To determine the maximum tolerated dose, observed toxicities, and dose limiting toxicities, and antitumor response of rapamycin plus ketoconazole in patients with advanced cancers.

Inclusion Criteria:

• 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 hematologic malignancies (lymphoma, multiple myeloma and CLL only) are eligible to participate in the phase Ib portion of the trial only

• At least 4 weeks since prior chemotherapy or radiation therapy (6 weeks if the last regimen included BCNU or mitomycin C).

• Age >18 years.

• ECOG performance status less than or equal to 2

• Life expectancy of more than 3 months.

• Normal organ and marrow function as defined below:

  • Hemoglobin ≥ 10 g/dl

  • Leukocytes ≥ 3,000/µL

    o WBC ≥ 1,500/µL for patients with hematologic malignancies

  • Absolute neutrophil count ≥ 1,500/µL (≥ 1,000/µL for patients with hematologic malignancies)

  • Absolute lymphocyte count ≥1000/µL

  • Platelets ≥ 100,000/µL (≥ 50,000/µL for patients with hematologic malignancies)

  • Total bilirubin within normal institutional limits

  • AST (SGOT) and ALT (SGPT) ≤ 2.5 times institutional ULN

  • Serum triglycerides ≤ 500 mg/dl

  • Creatinine within normal institutional limits OR

  • Creatinine clearance ≥ 60 mL/min/1.73 m2 for patients with creatinine levels above institutional normal.

• Women of childbearing 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.

• Able to understand and the willing to sign a written informed consent document.

Exclusion Criteria:

• Chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or not recovered from adverse events due to agents administered more than 4 weeks earlier.
• Receiving any other investigational agents.
• Uncontrolled brain metastases or malignancy.
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to rapamycin.
• 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.
• Severe immunodeficient state (as judged by the treating physician)
• Pregnancy (breast-feeding must be discontinued)
• HIV-positive patients receiving combination anti-retroviral therapy are excluded from the study because of possible pharmacokinetic interactions with rapamycin.
• Concurrent use of cyclosporine, tacrolimus, and rifampin, terfenadine, astemizole, cisapride, rosiglitazone or pioglitazone due to possible interactions with the study drugs. Ketoconazole cannot be taken within 2 hours of an antacid.