Alvocidib, Oxaliplatin, Fluorouracil, and Leucovorin Calcium in Treating Patients With Advanced Solid Tumors

Study Overview
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Brief Summary
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This phase I trial is studying the side effects and best dose of alvocidib when given together with oxaliplatin, fluorouracil, and leucovorin calcium in treating patients with advanced solid tumors. Drugs used in chemotherapy, such as alvocidib, oxaliplatin, fluorouracil, and leucovorin calcium, work in different ways to stop tumor cells from dividing so they stop growing or die. Alvocidib may also make tumor cells more sensitive to chemotherapy. Combining more than one chemotherapy drug may kill more tumor cells.

Detailed Description
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OBJECTIVES: I. Determine the maximum tolerated dose of flavopiridol when given in combination with oxaliplatin, fluorouracil, and leucovorin calcium in patients with advanced solid tumors. II. Determine the pharmacokinetics of this regimen in these patients. III. Determine, preliminarily, the therapeutic activity of this regimen in these patients. IV. Determine the dose-limiting toxicity and the recommended phase II dose of flavopiridol when administered with this regimen in these patients. V. Determine the safety and tolerability of this regimen in these patients. VI. Correlate p21, p53, and apoptotic markers with response in patients treated with this regimen. OUTLINE: This is a non-randomized, open-label, dose-escalation study of flavopiridol. Patients receive alvocidib intravenously (IV) over 1 hour, oxaliplatin IV over 2 hours, leucovorin calcium IV over 2 hours, and fluorouracil IV continuously over 48 hours on days 1, 15, and 29. Courses repeat every 42 days in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of alvocidib 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. Once the MTD is determined, the cohort is expanded and an additional 10 patients are treated at that dose.

Official Title
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An Open-Labeled, Non-Randomized Phase I Study of Alvocidib (Flavopiridol) Administered With Oxaliplatin 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: fluorouracil
* Drug: oxaliplatin
* Drug: leucovorin calcium


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed advanced solid tumor Refractory to standard therapy or no standard therapy exists Evaluable disease No known untreated CNS metastases Patients who have undergone local treatment for brain metastases and whose brain metastases are stable by repeat imaging study performed ≤ 4 weeks after treatment are allowed No primary CNS tumors Performance status - Karnofsky 60-100% WBC ≥ 3,500/mm^3 Neutrophil count ≥ 1,500/mm^3 Platelet count ≥ 100,000/mm^3 Bilirubin ≤ 1.5 mg/dL AST and ALT ≤ 2.5 times upper limit of normal (ULN) (5 times ULN for liver metastases) Creatinine ≤ 1.5 mg/dL No cardiac arrhythmias within the past 6 months No congestive heart failure within the past 6 months No myocardial infarction within the past 6 months No arterial or venous thrombosis within the past year No peripheral neuropathy > grade 1 No other medical condition that would preclude study participation No serious or uncontrolled infection HIV negative Not pregnant or nursing No nursing during and for 2 months after study participation Negative pregnancy test Fertile patients must use effective contraception during and for 2 months after study participation At least 2 weeks since prior immunotherapy At least 2 weeks since prior chemotherapy (6 weeks for nitrosoureas and mitomycin) No prior flavopiridol At least 2 weeks since prior radiotherapy Recovered from all prior therapy No concurrent therapy for thrombosis Prophylaxis for central lines or deep vein thrombosis allowed No other concurrent investigational medications No concurrent vitamins, antioxidants, or herbal preparations and supplements Concurrent single-tablet multivitamin allowed

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 (alvocidib with oxaliplatin, 5-FU, leucovorin)<br>Patients receive alvocidib IV over 1 hour, oxaliplatin IV over 2 hours, leucovorin calcium IV over 2 hours, and fluorouracil IV continuously over 48 hours on days 1, 15, and 29. Courses repeat every 42 days in the absence of disease progression or unacceptable toxicity. 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 of 3 or 2 of 6 patients experience dose-limiting toxicity. Once the MTD is determined, the cohort is expanded and an additional 10 patients are treated at that dose. | Drug: alvocidib<br>* Given IV<br>* Other names: L-868275;Drug: fluorouracil<br>* Given IV<br>* Other names: 5-FU;Drug: oxaliplatin<br>* Given IV<br>* Other names: L-OHP;Drug: leucovorin calcium<br>* Given IV<br>* Other names: LV;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum tolerated dose of biweekly alvocidib when given in conjunction with oxaliplatin, 5-fluorouracil, and leucovorin calcium | Defined as the dose level immediately preceding the dose where 2 or more patients experienced dose-limiting toxicity. | 6 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose-limiting toxicity as defined by 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 3 treatments in 6 weeks |  | 6 weeks | 
| Recommended phase II dose of alvocidib |  | 6 weeks |