A Phase I Study of PS-341 (Velcade, Bortezomib) in Combination With 17-allylamino-17-demethoxygeldanamycin (17-AAG) in Patients With Relapsed or Refractory Hematologic Malignancies
A Phase I Study of PS-341 (Velcade, Bortezomib) in Combination With 17-allylamino-17-demethoxygeldanamycin (17-AAG) in Patients With Relapsed or Refractory Hematologic Malignancies
This phase I trial is studying the side effects and best dose of 17-N-allylamino-17-demethoxygeldanamycin and bortezomib in treating patients with relapsed or refractory hematologic cancer. 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. Bortezomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving 17-N-allylamino-17-demethoxygeldanamycin together with bortezomib may kill more cancer cells.
PRIMARY OBJECTIVES:
I. To determine the maximum tolerated dose (MTD) of PS-341 (Velcade, Bortezomib) in combination with 17-allyamino-17-demethoxygeldanamycin (17-AAG) in patients with relapsed or refractory acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL).
II. To determine the MTD of PS-341 in combination with 17-AAG in patients with relapsed or refractory chronic lymphocytic leukemia (CLL), and non-Hodgkin's lymphoma (NHL).
III. To define the specific toxicities and the dose limiting toxicity (DLT) of PS-341 in combination with 17-AAG in the treatment of patients with relapsed or refractory hematologic malignancies.
SECONDARY OBJECTIVES:
I. To determine the pharmacokinetics of 17-AAG alone and in combination with PS-341 in patients with AML, ALL, CLL, and NHL.
II. To evaluate 20S proteasome inhibition following combination therapy with 17-AAG and PS-341 in patients with AML, ALL, CLL, and NHL.
III. To assess the relationship between FLT3 mutational status and leukemic cell response to PS-341 and 17-AAG in patients with AML.
IV. To assess the relationship between Bcl-2 over-expression and response to 17-AAG and PS-341 in patients with AML and NHL.
V. To evaluate the effects of the combination of PS-341 and 17-AAG on Hsp90 and NF-kappaB and their downstream targets including Hsp70, Akt, phosphorylated Akt, p21, and caspases 3 and 9 in patient-derived primary AML and NHL cells.
OUTLINE: This is a dose-escalation study. Patients are stratified according to diagnosis (acute myeloid leukemia [AML] or acute lymphoblastic leukemia vs chronic lymphoctyic leukemia or non-Hodgkin's lymphoma [NHL]).
Patients receive 17-N-allylamino-17-demethoxygeldanamycin (17-AAG) intravenously (IV) over 1-6 hours on days 1, 4, 8, and 11 and bortezomib IV over 3-5 seconds on days 4, 8, and 11 of course 1 and on days 1, 4, 8, and 11 of all subsequent courses.
Treatment repeats every 21 days for 3-12 courses provided patient is receiving clinical benefit. Patients achieving objective response may discontinue therapy to undergo stem cell transplantation.Cohorts of 3-6 patients with receive escalating doses of 17-AAG and bortezomib 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.
After the MTD is determined, an additional 20 patients (10 per stratum with AML or follicular NHL) are enrolled and receive 17-AAG and bortezomib as above at the MTD.
Inclusion Criteria:
Histologically or cytologically confirmed diagnosis of 1 of the following hematologic malignancies:
Acute myeloid leukemia or acute lymphoblastic leukemia
Non-Hodgkin's lymphoma (NHL), including 1 of the following subtypes:
Chronic lymphocytic leukemia (CLL)
Patients with NHL or CLL must meet the following criteria:
Relapsed or refractory disease
Willing to undergo serial bone marrow biopsy (for patients enrolled after the MTD is determined)
No untreated or active CNS leukemia or lymphoma
Performance status - ECOG 0-2
At least 12 weeks
Bilirubin ≤ 1.5 mg/dL
AST and ALT ≤ 2.5 times upper limit of normal
Creatinine ≤ 2.0 mg/dL
No uncontrolled cardiac disease
No New York Heart Association class III-IV symptomatic congestive heart failure
No unstable angina pectoris
No serious ventricular arrhythmia (i.e., ventricular tachycardia or ventricular fibrillation > 3 beats in a row) within the past 6 months
No other uncontrolled cardiac arrhythmia or requiring antiarrhythmic drugs
No myocardial infarction within the past year
No active ischemic heart disease within the past year
No congenital long QT syndrome
No left bundle branch block
QTc ≥ 450 msec (for men) or 470 (for women) on ECG/EKG
No history of LVEF < 50% by MUGA or echocardiogram
Resting ejection fraction ≥ 50% by MUGA or echocardiogram
No prior history of cardiac toxicity after receiving anthracycline therapy (e.g., doxorubicin hydrochloride, daunorubicin hydrochloride, or mitoxantrone hydrochloride)
No uncontrolled pulmonary disease
No symptomatic pulmonary disease requiring oxygen or medications
DLCO (i.e., oxygen diffusion capacity) ≥ 80% on pulmonary function testing
Resting and exercise oxygen saturation ≥ 90% by pulse oximetry
No ongoing pulmonary symptoms ≥ grade 2 including any of the following:
No Medicare requirement for home oxygen (e.g., Resting O_2 saturation ≥ 90% or desaturation to ≥ 90% with exertion)
Not pregnant or nursing
Negative pregnancy test
Fertile patients must use effective contraception
HIV negative
No preexisting sensory or motor peripheral neuropathy ≥ grade 2
No history of allergic reaction to eggs
No ongoing or active infection
No psychiatric illness or social situation that would preclude study compliance
No other uncontrolled illness
Prior stem cell transplantation for relapsed or refractory disease allowed
At least 2 weeks since prior immunotherapy and recovered
At least 2 weeks since prior chemotherapy (excluding hydroxyurea) and recovered
No other concurrent chemotherapy
No concurrent routine corticosteroids except for treatment of other medical problems (e.g., pulmonary, rheumatologic, or adrenal disorders)
At least 2 weeks since prior radiotherapy and recovered
No prior radiotherapy that potentially included the heart in the field (e.g., mantle)
No prior history of chest radiation
No concurrent palliative radiotherapy
At least 2 weeks since prior investigational therapy
Prior bortezomib allowed
No other concurrent commercial or investigational agents or therapies for the malignancy