RATIONALE: Drugs used in chemotherapy, such as 17-N-allylamino-17-demethoxygeldanamycin and fludarabine, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as rituximab, can block cancer growth in different ways. Some find cancer cells and kill them or carry cancer-killing substances to them. Others interfere with the ability of cancer cells to grow and spread. Monoclonal antibodies may kill cancer cells that are left after chemotherapy. Giving 17-N-allylamino-17-demethoxygeldanamycin with or without fludarabine and rituximab may kill more cancer cells.

PURPOSE: This phase I trial is studying the side effects and best dose of 17-N-allylamino-17-demethoxygeldanamycin when given with or without fludarabine and rituximab in treating patients with B-cell chronic lymphocytic leukemia or prolymphocytic leukemia that did not respond to fludarabine.

Condition	Treatment or Intervention	Phase
B-cell Chronic Lymphocytic Leukemia refractory chronic lymphocytic leukemia Prolymphocytic Leukemia	Drug: 17-N-allylamino-17-demethoxygeldanamycin  Drug: fludarabine  Drug: rituximab  Procedure: antibody therapy  Procedure: biological response modifier therapy  Procedure: chemosensitization/potentiation  Procedure: chemotherapy  Procedure: monoclonal antibody therapy	Phase I

Further Study Details: 

OBJECTIVES: Primary

• Determine the maximum tolerated dose of 17-N-allylamino-17-demethoxygeldanamycin (17-AAG) when administered alone or in combination with fludarabine and rituximab in patients with fludarabine-refractory B-cell chronic lymphocytic leukemia or prolymphocytic leukemia.
• Determine the pharmacology of this combination regimen in these patients.

Secondary

• Determine the toxicity and preliminary efficacy of 17-AAG administered as a single agent and in combination with fludarabine and rituximab in these patients.
• Determine the immunologic effects of this combination regimen in these patients.

OUTLINE: This is a multicenter, dose-escalation study of 17-N-allylamino-17-demethoxygeldanamycin (17-AAG).

Patients receive 17-AAG IV over 1 hour on days 1, 4, 8, 11, 15, and 18. Patients achieving a 25% reduction in absolute lymphocyte count after course 1 continue to receive single-agent 17-AAG every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Patients failing to achieve a 25% reduction in absolute lymphocyte count after course 1 OR with disease progression after any course of single-agent 17-AAG proceed to combination therapy comprising 17-AAG IV over 1 hour on days 1, 4, 8, 11, 15, and 18; fludarabine IV over 30 minutes of days 1-5; and rituximab IV over 4 hours on days 1, 3, and 5 of course 1 and day 1 of all subsequent courses. Combination therapy repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of 17-AAG as a single agent or in combination with fludarabine and rituximab 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.

Patients are followed at 2 months and then every 3 months for 2 years.

PROJECTED ACCRUAL: A total of 3-30 patients will be accrued for this study.

Ages Eligible for Study:  18 Years and above,  Genders Eligible for Study:  Both

Criteria

DISEASE CHARACTERISTICS:

• Histologically confirmed B-cell chronic lymphocytic leukemia or prolymphocytic leukemia requiring treatment, defined by 1 of the following criteria:
• Massive or progressive splenomegaly and/or lymphadenopathy
• Anemia (hemoglobin < 11 g/dL) OR thrombocytopenia (platelet count < 100,000/mm^3)
• Weight loss > 10% within the past 6 months
• Grade 2 or 3 fatigue
• Fevers > 100.5°F or night sweats for > 2 weeks with no evidence of infection
• Progressive lymphocytosis with an increase of > 50% over a 2 month period OR an anticipated doubling time of < 6 months
• Fludarabine-refractory disease, defined by both of the following criteria:
• Relapsed disease after prior fludarabine
• No response or a response lasting < 6 months from the last course of treatment before study entry
• Lymphocyte count ≥ 5,000/mm^3

PATIENT CHARACTERISTICS: Age

• 18 and over

Performance status

• ECOG 0-2 OR
• Karnofsky 60-100%

Life expectancy

• More than 12 weeks

Hematopoietic

• See Disease Characteristics

Hepatic

• Bilirubin < 1.5 times upper limit of normal (ULN)
• AST and ALT ≤ 2.5 times ULN

Renal

• Creatinine ≤ 2.0 mg/dL

Cardiovascular

• No symptomatic congestive heart failure
• No unstable angina pectoris
• No cardiac arrhythmia

Other

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• HIV negative
• No history of allergic reaction attributed to compounds of similar chemical or biologic composition to 17-N-allylamino-17-demethoxygeldanamycin
• No history of serious allergic reaction to eggs
• No ongoing or active infection
• No psychiatric illness or social situation that would preclude study compliance
• No other uncontrolled illness that would preclude study participation

PRIOR CONCURRENT THERAPY: Biologic therapy

• More than 3 months since prior rituximab and recovered

Chemotherapy

• See Disease Characteristics
• More than 4 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin) and recovered

Endocrine therapy

• Not specified

Radiotherapy

• More than 4 weeks since prior radiotherapy and recovered

Surgery

• Not specified

Other

• No other concurrent investigational agents
• No other concurrent anticancer therapy

Study chairs or principal investigators

Thomas Lin, MD,  Study Chair,  Arthur G. James Cancer Hospital & Richard J. Solove Research Institute   

Study ID Numbers:  CDR0000401516; OSU-0429; NCI-6518; NCT00098488
Record last reviewed:  November 2004
Last Updated:  February 4, 2005
Record first received:  December 7, 2004
ClinicalTrials.gov Identifier:  NCT00098488
Health Authority: United States: Federal Government
ClinicalTrials.gov processed this record on 2005-04-08