Combination Chemotherapy in Treating Patients With Locally Advanced or Metastatic Solid Tumors

Study Overview
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Brief Summary
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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. This phase I trial is studying the side effects and best dose of combination chemotherapy in treating patients with locally advanced or metastatic solid tumors.

Detailed Description
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PRIMARY OBJECTIVES: I. Determine the maximum tolerated dose of flavopiridol (alvocidib) when administered with irinotecan hydrochloride, fluorouracil, and leucovorin calcium in patients with locally advanced or metastatic solid tumors. II. Determine the clinical pharmacokinetics of fluorouracil when administered in this regimen in these patients. III. Determine, preliminarily, the therapeutic activity of this regimen in these patients.Correlate the role of p21 and Drg1 with apoptosis and treatment response in patients receiving this regimen. OUTLINE: This is a dose-escalation study of alvocidib and fluorouracil (5-FU). Patients receive irinotecan hydrochloride IV over 90 minutes followed 5 hours later by leucovorin calcium IV over 2 hours and alvocidib IV over 1 hour immediately followed by 5-FU IV continuously over 48 hours beginning on day 1 of weeks 1, 3, and 5. Courses repeat every 6 weeks in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of alvocidib and 5-FU 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. Ten additional patients are treated at the MTD. PROJECTED ACCRUAL: A total of 27-77 patients will be accrued for this study within 11-38 months.

Official Title
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An Open-Labeled, Non-Randomized Phase I Study of Alvocidib (Flavopiridol) Administered With Irinotecan (CPT-11) and Fluorouracil/Leucovorin in Patients With Advanced Solid Tumors

Conditions
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Unspecified Adult Solid Tumor, Protocol Specific

Intervention / Treatment
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* Drug: alvocidib
* Drug: irinotecan hydrochloride
* Drug: fluorouracil
* Drug: leucovorin calcium
* Other: laboratory biomarker analysis


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically confirmed locally advanced or metastatic solid tumor Refractory to standard therapy or for which there is no standard therapy Preference given to colorectal cancer, upper gastrointestinal cancer, or neuroendocrine tumors Evaluable disease No CNS metastases or primary CNS malignancy Performance status - Karnofsky 60-100% WBC at least 3,500/mm^3 Absolute neutrophil count at least 1,500/mm^3 Platelet count at least 100,000/mm^3 Bilirubin no greater than 1.5 mg/dL AST and ALT no greater than 2.5 times upper limit of normal (ULN) (5 times ULN if liver metastases are present) Creatinine no greater than 1.5 mg/dL No history of cardiac arrhythmia No congestive heart failure No myocardial infarction within the past 6 months No prior grade 3 or 4 diarrhea secondary to irinotecan, despite optimal antidiarrheal prophylaxis HIV negative No serious or uncontrolled infection No other medical condition or reason that would preclude study participation Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception during and for at least 2 months after study participation At least 2 weeks since prior immunotherapy No more than 2 prior chemotherapy regimens unless there is no evidence of significant myelotoxicity as determined by the primary investigator At least 2 weeks since prior chemotherapy (6 weeks for nitrosoureas and mitomycin) Prior irinotecan and fluorouracil allowed At least 2 weeks since prior radiotherapy Recovered from all prior therapy No other concurrent investigational medications No concurrent vitamins, antioxidants, or herbal preparations or supplements except a single daily multivitamin

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (combination chemotherapy)<br>Patients receive irinotecan hydrochloride IV over 90 minutes followed 5 hours later by leucovorin calcium IV over 2 hours and alvocidib IV over 1 hour immediately followed by 5-FU IV continuously over 48 hours beginning on day 1 of weeks 1, 3, and 5. Courses repeat every 6 weeks in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of alvocidib and 5-FU 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. Ten additional patients are treated at the MTD. | Drug: alvocidib<br>* Given IV<br>* Other names: L-868275;Drug: irinotecan hydrochloride<br>* Given IV<br>* Other names: U-101440E;Drug: fluorouracil<br>* Given IV<br>* Other names: 5-FU;Drug: leucovorin calcium<br>* Given IV<br>* Other names: LV;Other: laboratory biomarker analysis<br>* Correlative studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| MTD of biweekly flavopiridol when given in conjunction with irinotecan hydrochloride, fluorouracil, and leucovorin |  | 8 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical pharmacokinetics of the regimen under investigation |  | Day 1, prior to flavopiridol infusion (t=3:30hr), post flavopiridol infusion (t=4:30hr), prior to flavopiridol infusion (t=3:30hr), post 30 minute flavopiridol bolus (t=4:00), post 4 hour flavopiridol infusion (t=8:00hr) | 
| Therapeutic activity of flavopiridol in combination with irinotecan hydrochloride in patients with advanced solid tumors |  | Up to 7 years | 
| Change in molecular marker expression |  | Baseline to 2 weeks post-treatment |