Vinorelbine in Treating Patients With Advanced Solid Tumors That Have Not Responded to Treatment and Liver Dysfunction

Study Overview
=================
Brief Summary
-----------------
RATIONALE: Drugs used in chemotherapy, such as vinorelbine, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. PURPOSE: This pilot trial is studying the side effects and best dose of vinorelbine in treating patients with advanced solid tumors that have not responded to treatment and liver dysfunction.

Detailed Description
-----------------
OBJECTIVES: To correlate indocyanine green and lidocaine metabolism with vinorelbine ditartrate pharmacokinetics in patients with advanced, refractory solid tumors and varying degrees of liver dysfunction. To determine the pharmacokinetics of vinorelbine ditartrate in these patients. To test a plan of dose adjustment for vinorelbine ditartrate administration in these patients. OUTLINE: Patients are stratified according to extent of clinical liver dysfunction (normal vs mild vs moderate vs severe). Patients receive dose-adjusted vinorelbine ditartrate IV over 10 minutes once weekly in the absence of disease progression or unacceptable toxicity. Patients achieving an objective complete response receive 2 additional courses of study therapy. Patients undergo blood sample collection periodically during study for pharmacokinetic and pharmacodynamic correlative studies. Blood is also collected after patients receive lidocaine IV push and indocyanine green (ICG) IV push. Samples are analyzed for whole blood and plasma concentrations of vinorelbine ditartrate and its metabolites by high performance liquid chromatography (15) or by liquid chromatography/tandem mass spectrometry assay. Samples are also analyzed for ICG clearance and lidocaine hydrochloride metabolic capacity by fluorescent polarization immunoassay. After completion of study therapy, patients are followed periodically.

Official Title
-----------------
Pilot Pharmacokinetic Study of Dose Adjustment of Vinorelbine in Patients With Varying Degree of Liver Dysfunction

Conditions
-----------------
Lung Cancer, Unspecified Adult Solid Tumor, Protocol Specific

Intervention / Treatment
-----------------
* Drug: indocyanine green
* Drug: lidocaine
* Drug: vinorelbine ditartrate
* Other: high performance liquid chromatography
* Other: intracellular fluorescence polarization analysis
* Other: liquid chromatography
* Other: mass spectrometry
* Other: pharmacological study


Participation Criteria
=================
Eligibility Criteria
-----------------
DISEASE CHARACTERISTICS: Histologically confirmed advanced solid tumor Any histology allowed Refractory to standard therapy OR no standard therapy exists Previously untreated non-small cell lung cancer allowed, provided abnormal liver function is present, defined as moderate (group 3) or severe (group 4) Measurable disease not required Present measurable disease requires baseline measurements within 4 weeks of study entry Patients with acute hepatitis from viral or drug etiologies should recover to a stable baseline prior to study therapy History of brain metastasis allowed, provided the following criteria are met: Metastasis has been controlled by radiotherapy or surgery Patient is not currently on corticosteroids Neurologic status is stable PATIENT CHARACTERISTICS: Karnofsky performance status 70-100% Life expectancy ≥ 2 months ANC = 1,500/mm³ Platelet count = 100,000/mm³ Hemoglobin = 10 g/dL (transfusion to this level allowed) Creatinine < 1.5 mg/dL OR creatinine clearance > 60 mL/ min Patients with EKG evidence of first- or second-degree AV block or left or right bundle branch block are ineligible for the lidocaine bolus, but may otherwise be treated on this protocol Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception No concurrent illness (e.g., cardiovascular, pulmonary, or central nervous system) that is poorly controlled or of such severity that the investigator deems unwise to enter the patient on protocol Must have ability to comply with study treatment and required tests Obstructive jaundice requires a drainage procedure prior to study treatment PRIOR CONCURRENT THERAPY: See Disease Characteristics Recovered from prior therapy At least 3 weeks since prior chemotherapy (6 weeks for mitomycin or nitrosourea therapy) No prior radiotherapy to > 30% of the bone marrow or more than standard adjuvant pelvic radiotherapy for rectal cancer

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 120 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Normal Liver Function<br> | Drug: indocyanine green<br>* 0.5 mg/kg will be administered by IV push to determine clearance<br>Drug: lidocaine<br>* 1 mg/kg will be administered to determine metabolic capacity<br>Drug: vinorelbine ditartrate<br>* Varying doses ranging from 30 mg/m2 to 7.5 mg/m2 will be administered based upon liver function<br>Other: high performance liquid chromatography<br>* Used to determine plasma concentrations of vinorelbine<br>Other: intracellular fluorescence polarization analysis<br>* Used to determine concentration of lidocaine metabolic capacity<br>Other: liquid chromatography<br>* Used to determine concentrations of vinorelbine and its metabolites<br>Other: mass spectrometry<br>* Used to determine concentrations of vinorelbine and its metabolites<br>Other: pharmacological study<br>* Determination of concentrations of vinorelbine and its metabolites<br>|
| Experimental: Mild Liver Dysfunction<br> | Drug: indocyanine green<br>* 0.5 mg/kg will be administered by IV push to determine clearance<br>Drug: lidocaine<br>* 1 mg/kg will be administered to determine metabolic capacity<br>Drug: vinorelbine ditartrate<br>* Varying doses ranging from 30 mg/m2 to 7.5 mg/m2 will be administered based upon liver function<br>Other: high performance liquid chromatography<br>* Used to determine plasma concentrations of vinorelbine<br>Other: intracellular fluorescence polarization analysis<br>* Used to determine concentration of lidocaine metabolic capacity<br>Other: liquid chromatography<br>* Used to determine concentrations of vinorelbine and its metabolites<br>Other: mass spectrometry<br>* Used to determine concentrations of vinorelbine and its metabolites<br>Other: pharmacological study<br>* Determination of concentrations of vinorelbine and its metabolites<br>|
| Experimental: Moderate Liver Dysfunction<br> | Drug: indocyanine green<br>* 0.5 mg/kg will be administered by IV push to determine clearance<br>Drug: lidocaine<br>* 1 mg/kg will be administered to determine metabolic capacity<br>Drug: vinorelbine ditartrate<br>* Varying doses ranging from 30 mg/m2 to 7.5 mg/m2 will be administered based upon liver function<br>Other: high performance liquid chromatography<br>* Used to determine plasma concentrations of vinorelbine<br>Other: intracellular fluorescence polarization analysis<br>* Used to determine concentration of lidocaine metabolic capacity<br>Other: liquid chromatography<br>* Used to determine concentrations of vinorelbine and its metabolites<br>Other: mass spectrometry<br>* Used to determine concentrations of vinorelbine and its metabolites<br>Other: pharmacological study<br>* Determination of concentrations of vinorelbine and its metabolites<br>|
| Experimental: Severe Liver Dysfunction<br> | Drug: indocyanine green<br>* 0.5 mg/kg will be administered by IV push to determine clearance<br>Drug: lidocaine<br>* 1 mg/kg will be administered to determine metabolic capacity<br>Drug: vinorelbine ditartrate<br>* Varying doses ranging from 30 mg/m2 to 7.5 mg/m2 will be administered based upon liver function<br>Other: high performance liquid chromatography<br>* Used to determine plasma concentrations of vinorelbine<br>Other: intracellular fluorescence polarization analysis<br>* Used to determine concentration of lidocaine metabolic capacity<br>Other: liquid chromatography<br>* Used to determine concentrations of vinorelbine and its metabolites<br>Other: mass spectrometry<br>* Used to determine concentrations of vinorelbine and its metabolites<br>Other: pharmacological study<br>* Determination of concentrations of vinorelbine and its metabolites<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under the Curve | Pharmacokinetics were evaluated in patients with sufficient dosing information and plasma concentration versus time data over 0-24 hours following vinorelbine infusion to allow calculation of area-under-the-curve from zero to 24 hours after infusion (AUC0-24). Furthermore, dose-normalization of AUC0-24 to the standard 30 mg/m2 dose was performed to allow evaluation of the relationship between liver function and AUC of vinorelbine. Data were collected at 0 and 24 hours post-dose. | 2 months post treatment | 
| Number of Participants With Grade 3 and 4 Toxicities | Grade 3 & 4 toxicities at least possible related to study drugs during any cycle of treatment. Toxicity graded according to Common Terminology Criteria for Adverse Events version 2.0. | 3 weeks after the stop of treatment | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
unspecified adult solid tumor, protocol specific, recurrent non-small cell lung cancer, stage IIIA non-small cell lung cancer, stage IIIB non-small cell lung cancer, stage IV non-small cell lung cancer