A Phase 1 Study of 17-allylamino-17-demethoxygeldanamycin (17-AAG) (NSC 330507; IND 57,966) and Rituximab in Patients With Relapsed B-cell Chronic Lymphocytic Leukemia (CLL)
A Phase 1 Study of 17-allylamino-17-demethoxygeldanamycin (17-AAG) (NSC 330507; IND 57,966) and Rituximab in Patients With Relapsed B-cell Chronic Lymphocytic Leukemia (CLL)
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:
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:
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:
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