Combination Chemotherapy in Treating Patients With Advanced Solid Tumors

Study Overview
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Brief Summary
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Phase I trial to study the effectiveness of combining alvocidib, irinotecan hydrochloride, and cisplatin in treating patients who have advanced solid tumors. 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.

Detailed Description
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OBJECTIVES: I. Determine the maximum tolerated dose of flavopiridol (alvocidib), irinotecan (irinotecan hydrochloride), and cisplatin in patients with advanced solid tumors. II. Determine the clinical pharmacokinetics of this regimen in these patients. III. Determine, preliminarily, the therapeutic activity of this regimen in these patients. OUTLINE: This is a dose-escalation study. Patients are stratified according to the number of prior treatment regimens (0 or 1 vs more than 1). Patients receive irinotecan hydrochloride intravenously (IV) over 30 minutes followed immediately by cisplatin IV over 30 minutes followed 7 hours later by alvocidib IV over 1-4.5 hours weekly for 2 weeks. Courses repeat every 3 weeks in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of cisplatin, alvocidib, and irinotecan hydrochloride until the maximum tolerated dose (MTD) of each is determined. The MTD is defined as the dose preceding that at which at least 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. Once the MTD is determined, 12 additional patients are treated at the recommended phase II dose.

Official Title
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An Open-Labeled, Non-Randomized Phase I Study of Alvocidib (Flavopiridol) Administered With Irinotecan (CPT-11) and Cisplatin 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: cisplatin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed locally advanced or metastatic solid tumor that is refractory to standard therapy or for which no standard therapy exists Evaluable disease No previously untreated CNS metastasis No primary CNS tumors Performance status - Karnofsky 60-100% Performance status - ECOG 0-2 Not specified WBC at least 3,000/mm^3 Neutrophil count at least 1,500/mm^3 Platelet count at least 100,000/mm^3 Bilirubin no greater than 2.0 mg/dL AST and ALT no greater than 3 times upper limit of normal (ULN) (5 times ULN if liver metastases are present) Creatinine no greater than 1.5 mg/dL Creatinine clearance at least 60 mL/min No cardiac arrhythmia No congestive heart failure No myocardial infarction within the past 6 months HIV negative No neuropathy grade 2 or greater 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 4 weeks since prior immunotherapy At least 1 week since prior irinotecan and cisplatin alone At least 4 weeks since other prior chemotherapy (6 weeks for nitrosoureas or mitomycin) Not specified At least 4 weeks since prior radiotherapy Not specified Recovered from all prior therapy No concurrent vitamins, antioxidants, or herbal supplements except a daily multivitamin No other concurrent investigational drugs

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 (chemotherapy)<br>Patients are stratified according to the number of prior treatment regimens (0 or 1 vs more than 1). Patients receive irinotecan hydrochloride IV over 30 minutes followed immediately by cisplatin IV over 30 minutes followed 7 hours later by alvocidib IV over 1-4.5 hours weekly for 2 weeks. Courses repeat every 3 weeks in the absence of disease progression or unacceptable toxicity. | Drug: alvocidib<br>* Given IV<br>* Other names: L-868275;Drug: irinotecan hydrochloride<br>* Given IV<br>* Other names: U-101440E;Drug: cisplatin<br>* Given IV<br>* Other names: DDP;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| MTD alvocidib when administered in conjunction with irinotecan hydrochloride and cisplatin | Defined as the dose one level below the dose at which two or more of the patients in the initial cohort experience dose limiting toxicity (DLT) during the first treatment course. DLT is defined as the occurrence of Grade 4 hematologic toxicity, Grade 3 or 4 non-hematologic toxicity including diarrhea despite antidiarrheal prophylaxis, or any delay in treatment resulting in less than 2 treatments in 3 weeks. | Course 1 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical pharmacokinetics of the regimen |  | Week 1 of courses 1 and 2 | 
| Therapeutic activity of alvocidib in combination with irinotecan hydrochloride in patients with advanced solid tumors | Evaluated using Response Evaluation Criteria In Solid Tumors (RECIST). | After 2 courses of treatment | 
| Safety and tolerability | Evaluated using the National Cancer Institute (NCI) Common Toxicity Criteria. Tabulated individually, and summarized by body system, according to dosage of study medication. | Weekly |