Imatinib Mesylate in Treating Patients With Advanced Cancer and Liver Dysfunction

Phase 1

Completed

• Conditions: Accelerated Phase Chronic Myelogenous Leukemia; Acute Undifferentiated Leukemia; AIDS-related Peripheral/Systemic Lymphoma; AIDS-related Primary CNS Lymphoma; Anaplastic Large Cell Lymphoma; Angioimmunoblastic T-cell Lymphoma; Atypical Chronic Myeloid Leukemia, BCR-ABL1 Negative; Blastic Phase Chronic Myelogenous Leukemia; Childhood Myelodysplastic Syndromes; Chronic Eosinophilic Leukemia
• Interventions: Drug: imatinib mesylate; Other: pharmacological study

• Registration Number: NCT00025415
• Lead Sponsor: National Cancer Institute (NCI)

Brief Summary

Drugs used in chemotherapy use different ways to stop cancer cells from dividing so they stop growing or die. Phase I trial to study the effectiveness of imatinib mesylate in treating patients who have advanced cancer and liver dysfunction

Detailed Description

PRIMARY OBJECTIVES:

I. Determine the maximum tolerated dose and dose-limiting toxicity of imatinib mesylate in patients with advanced malignancies and varying degrees of liver dysfunction.

II. Determine the effects of hepatic dysfunction on the pharmacodynamics and pharmacokinetics of this drug in these patients.

III. Determine the non-dose-limiting toxic effects of this drug in these patients.

IV. Determine the response rate of these patients treated with this drug. V. Correlate the Childs-Pugh classification of hepatic dysfunction with observed toxic effects, pharmacodynamics, and pharmacokinetics of this drug in these patients.

OUTLINE: This is a dose-escalation, multicenter study. Patients are stratified according to liver dysfunction (normal vs mild vs moderate vs severe).

Patients receive oral imatinib mesylate daily. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients within each stratum (except normal stratum) receive escalating doses of imatinib mesylate 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.

PROJECTED ACCRUAL: A total of 60 patients will be accrued for this study within 1 year.

Study Timeline

• Study Start: 2001-08
• Study First Submitted: 2001-10-11
• Study First Submitted QC: 2003-01-26
• Study First Posted: 2003-01-27
• Primary Completion: 2005-01
• Status Verified: 2013-02
• Last Update Submitted: 2013-02-06
• Last Update Posted: 2013-02-07

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 60

Inclusion Criteria

• Histologically or cytologically confirmed surgically incurable solid tumor orhematologic malignancy for which no standard or palliative therapy exists oris no longer effective

  • All tumor types are eligible, including:

    • Chronic myelogenous leukemia or other Philadelphia chromosome-positive leukemia OR
    • Gastrointestinal stromal tumors

• Patients with gliomas that require corticosteroids or anticonvulsants must beon a stable dose and seizure-free for 1 month

• No unstable or untreated (non-irradiated) brain metastases

• Performance status - ECOG 0-2

• Performance status - Karnofsky 60-100%

• More than 3 months

• WBC at least 3,000/mm^3

• Absolute neutrophil count at least 1,500/mm^3

• Platelet count at least 100,000/mm^3

• No active hemolysis

• See Surgery

• No evidence of biliary sepsis

• Creatinine normal

• Creatinine clearance at least 60 mL/min

• No symptomatic congestive heart failure

• No unstable angina pectoris

• No cardiac arrhythmia

• Able to swallow pills

• No other uncontrolled concurrent illness that would preclude study participation

• No ongoing or active infection

• No uncontrolled diarrhea

• No psychiatric illness or social situation that would preclude study compliance

• Not pregnant or nursing

• Negative pregnancy test

• Fertile patients must use effective barrier contraception during and for 6 months after study completion

• At least 24 hours since prior colony-stimulating factors

• No concurrent colony-stimulating factors

• At least 4 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin) and recovered

• See Disease Characteristics

• See Disease Characteristics

• At least 4 weeks since prior radiotherapy and recovered

• See Disease Characteristics

• At least 10 days since prior placement of shunt for treatment of biliary obstruction

• At least 14 days since prior major surgery

• No prior solid organ transplantation

• No other concurrent investigational agents

• No concurrent therapeutic doses of warfarin for anticoagulation

• No other concurrent investigational or commercial agents or therapies for treatment of this disease

• No concurrent combination antiretroviral therapy for HIV-positive patients

• No concurrent acetaminophen of more than 4,000 mg/day

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Exclusion Criteria

Not provided

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Treatment (imatinib mesylate)	imatinib mesylate	Patients receive oral imatinib mesylate daily. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients within each stratum (except normal stratum) receive escalating doses of imatinib mesylate 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
Treatment (imatinib mesylate)	pharmacological study	Patients receive oral imatinib mesylate daily. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients within each stratum (except normal stratum) receive escalating doses of imatinib mesylate 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

Primary Outcome Measures

Name	Time	Method
MTD defined based on the toxicities observed during the first cycle of treatment	4 weeks
Toxicity evaluation graded according to the NCI common toxicity criteria and relationship to the study drug	Up to 4 years	Results will be tabulated by liver dysfunction group.

Secondary Outcome Measures

Name	Time	Method
Pharmacokinetic data	Day 1, 2, 3, 4, 15, 16	Will be analyzed with ADAPT II, and results will be summarized separately for the four study groups. Additionally, results for pharmacokinetic parameters will be related to the measured level of liver dysfunction in exploratory analyses.
Responses	Up to 4 years	Will be tabulated by liver dysfunction group, and by dose if appropriate.
Child-Pugh Classification	Baseline	Will be correlated to the toxicities, pharmacokinetic and pharmacodynamic data seen with STI571.

Trial Locations

Locations (1)

University of Pittsburgh; 🇺🇸 Pittsburgh, Pennsylvania, United States