OBJECTIVES:

Primary

• Determine the maximum tolerated dose of 17-N-allylamino-17-demethoxygeldanamycin (17-AAG) when administered alone or in combination with rituximab in patients with relapsed 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 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 2 hours on days 1, 4, 8, 11, 15 and 18 (course 1). Patients achieving ≥ 25% reduction in measurable disease after course 1 receive an additional course of single-agent 17-AAG approximately 10 days later in the absence of disease progression or unacceptable toxicity and provided absolute lymphocyte count continues to decrease. Patients failing to achieve a 25% reduction in measurable disease after course 1 OR with disease progression after courses 1 or 2 of single-agent 17-AAG proceed to combination therapy comprising 17-AAG IV over 2 hours on days 1, 4, 8, 11, 15, 18, and 22; and rituximab IV over 4 hours on days 1 and 2 and over 1 hour on days 4, 8, 15, and 22 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 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.

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
• Relapsed disease
• Failed prior fludarabine or pentostatin therapy OR cannot receive fludarabine
• 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

• LVEF > 40% by MUGA
• QTc < 450 msec for male patients and < 470 msec for female patients
• Resting ejection fraction ≥ 50% by MUGA or echocardiogram
• No symptomatic congestive heart failure
• No unstable angina pectoris
• No cardiac arrhythmia

• No significant cardiac disease including any of the following:

  • New York Heart Association class III or IV heart failure
  • History of myocardial infarction within the past year
  • History of uncontrolled dysrhythmias
  • Active ischemic heart disease within the past year
  • Poorly controlled angina
• No history of serious ventricular arrhythmia (e.g., ventricular fibrillation, history of symptomatic or sustained ventricular tachycardia, nonsustained ventricular tachycardia > 3 beats within the past 6 months)
• No history of cardiac toxicity due to anthracyclines (e.g., doxorubicin hydrochloride, daunorubicin hydrochloride, or mitoxantrone hydrochloride)
• No other cardiac symptoms ≥ grade 2

Pulmonary

• DLCO (i.e., oxygen diffusion capacity) ≥ 80% by pulmonary function testing
• Resting and exercise oxygen saturation ≥ 90% by pulse oximetry
• No pulmonary symptoms ≥ grade 2
• No history of pulmonary toxicity due to bleomycin or carmustine
• No significant, symptomatic pulmonary disease requiring oxygen or medications

• No ongoing pulmonary symptoms ≥ grade 2 including any of the following:

  • Dyspnea on or off exertion
  • Paroxysmal nocturnal dyspnea
  • Significant pulmonary disease (e.g., chronic obstructive or restrictive pulmonary disease)
• No Medicare requirements for home oxygen (e.g., resting O_2 saturations ≥ 90% or desaturation to ≥ 90% with exertion)

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
• No prior radiotherapy that potentially included the heart in the field (e.g., mantle)
• No history of chest radiation

Surgery

• Not specified

Other

• No concurrent medications that prolong or may prolong QTc
• No concurrent antiarrhythmic drugs
• No other concurrent investigational agents
• No other concurrent anticancer therapy