an herb)

All subjects enrolled were included in the analysis