Study of Rapamycin Plus Ketoconazole in Advanced Cancers

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

Official Title
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A Phase Ib Study Administering Rapamycin (Sirolimus) With Ketoconazole in Patients With Advanced Malignancies

Conditions
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Advanced Cancer

Intervention / Treatment
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* Drug: Rapamycin
* Drug: Ketoconazole


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br> | Drug: Rapamycin<br>* Oral Rapamycin once weekly at assigned dose in 4 week cycles. Dosing can continue until disease progression or severe side effects are seen.<br>* Other names: Sirolimus;Drug: Ketoconazole<br>* Twice daily (200mg each time) at the start of the second week of therapy for 4 consecutive days. Dosing continues every week after the second week of therapy.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| maximum tolerated dose |  | 4 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| observed toxicities |  | 4 weeks | 
| anti-tumor response |  | 8 weeks |