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A Phase 2 Study of Tipifarnib in Large Granular Lymphocyte (LGL) Leukemia

Phase 2
18 Years
Not Enrolling
Stage III Chronic Lymphocytic Leukemia, Stage IV Chronic Lymphocytic Leukemia, T-cell Large Granular Lymphocyte Leukemia

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Trial Information

A Phase 2 Study of Tipifarnib in Large Granular Lymphocyte (LGL) Leukemia


I. Estimate the complete response rate, partial response rate, and overall response rate in
patients with natural killer (NK)- or T-cell-large granular lymphocyte (LGL) leukemia who
present with neutropenia or anemia treated with tipifarnib.


I. Determine the toxicity of tipifarnib in these patients. II. Determine the mechanism of
treatment responses in these patients through correlative laboratory studies.

OUTLINE: Patients are stratified by disease type (natural killer-large granular lymphocyte
[LGL] leukemia vs T-cell-LGL leukemia).

Patients receive oral tipifarnib twice daily on days 1-21. Treatment repeats every 28 days
for 4 courses in the absence of disease progression or unacceptable toxicity. Patients are
evaluated after completion of course 4. Patients achieving complete response receive 1
additional course of treatment. Patients achieving partial response receive 4 additional
courses of treatment in the absence of disease progression or unacceptable toxicity.

Patients undergo blood collection periodically during study for response mechanism studies
and other biomarker correlative studies, including mutations of K-ras and N-ras genes.

After completion of study treatment, patients are followed every 6 months for 5 years.

Inclusion Criteria:

- Diagnosis of T-cell-large granular lymphocyte (LGL) leukemia or natural killer
(NK)-LGL leukemia associated with ≥ 1 of the following clinical manifestations:

- Severe neutropenia (i.e., < 500/mm³)

- Neutropenia associated with recurrent infections, meeting 1 of the following
criteria: one severe infection requiring hospitalization or at least 2
infections requiring antibiotic therapy

- Symptomatic anemia with significant fatigue with a score of greater than 1 on
the Eastern Cooperative Oncology Group (ECOG) Performance Status Scale; dyspnea
on exertion, but able to walk one flight of stairs without stopping (less than
grade 1 respiratory symptoms); cardiac symptoms including worsening of angina or
new onset of chest pain

- Transfusion-dependent anemia

- Willing to discontinue use of MTX, Cy, or cyclosporine for 1 month prior to study

- T-cell-LGL leukemia must meet all of the following criteria: CD3+ and CD57+ cells >
300/mm³ or CD8+ cells > 650/mm³ by phenotypic studies of peripheral blood, evidence
for clonal T-cell receptor gene rearrangement based on positive flow cytometric
analysis, T-cell receptor (TCR)-γ chain polymerase chain reaction (PCR), TCR-Vβ PCR,
or by Southern blot analysis

- NK-LGL leukemia must have CD56+ or CD16+ NK cells > 750/mm³ by phenotypic studies of
peripheral blood

- Life expectancy > 2 years

- ECOG performance status (PS) 0-2 OR Karnofsky PS 60-100%

- Fertile patients must use effective contraception prior to and during study

- Negative pregnancy test

- Normal kidney and liver function, as determined by the following laboratory results:
total bilirubin less than or equal to 2.0 mg/dl; AST (SGOT) and ALT (SGPT) less than
or equal to 2.5 times the upper limit of normal; and creatinine less than or equal to
2.0 mg/dl

Exclusion Criteria:

- Not pregnant or nursing

- No history of allergic reactions attributed to compounds of similar chemical or
biologic composition to tipifarnib

- No allergies to imidazoles (e.g., clotrimazole, ketoconazole, miconazole, econazole,
fenticonazole, isoconazole, sulconazole, tioconazole, or terconazole)

- No uncontrolled concurrent illness including, but not limited to, any of the
following: ongoing or active infection, symptomatic congestive heart failure,
unstable angina pectoris, cardiac arrhythmia, psychiatric illness or social
situations that would limit study compliance

- No other serious medical illness that would limit survival to < 2 years

- No other malignancy within the past 5 years except inactive nonmelanoma skin cancer
or carcinoma in situ of the cervix

- Psychiatric illness that may interfere with study participation

- No other anticancer agents or therapies

- No concurrent antiretroviral therapy for HIV-positive patients

- No other concurrent investigational agents

- No prior tipifarnib or other inhibitors of MAPK signaling intermediates

Type of Study:


Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Response rates to tipifarib defined as the proportion of patients achieving a complete response (CCR) or partial response (PR)

Outcome Time Frame:

Up to 5 years

Safety Issue:


Principal Investigator

Thomas Loughran

Investigator Role:

Principal Investigator

Investigator Affiliation:

Case Comprehensive Cancer Center


United States: Food and Drug Administration

Study ID:




Start Date:

June 2006

Completion Date:

Related Keywords:

  • Stage III Chronic Lymphocytic Leukemia
  • Stage IV Chronic Lymphocytic Leukemia
  • T-cell Large Granular Lymphocyte Leukemia
  • Leukemia
  • Leukemia, Lymphocytic, Chronic, B-Cell
  • Leukemia, Lymphoid
  • Leukemia, Large Granular Lymphocytic



Case Western Reserve University Cleveland, Ohio  44106