A Phase II, Pharmacokinetic And Biologic Correlative Study of OSI-774, An EGFR Tyrosine Kinase Inhibitor, In Patients With Advanced Renal Cell Carcinoma

Inclusion Criteria:

- Patients must have histologically or cytologically confirmed diagnosis of advanced
renal cell carcinoma (RCC). Papillary RCC is permitted only if immunohistochemical
evidence of strong (2-3+) EGFR expression.

- Disease that is recurrent or refractory to IL-2 or IFN-based therapy or new diagnosis
in previously untreated patients who are not appropriate candidates to receive IL-2
-based treatment

- 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 CT scan.

- Prior nephrectomy or resection of metastatic lesions permitted if full surgical
recovery has occurred.

- Age > 18 years Because no dosing or adverse event data are currently available on the
use of OSI-774 in patients <18 years of age, children are excluded from this study
but will be eligible for future pediatric single-agent trials, if applicable.

- Life expectancy of at least 12 weeks

- ECOG performance status of 0,1 or 2 or Karnofsky >60%

- Patients must have normal organ and marrow function as defined below:

Hematopoietic

1. Absolute neutrophil count at least ≥ 1,500/ul

2. Platelet ≥ 100,000/uL

3. Hemoglobin ≥ 9.0 g/dL, concomitant erythropoetin permitted Hepatic

a. Total bilirubin within normal institutional limits b. AST (SGOT)/ALT (SGPT) ≤ 2.5 times
institutional upper limit of normal (≤5 times ULN if liver metastases present) Renal

a. Serum creatinine ≤ 1.5 times ULN or calculated creatinine clearance > 60 mL/min/1.73m2
Calcium

a. Corrected calcium < 12.0 mg/dl, concomitant hypocalcemic agents permitted

- Complete supportive and palliative care will continue to be provided to ameliorate
signs and symptoms that were pre-existing or may arise while on study and which do
not interfere with the objectives of the study. The use of erythropoietin and
biphosphonates is permitted.

- Patients must have tumor blocks available for EGFR expression analysis to be eligible
for treatment on this study.

Exclusion Criteria:

- History of active malignancy (other than RCC) in the past 3 years, other than
nonmelanomatous skin cancer or in situ breast cancer or in situ cervical cancer.

- Patients with known brain metastases will 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.

- Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for
nitrosoureas or mitomycin C) prior to entering the study or those who have not
recovered from adverse events due to agents administered more than 4 weeks earlier.

- Patients may not be receiving any other investigational agents.

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to OSI-774.

- Prior treatment with EGFR targeting therapies.

- Inability to understand the written informed consent document.

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements.

- Major surgery, or significant traumatic injury occurring within 21 days prior to
treatment.

- Abnormalities of the cornea based on history (e.g., dry eye syndrome, Sjogren's
syndrome), congenital abnormality (e.g., Fuch's dystrophy), abnormal slit-lamp
examination using a vital dye (e.g., fluorescein, Bengal Rose), and/or an abnormal
corneal sensitivity test (Schirmer test or similar tear production test).

- Gastrointestinal tract disease resulting in an inability to take oral medication or a
requirement for IV alimentation, prior surgical procedures affecting absorption, or
active peptic ulcer disease.

- Pregnant women are excluded from this study because OSI-774 is an epidermal growth
factor inhibitor with the potential for teratogenic or abortifacient effects based on
the data suggesting that EGFR expression is important for normal organ development.
For this reason, women of childbearing potential and men must also agree to use
adequate contraception (hormonal or barrier method of birth control) 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. Because there is an unknown but potential risk for
adverse events in nursing infants secondary to treatment of the mother with OSI-774,
breastfeeding should be discontinued if the mother is treated with OSI-774.

- Because patients with immune deficiency are at increased risk of lethal infections
when treated with marrow-suppressive therapy, HIV-positive patients receiving
combination anti-retroviral therapy are excluded from the study because of possible
pharmacokinetic interactions with OSI-774. Appropriate studies will be undertaken in
patients receiving combination anti-retroviral therapy when indicated.

- Informed Consent - No study specific procedures will be performed without a written
and signed informed consent document. Patients who do not demonstrate the ability to
understand or the willingness to sign the written informed consent document are
excluded from study entry.