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

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

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.

Study Overview

• Status: Completed
• 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

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.

• Study Type: Interventional
• Enrollment (Actual): 47
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Duarte, California, United States, 91010-3000
      • City of Hope Medical Center
    • Pasadena, California, United States, 91105
      • City of Hope Medical Group

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 120 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

4

Arms and Interventions

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

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

Collaborators and Investigators

• Sponsor: City of Hope Medical Center
• Collaborators: National Cancer Institute (NCI)
• Investigators: Study Chair: Joseph Chao, City of Hope Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): February 20, 1997
• Primary Completion (Actual): May 20, 2010
• Study Completion (Actual): May 20, 2010

Study Registration Dates

• First Submitted: October 5, 2007
• First Submitted That Met QC Criteria: October 5, 2007
• First Posted (Estimated): October 8, 2007

Study Record Updates

• Last Update Posted (Actual): July 2, 2025
• Last Update Submitted That Met QC Criteria: June 24, 2025
• Last Verified: June 1, 2025

More Information

Terms related to this study

• Keywords: 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; unspecified adult solid tumor, protocol specific
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Respiratory Tract Diseases; Digestive System Diseases; Lung Diseases; Respiratory Tract Neoplasms; Thoracic Neoplasms; Lung Neoplasms; Liver Diseases; Antineoplastic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Anesthetics, Local; Anesthetics; Central Nervous System Depressants; Sensory System Agents; Anti-Arrhythmia Agents; Voltage-Gated Sodium Channel Blockers; Sodium Channel Blockers; Membrane Transport Modulators; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Phytogenic; Vinorelbine; Lidocaine
• Other Study ID Numbers: 96032; P30CA033572 (U.S. NIH Grant/Contract); CHNMC-96032; CDR0000567457 (Registry Identifier: NCI PDQ)