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)
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.
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
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
Patients are followed up at 2 months and then every 3 months for 2 years.
Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Maximum tolerated dose (MTD) of 17-N-allylamino-17-demethoxygeldanamycin (17-AAG)
Defined at the dose level of 17-AAG at which 2 (or more) of 6 patients develop dose-limiting toxicity (DLT).
Ohio State University
United States: Food and Drug Administration
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