A Phase I Trial of the Combination of Sirolimus and SU11248 (Sutent(R)) in Patients With Advanced Solid Tumors That Are Non-Curable With Standard Therapy

Inclusion Criteria:

- Patients must have histologically confirmed malignancy that is metastatic or
unresectable and for which standard curative or palliative measures do not exist or
are no longer effective. Patients with previously untreated metastatic renal cell
carcinoma are eligible.

- Patients must have measurable disease by RECIST criteria.

- Patients must have at least 1 lesion located in the neck, lung, solid organ
(including liver) or soft tissue in abdomen or pelvis, or soft tissue in lower
extremities that is 3 cm and ideally <7 cm in the transaxial plane. Larger lesions
may be considered if they meet all other criteria. Index lesions must be well
demarcated.

- ECOG performance status of 0-1.

- Must be ≥18 years of age.

- Expected survival of at least 3 months.

- Women of child-bearing potential (i.e., women who are pre-menopausal or not
surgically sterile) must use acceptable contraceptive methods (abstinence,
intrauterine device [IUD], oral contraceptive or double barrier device), and must
have a negative serum or urine pregnancy test within 1 week prior to beginning
treatment on this trial. Nursing patients are excluded. Sexually active men must also
use acceptable contraceptive methods. Pregnant and nursing patients are excluded
because the effects of the combination of SU11248 (Sutent®) and sirolimus on a fetus
or nursing child are unknown.

- Must be able and willing to give written informed consent.

- Patients must have the following clinical laboratory values: ANC count ≥1500/mm3;
Platelets ≥100,000/mm3; Serum creatinine ≤2x upper limit of normal. If serum
creatinine is above the upper limit of normal (but less than 2x normal), patients
must have a measured 24 hour urine creatinine clearance ≥ 50 ml/min to be eligible;
Total bilirubin < 1.5x upper limit of normal; Serum calcium < 12.0 mg/dl; Alanine
aminotransferase (ALT) and aspartate aminotransferase (AST) ≤3x the upper limit of
normal; Prothrombin Time (PT), activated partial thromboplastin time (aPTT) and INR
in the normal range;. Hemoglobin ≥9 gm/dl (may be corrected by transfusion).

- Normal cardiac ejection fraction

Exclusion Criteria:

- Diagnosis or history of central nervous system (CNS) disease (i.e. primary brain
tumor, malignant seizures, CNS metastases or carcinomatous meningitis).

- Any active uncontrolled bleeding and any patient with a bleeding diathesis (for
example, active peptic ulcer disease). Any grade 3 hemorrhage within 4 weeks prior to
starting treatment.

- Any ongoing coagulopathies or receiving anticoagulants.

- Hypertension that cannot be controlled by medications (>150/100 mm Hg despite optimal
medical therapy).

- QTc interval > 500 msec on baseline EKG.

- Cardiac ejection fraction below institutional lower limit of normal.

- Measured 24-hour urine creatinine clearance < 50 ml/min.

- Active infection of any kind.

- Unwilling or unable to follow protocol requirements or to give informed consent.

- Dyspnea at rest or with minimal exertion.

- No treatment with cytotoxic or biologic agents within the 4 weeks prior to beginning
treatment on this study (6 weeks for mitomycin or nitrosoureas). At least 4 weeks
must have elapsed from any prior surgery, radiation, hormonal or other drug therapy
for their cancer. Patients must have fully recovered from the acute toxicities of any
prior treatment with cytotoxic drugs, radiotherapy or other anti-cancer modalities
(returned to baseline status as noted before most recent treatment). Patients with
persisting, stable chronic toxicities from prior treatment ≤ grade 1 are eligible.

- Any of the following within 6 months prior to first dose of treatment: myocardial
infarction, symptomatic coronary artery disease (severe or unstable angina), artery
bypass graft, uncontrolled arrhythmias, symptomatic congestive heart failure,
cerebrovascular accident or transient ischemic attack, or pulmonary embolus.

- Known HIV infection. Patients with HIV infection are excluded because there may be
unknown or dangerous drug interactions between sirolimus/SU11248 (Sutent®) and the
anti-retroviral agents used to treat HIV infections.

- Patients receiving any other standard or investigational treatment for their cancer,
or any other investigational agent for any indication.

- Diagnosis of second malignancy (except malignancies treated with no evidence of
recurrence for at least 5 years, and curatively treated basal cell or squamous cell
carcinomas of the skin, or in situ cervical cancer, or any stage I malignancy > 2
years from treatment).

- Other severe acute or chronic medical or psychiatric condition or laboratory
abnormality that may increase the risk associated with study participation or study
drug administration, or may interfere with the interpretation of study results, and
in the judgment of the investigator would make the subject inappropriate for entry
into this study.

- Patients taking concurrent medications of any kind which are strong inducers or
inhibitors of CYP3A4. Patients receiving any of the following will be excluded:
ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone,
nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole, dexamethasone,
phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, St. John's
Wort.