Flavopiridol and Irinotecan in Treating Patients With Advanced Solid Tumors

An Open-Labeled, Non-Randomized Phase I Study Of Flavopiridol Administered With Irinotecan (CPT-11) In 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. Combining more than one drug may kill more tumor cells.

PURPOSE: Phase I trial to study the effectiveness of combining flavopiridol with irinotecan in treating patients who have locally advanced or metastatic solid tumors.

OBJECTIVES:

• Determine the maximum tolerated dose of flavopiridol when combined with irinotecan in patients with advanced solid tumors.
• Determine the clinical pharmacokinetics of this regimen, as well as the plasma levels of the active metabolite SN-38 and metabolic product SN-38 glucuronide in these patients.
• Determine, in a preliminary manner, the therapeutic activity of this regimen in these patients.
• Determine the role of p21 relative to treatment response and apoptosis in these patients treated with this regimen.

OUTLINE: This is a dose-escalation, open-label, non-randomized study of flavopiridol.

Patients receive irinotecan IV over 30 minutes followed 7 hours later by flavopiridol IV over 1 hour on days 1, 8, 15, and 22. Treatment continues every 6 weeks for a minimum of 2 courses in the absence of disease progression or unacceptable toxicity. During the first week of the second course, patients receive flavopiridol alone on day 1 and irinotecan alone on day 2.

Cohorts of 3-6 patients receive escalating doses of flavopiridol until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 or more of 6 patients in the initial cohort experience dose limiting toxicity during the first course of treatment. An additional 10 patients are treated at the MTD.

PROJECTED ACCRUAL: A total of 44-50 patients will be accrued for this study within 1 year.

DISEASE CHARACTERISTICS:

• Histologically proven locally advanced or metastatic solid tumor that is refractory to standard therapy or for which no standard therapy exists

• Eligible for treatment at the maximum tolerated dose only if disease accessible for tissue biopsy by Tru-Cut, CT guidance, or endoscopy

  • Pleural effusions or abdominal ascites do not constitute adequate tissue for biopsy

• No known CNS metastasis or primary CNS tumor

PATIENT CHARACTERISTICS:

Age:

• 18 and over

Performance status:

• Karnofsky 60-100%

Life expectancy:

• Not specified

Hematopoietic:

• WBC at least 3,500/mm^3
• Total neutrophil count at least 1,500/mm^3
• Platelet count at least 100,000/mm^3

Hepatic:

• Bilirubin no greater than 1.5 mg/dL
• SGOT and SGPT no greater than 2.5 times upper limit of normal

Renal:

• Creatinine no greater than 1.5 mg/dL

Cardiovascular:

• No cardiac arrhythmias, congestive heart failure, or myocardial infarction within the past 6 months

Other:

• Not pregnant or nursing (during and for at least 2 months after study)
• Negative pregnancy test
• Fertile patients must use effective contraception during and for at least 2 months after study
• No concurrent serious or uncontrolled infection
• HIV negative
• No other medical condition that would preclude study participation

PRIOR CONCURRENT THERAPY:

Biologic therapy:

• At least 4 weeks since prior immunotherapy and recovered

Chemotherapy:

• At least 4 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin) and recovered
• Prior irinotecan allowed

Endocrine therapy:

• Not specified

Radiotherapy:

• At least 4 weeks since prior radiotherapy and recovered

Surgery:

• See Disease Characteristics

Other:

• Recovered from prior therapy
• No other concurrent investigational medication
• No concurrent vitamins (except a single multivitamin tablet), antioxidants, or herbal preparations or supplements
• No concurrent subcutaneous heparin or heparinoids