Alvocidib in Treating Patients With Locally Advanced or Metastatic 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 in treating patients with locally advanced or metastatic solid tumors. Drugs used in chemotherapy, such as alvocidib, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Alvocidib may also stimulate the immune system in different ways and stop tumor cells from growing. It may also stop the growth of solid tumors by blocking blood flow to the tumor.

Detailed Description
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PRIMARY OBJECTIVES: I. Determine the toxicity profile and dose-limiting toxicity of flavopiridol (alvocidib) in patients with locally advanced or metastatic solid tumors. II. Determine the maximum tolerated dose of this drug in these patients. SECONDARY OBJECTIVES: I. Determine the pharmacokinetics and pharmacodynamics of this drug in these patients. II. Determine the immunomodulatory effects of this drug in these patients. III. Determine pharmacogenomics of this drug, using peripheral blood mononuclear cells, in patients who experience clinical response. OUTLINE: This is a pilot, dose-escalation study. Patients receive alvocidib intravenously (IV) over 4½ hours once weekly in weeks 1-4. Treatment repeats every 6 weeks for up to 6 courses in the absence of disease progression or unacceptable toxicity. Patients achieving stable disease after 4 courses of therapy discontinue study treatment. Patients who achieve complete remission (CR) receive 1 additional course of therapy beyond documentation of CR. 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. A total of 10 patients are treated at the MTD. After completion of study treatment, patients are followed within 4 weeks.

Official Title
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A Pilot Study of Flavopiridol 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
* Other: pharmacological study
* Other: laboratory biomarker analysis


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically confirmed solid tumor Locally advanced or metastatic disease for which curative treatment does not exist or is no longer effective Measurable disease, defined as ≥ 1 unidimensionally measurable lesion ≥ 20 mm by conventional techniques OR ≥ 10 mm by spiral CT scan No previously irradiated* measurable lesion unless lesion demonstrates progressive disease OR there are other measurable lesions outside the irradiated* field The following are not considered measurable disease: Bone lesions Leptomeningeal disease Ascites Pleural or pericardial effusion Lymphangitis cutis/pulmonis Abdominal masses that are not confirmed and followed by imaging techniques Cystic lesions No uncontrolled brain metastases Performance status - ECOG 0-1 At least 6 months Absolute neutrophil count ≥ 1,500/mm^3 Platelet count ≥ 100,000/mm^3 AST and ALT ≤ 2.5 times upper limit of normal (ULN) Bilirubin ≤ 1.5 times ULN Creatinine ≤ 1.5 times ULN No symptomatic congestive heart failure No unstable angina pectoris No uncontrolled cardiac arrhythmia No uncontrolled hypertension Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception No history of allergic reaction attributed to compounds of similar chemical or biological composition to flavopiridol No ongoing or active infection No uncontrolled illness No psychiatric illness or social situation that would preclude study compliance More than 12 weeks since prior hepatic arterial chemoembolization More than 4 weeks since prior systemic chemotherapy No prior flavopiridol See Disease Characteristics More than 12 weeks since prior radioactive metaiodobenzylguanidine (MIBG) More than 4 weeks since prior external beam radiotherapy Recovered from all prior tumor-specific therapy More than 4 weeks since prior investigational tumor-specific therapy Concurrent octreotide for control of carcinoid syndrome allowed No concurrent combination anti-retroviral therapy for HIV-positive patients No other concurrent tumor-specific therapy No other concurrent investigational therapy No other concurrent anticancer therapy

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, biological therapy)<br>Patients receive alvocidib IV over 4½ hours once weekly in weeks 1-4. Treatment repeats every 6 weeks for up to 6 courses in the absence of disease progression or unacceptable toxicity. | Drug: alvocidib<br>* Given IV<br>* Other names: L-868275;Other: pharmacological study<br>* Correlative studies<br>* Other names: pharmacological studies;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 |
| --- | --- | --- |
| Adverse events of dose escalated alvocidib administered in patients with advanced solid tumors | Graded using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. | At weeks 1-4, 7-10, 11 or 12, and within 4 weeks after the completion of study treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics of alvocidib administered in this schedule | The pharmacokinetic parameters include Cmax, Css, Clearance, t1/2 α, t1/2 β, central volume of distribution and steady state volume of distribution. | After the first dose of treatment drug | 
| Immunomodulatory effects of alvocidib | Gene expression quantified using Real Time PCR; type 1 and type 2 cytokines, co-stimulatory molecules, and adhesion molecules in PBMCs. Activation of lymphocyte subsets and presence of co-stimulatory and adhesion molecules assessed using multicolor flow cytometry. IL-6 levels in plasma will be measured by ELISA. T-cells will be enriched from PBMCs using mAb-coated immunomagnetic beads and activated with anti-CD3/anti-CD28 mAbs, inomycin or PMA. Cytokine production will be measured using cytometric bead array. | Baseline, days 1 and 15 of courses 1 and 2, and within 4 weeks after the completion of study treatment | 
| Pharmacogenomics studies on procured PBMCs if clinical responses are observed | Performed if clinical responses are observed. Examine for selected polymorphisms of genes influencing alvocidib metabolism and/or resistance genes that may predict response or toxicity. These changes will be correlated with AUC, toxicity and clinical response to therapy. | Baseline, and within 4 weeks after the completion of study treatment | 
| Measurement of serum tumor markers depending on the tumor type | Markers include CEA, CA 19-9, CA 15-3, PSA, LDH, AFP, b-HCG, pancreastatin, gastrin, pancreatic polypeptide, glucagon, substance-P, neurotensin, calcitonin, somatostatin, vasoactive intestinal peptide, gastrin releasing polypeptide, ACTH, and chromogranin-A. | Baseline, week 11 or 12, and within 4 weeks after the completion of study treatment |