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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)


Phase 1
18 Years
N/A
Not Enrolling
Both
B-cell Chronic Lymphocytic Leukemia, Prolymphocytic Leukemia, Refractory Chronic Lymphocytic Leukemia

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Trial Information

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)


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

Type of Study:

Interventional

Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Maximum tolerated dose (MTD) of 17-N-allylamino-17-demethoxygeldanamycin (17-AAG)

Outcome Description:

Defined at the dose level of 17-AAG at which 2 (or more) of 6 patients develop dose-limiting toxicity (DLT).

Outcome Time Frame:

Week 4

Safety Issue:

Yes

Principal Investigator

Thomas Lin

Investigator Role:

Principal Investigator

Investigator Affiliation:

Ohio State University

Authority:

United States: Food and Drug Administration

Study ID:

NCI-2012-01460

NCT ID:

NCT00098488

Start Date:

April 2005

Completion Date:

Related Keywords:

  • B-cell Chronic Lymphocytic Leukemia
  • Prolymphocytic Leukemia
  • Refractory Chronic Lymphocytic Leukemia
  • Leukemia
  • Leukemia, Lymphocytic, Chronic, B-Cell
  • Leukemia, Lymphoid
  • Leukemia, Prolymphocytic

Name

Location

Ohio State University Medical CenterColumbus, Ohio  43210