Sorafenib, Gemcitabine, and Capecitabine in Treating Patients With Unresectable and/or Metastatic Kidney Cancer

OBJECTIVES:

I. Determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of sorafenib
administered in combination with gemictabine and capecitabine in patients with advanced renal
cell carcinoma.

II. Determine the objective response rate for sorafenib in combination with gemictabine and
capecitabine in patients with advanced renal cell carcinoma.

III. Determine the duration of overall survival and progression free survival in these
patients.

OUTLINE: This is a multicenter, non-randomized, phase I dose-escalation study followed by a
phase II study.

PHASE I: Patients receive sorafenib* orally (PO) twice daily (BID) on days 1-21, gemcitabine
intravenously (IV) over 30 minutes on days 1 and 8, and capecitabine PO BID on days 1-14.
Treatment repeats every 21 days for at least 3 courses in the absence of unacceptable
toxicity or disease progression.

Cohorts of 3-6 patients receive escalating doses of sorafenib, gemcitabine, and capecitabine
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.

Note: *Patients who complete at least 3 courses of treatment with objective response or
stable disease but are deemed poor candidates for continued chemotherapy may continue
treatment with sorafenib

PHASE II: Patients receive sorafenib, gemcitabine, and capecitabine as in phase I at the MTD
determined in phase I.

After completion of study treatment patients are followed periodically.

Inclusion Criteria:

- Patients must have histologically or cytologically confirmed renal cell carcinoma that
is unresectable and/or metastatic; patients with collecting duct carcinoma,
oncocytomas, or transitional cell carcinoma are not eligible; patients with
sarcomatoid renal cell carcinoma are eligible, but those with pure sarcomas are not;
histologic documentation of metastatic disease is not required; clinical confirmation,
but not pathologic staging, of metastatic disease is required

- Patients must have measurable disease, defined as at least one lesion that can be
accurately measured in at least one dimension (longest diameter to be recorded) as >=
20 mm with conventional techniques or as >= 10 mm with spiral computed tomography (CT)
scan

- Patients may have received one prior immunotherapy based regimen (i.e. interleukin-2
or interferon alpha) ending >= 4 weeks prior to enrollment

- Patients may have received up to 2 prior regimens containing mitogen-activated protein
kinases (MAPK), vascular endothelial growth factor (VEGF) pathway inhibitors (e.g.
sunitinib or bevacizumab) and/or mammalian target of rapamycin (mTOR) inhibitor (e.g.
temsirolimus) ending >= 4 weeks prior to enrollment

- Life expectancy of more than 3 months

- Eastern Cooperative Oncology Group (ECOG) =< 2 OR Karnofsky >= 60%

- Leukocytes >= 3000/uL

- Absolute neutrophil count >= 1,500/uL

- Platelet count >= 100,000/uL

- Total bilirubin =< 1.5 x institutional upper limit of normal (IULN)

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamic pyruvate transaminase [SGPT])
=< 2.5 x IULN

- Creatinine =< 1.5 x IULN OR creatinine clearance >= 60 mL/min/1.73m^2 for patients
with creatinine levels above institutional normal

- The effects of sorafenib on the developing human fetus at the recommended therapeutic
dose are unknown; for this reason and because raf kinase inhibitor agents as well as
other therapeutic agents used in this trial are known to be teratogenic, 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 or suspect she is 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

Exclusion Criteria:

- Patients may not have received prior chemotherapy; if patients have had prior
definitive or other surgery, prior radiation therapy, they must have fully recovered
from the effects of therapy with at least 4 weeks recovery time; for patients who have
had a surgical biopsy only, they must have simply recovered

- Patients may not be receiving any other investigational agents

- Patients with known active brain metastases should be excluded from this clinical
trial because of their poor prognosis and because they often develop progressive
neurologic dysfunction that would confound the evaluation of neurologic and other
adverse events; previously treated brain metastases are allowed if they show no
evidence of progression on CT or magnetic resonance imaging (MRI) at least 8 weeks
after completion of surgery and/or radiotherapy

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to sorafenib, gemcitabine and capecitabine

- No concurrent megestrol is permitted; no megestrol therapy within 4 weeks prior to
protocol treatment is allowed; no concurrent cytochrome P450 enzyme-inducing
antiepileptic drugs (phenytoin, phenobarbitol or carbamazepine), rifampin, or St.
John's wort

- Uncontrolled intercurrent illness including, but not limited to, uncontrolled
hypertension, ongoing or active infection, symptomatic congestive heart failure,
unstable angina pectoris, cardiac arrhythmia, pulmonary disease including asthma,
chronic bronchitis, emphysema with requirements for chronic oxygen use or psychiatric
illness/social situations that would limit compliance with study requirements

- Pregnant women are excluded from this study because sorafenib is a kinase inhibitor
agent with the potential for teratogenic or abortifacient effects; because there is an
unknown but potential risk for adverse events in nursing infants secondary to
treatment of the mother with sorafenib, breastfeeding should be discontinued if the
mother is treated with sorafenib; the potential risks may apply to other agents used
in this study

- Because patients with immune deficiency are at increased risk of lethal infections
when treated with marrow-suppressive therapy, human immunodeficiency virus
(HIV)-positive patients receiving combination anti-retroviral therapy are excluded
from the study because of possible pharmacokinetic interactions with sorafenib,
gemcitabine, or capecitabine administered during the study; appropriate studies will
be undertaken in patients receiving combination ant-retroviral therapy when indicated

- Any swallowing dysfunction leading to difficulty taking the investigational therapy or
capecitabine

- Prior treatment with sorafenib

- Patients with any history or evidence of a bleeding diathesis

- Patients on therapeutic anticoagulation with coumarins (e.g. warfarin); prophylactic
coumarin-based anticoagulation (i.e. low dose warfarin) for venous or arterial access
devices is allowed provided that the requirements for prothrombin time (PT),
international normalization ratio (INR) and/or partial thromboplastin time (PTT) are
met; prophylactic or therapeutic low molecular weight heparin is allowed; patients
with known brain metastases are excluded (even if treated and stable) if they are also
on therapeutic doses of anticoagulation

- Patients with known dihydropyrimidine dehydrogenase deficiency