17-N-Allylamino-17-Demethoxygeldanamycin With or Without Rituximab in Treating Patients With Relapsed B-Cell Chronic Lymphocytic Leukemia or Prolymphocytic Leukemia
17-N-Allylamino-17-Demethoxygeldanamycin With or Without Rituximab in Treating Patients With Relapsed B-Cell Chronic Lymphocytic Leukemia or Prolymphocytic Leukemia
This phase I trial is studying the side effects and best dose of
 17-N-allylamino-17-demethoxygeldanamycin when given with or without rituximab in treating
 patients with relapsed B-cell chronic lymphocytic leukemia or prolymphocytic leukemia. Drugs
 used in chemotherapy, such as 17-N-allylamino-17-demethoxygeldanamycin, 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 rituximab may kill more cancer
 cells.
PRIMARY OBJECTIVES:

 I. To determine the maximum tolerated dose (MTD) of twice weekly
 17-allylamino-17-demethoxygeldanamycin (17-AAG) in combination with weekly rituximab in
 patients with relapsed chronic lymphocytic leukemia (CLL).

 II. To examine the pharmacology of twice weekly 17-AAG in combination with weekly rituximab
 in patients with relapsed CLL.

 SECONDARY OBJECTIVES:

 I. To evaluate toxicity (using NCI CTCAE v3.0 criteria) and preliminary efficacy of twice
 weekly 17-AAG when used in combination with weekly rituximab in this patient population.

 II. To examine the kinetics of depletion of PDK1/AKT-related proteins, mutant p53 and
 up-regulation of alternative targets that mediate resistance to therapy following treatment
 with twice weekly 17-AAG; and the relationship of this to spontaneous and drug-induced
 apoptosis in patients with relapsed CLL.

 III. To examine the immunologic effects of twice weekly 17-AAG, in conjunction with weekly
 rituximab, in patients with relapsed CLL.

 IV. To evaluate toxicity and preliminary efficacy of twice weekly 17-AAG as a single agent in
 this patient population.

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

 Patients receive 17-AAG intravenously (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 up at 2 months and then every 3 months for 2 years.
Inclusion Criteria:

 -  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

 -  Performance status - ECOG 0-2

 -  Performance status - Karnofsky 60-100%

 -  More than 12 weeks

 -  Bilirubin < 1.5 times upper limit of normal (ULN)

 -  AST and ALT ≤ 2.5 times ULN

 -  Creatinine ≤ 2.0 mg/dL

 -  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

 -  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)

 -  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

 -  More than 3 months since prior rituximab and recovered

 -  More than 4 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin) and
 recovered

 -  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

 -  No concurrent medications that prolong or may prolong QTc

 -  No concurrent antiarrhythmic drugs

 -  No other concurrent investigational agents

 -  No other concurrent anticancer therapy