An Open-Labeled, Non-Randomized Phase I Study Of Flavopiridol Administered With Irinotecan (CPT-11) In Patients With Advanced 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.