A Phase Ib Study Administering Rapamycin (Sirolimus) With Ketoconazole in Patients With Advanced Malignancies
- 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
- 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.
- 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
- 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.