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

Inclusion Criteria:

- Histologically or cytologically confirmed diagnosis of 1 of the following hematologic
malignancies:

- Acute myeloid leukemia or acute lymphoblastic leukemia

- Not a candidate for potentially curative therapy

- WBC ≤ 10,000/mm^3 OR WBC ≤ 40,000/mm^3 that is stable for 5 days
(hydroxyurea allowed)

- No acute promyelocytic leukemia

- Non-Hodgkin's lymphoma (NHL), including 1 of the following subtypes:

- Small lymphocytic lymphoma

- Marginal zone lymphoma

- Lymphoplasmacytic lymphoma

- Follicular lymphoma

- Mantle cell lymphoma

- Diffuse large B-cell lymphoma

- Anaplastic large cell lymphoma

- Peripheral T-cell lymphoma

- Extranodal NK/T cell lymphoma (nasal and nasal type)

- Enteropathy-type T-cell lymphoma

- Hepatosplenic T-cell lymphoma

- Angioimmunoblastic T-cell lymphoma

- Subcutaneous panniculitis-like T-cell lymphoma

- Chronic lymphocytic leukemia (CLL)

- Patients with NHL or CLL must meet the following criteria:

- Ineligible for, or refused potentially curative stem cell transplantation

- Transformed lymphoma/Richter's transformation, defined as the transformation of
low-grade lymphoma, including follicular lymphoma, CLL, or small lymphocytic
lymphoma to high-grade lymphoma (i.e., diffuse large cell lymphoma) allowed at
time of transformation

- Evidence of ≥ 50% bone marrow involvement at the time of enrollment OR tumor
tissue accessible for biopsy (for patients enrolled after the maximum tolerated
dose [MTD] is determined)

- Absolute neutrophil count ≥ 1,000/mm^3

- Platelet count ≥ 100,000/mm^3

- 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:

- Dyspnea on or off exertion

- Paroxysmal nocturnal dyspnea

- Significant pulmonary disease including chronic obstructive or restrictive
pulmonary disease

- No prior history of pulmonary toxicity after bleomycin or carmustine

- 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