CCI-779 and EKB-569 in Treating Patients With Advanced Solid Tumors

OBJECTIVES:

I. Determine the maximum tolerated dose of the combination of CCI-779 and EKB-569 in patients with advanced solid tumors.

II. Determine the toxicity of this regimen in these patients. III. Determine the response rate in patients treated with this regimen.

OUTLINE: This is a dose-escalation study. Patients are assigned to 1 of 3 treatment groups.

Group I: Patients receive oral EKB-569 on days 1-28 and oral CCI-779 on days 1-7 and 15-21.

Cohorts of 3-6 patients receive escalating doses of EKB-569 and CCI-779 until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity.

Group II: Patients receive oral EKB-569 at the MTD on days 4-28 of course 1 and days 1-28 of all subsequent courses and CCI-779 at the MTD on days 1-3 and 15-17.

Group III: Patients receive EKB-569 at the MTD as in group I and oral CCI-779 at the MTD on days 7-9 and 19-21 of course 1 and days 1-3 and 15-17 of all subsequent courses.

In all groups, courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

PROJECTED ACCRUAL: A total of 30-42 patients (18-30 for group I, 6 for group II, and 6 for group III) will be accrued for this study within 1.35-1.75 years.

Inclusion criteria

• Histologically confirmed unresectable solid tumor for which there is no known standard therapy that is potentially curative or capable of extending life expectancy
• No CNS metastases
• Performance status - ECOG 0-2
• At least 12 weeks
• Absolute neutrophil count ≥ 1,500/mm^3
• Platelet count ≥ 100,000/mm^3
• Hemoglobin ≥ 10 g/dL
• Bilirubin normal
• AST ≤ 3 times upper limit of normal (ULN) (5 times ULN if liver involvement)
• Creatinine ≤ 1.5 times ULN
• No New York Heart Association class III or IV heart disease
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception during and for 3 months after study participation
• Fasting cholesterol < 350 mg/dL
• Fasting triglycerides < 400 mg/dL
• No uncontrolled infection
• No seizure disorder
• More than 4 weeks since prior immunotherapy
• More than 4 weeks since prior biologic therapy
• No concurrent immunotherapy
• No concurrent prophylactic colony-stimulating factor therapy
• More than 4 weeks since prior chemotherapy (6 weeks for mitomycin or nitrosoureas) and recovered
• No other concurrent chemotherapy
• No concurrent oral contraceptives
• More than 4 weeks since prior radiotherapy
• No prior radiotherapy to > 30% of bone marrow
• No concurrent radiotherapy
• More than 7 days since prior CYP3A4 inducers
• No prior mTOR-targeting agents
• No prior epidermal growth factor receptor-targeting agents
• No concurrent antiretroviral therapy that induces or inhibits CYP3A4 for HIV-positive patients
• No other concurrent investigational agents
• No concurrent warfarin