CCI-779 in Treating Patients With Advanced Solid Tumors

A Phase I Study of the Safety, Tolerability, and Pharmacokinetics of Intravenous CCI-779 Given Once Daily for 5 Days Every 2 Weeks to Patients With Advanced Solid Tumors

RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die.

PURPOSE: Phase I trial to study the effectiveness of CCI-779 in treating patients who have advanced solid tumors.

OBJECTIVES:

• Determine the safety, tolerability, and maximum tolerated dose (MTD) of CCI-779 in patients with advanced solid tumors (part I) who are not receiving anticonvulsant therapy.
• Determine the safety, tolerability, and MTD in patients with recurrent gliomas or brain metastases (part II) who are receiving anticonvulsant therapy.
• Determine the preliminary pharmacokinetic profile and antitumor activity of CCI-779 in these patients.

OUTLINE: This is an open-label, dose-escalation study.

• Part I: Patients receive CCI-779 IV over 30 minutes on days 1-5, followed by a 9 day rest period. Treatment courses repeat every 2 weeks in the absence of disease progression or unacceptable toxicity.

The maximum tolerated dose for part I is defined as the dose level at which 33% of patients experience dose limiting toxicity.

• Part II: Patients receive the same treatment schedule as part I. Three patients with CNS tumors are entered at the dose of CCI-779 determined to be the MTD in Part I. At least 3 patients are entered at each dose level in part II.

PROJECTED ACCRUAL: Approximately 20 patients will be accrued for part I for this study within 8 months, and 12 patients will be accrued for part II within 7 months.

DISEASE CHARACTERISTICS:

Part I:

• Histologically proven advanced solid tumors that are refractory or for which no curative therapy exists
• No CNS metastases, peritumoral edema, or symptomatic brain metastases (part I)
• Measurable or evaluable disease

Part II:

• Histologically proven recurrent gliomas or brain metastases for which no curative therapy exists
• Receiving anticonvulsants
• Measurable or evaluable disease

PATIENT CHARACTERISTICS:

Age:

• 18 and over

Performance status:

• ECOG 0-2

Life expectancy:

• At least 3 months

Hematopoietic:

• Absolute neutrophil count at least 1,500/mm^3
• Platelet count at least 100,000/mm^3
• Hemoglobin at least 9 g/dL

Hepatic:

• Bilirubin less than 1.5 mg/dL
• AST or ALT less than 3 times upper limit of normal (ULN) (less than 5 times ULN if liver metastases)

Renal:

• Creatinine less than 2 mg/dL

Cardiovascular:

• No unstable angina
• No myocardial infarction within past 6 months
• No maintenance therapy for life-threatening arrhythmias

Other:

• Not pregnant or nursing
• Fertile patients must use effective contraception
• HIV negative
• No active infection or other serious concurrent illness
• Triglycerides no greater than 300 mg/dL
• Cholesterol no greater than 350 mg/dL
• No known hypersensitivity to macrolide antibiotics (e.g., clarithromycin, erythromycin, or azithromycin)

PRIOR CONCURRENT THERAPY:

Biologic therapy:

• Not specified

Chemotherapy:

• At least 3 weeks since prior chemotherapy (6 weeks since nitrosoureas and mitomycin)
• No other concurrent chemotherapy

Endocrine therapy:

• Concurrent corticosteroids used to reduce edema in patients with primary or metastatic CNS tumors allowed
• No concurrent hormonal therapy

Radiotherapy:

• At least 3 weeks since prior radiotherapy
• No concurrent radiotherapy

Surgery:

• Not specified

Other:

• At least 1 month since prior investigational agents
• At least 3 weeks since prior immunosuppressive therapy
• No concurrent anticonvulsant therapy (part I)
• No concurrent immunosuppressive therapy (e.g., terfenadine, cisapride, astemizole, pimozide)
• No known agents that inhibit or induce cytochrome p450