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.
- 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
- Determine, in a preliminary manner, the therapeutic activity of this regimen in these
- 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.
- 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
- No known CNS metastasis or primary CNS tumor
- 18 and over
- Karnofsky 60-100%
- Not specified
- WBC at least 3,500/mm^3
- Total neutrophil count at least 1,500/mm^3
- Platelet count at least 100,000/mm^3
- Bilirubin no greater than 1.5 mg/dL
- SGOT and SGPT no greater than 2.5 times upper limit of normal
- Creatinine no greater than 1.5 mg/dL
- No cardiac arrhythmias, congestive heart failure, or myocardial infarction within the
past 6 months
- 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
- No concurrent serious or uncontrolled infection
- HIV negative
- No other medical condition that would preclude study participation
PRIOR CONCURRENT THERAPY:
- At least 4 weeks since prior immunotherapy and recovered
- At least 4 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin) and
- Prior irinotecan allowed
- Not specified
- At least 4 weeks since prior radiotherapy and recovered
- See Disease Characteristics
- 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