Nelfinavir Mesylate and Bortezomib in Treating Patients With Relapsed or Progressive Advanced Hematologic Cancer

OBJECTIVES:

• To assess the safety of nelfinavir mesylate in combination with bortezomib in patients with relapsed or progressive, advanced hematologic malignancies.
• To establish the phase II recommended dose of nelfinavir mesylate in these patients.

OUTLINE: This is a multicenter, dose-escalation study of nelfinavir mesylate.

Patients receive oral nelfinavir mesylate twice daily on days 1-21 and bortezomib IV on days 8, 11, 15, and 18 in course 1. Course 1 has a duration of 28 days. Beginning in course 2, patients receive oral nelfinavir mesylate twice daily on days 1-14 and bortezomib IV on days 1, 4, 8, and 11. Treatment repeats every 21 days for 2 courses. Patients with responding disease may continue to receive nelfinavir mesylate and bortezomib for up to 4 additional courses.

After completion of study treatment, patients are followed for 30 days.

DISEASE CHARACTERISTICS:

• Diagnosed with advanced hematologic malignancies meeting the following criteria:

• Multiple myeloma

• Received ≥ 2 lines of prior chemotherapy (induction chemotherapy followed by high-dose chemotherapy and autologous stem cell transplant with or without maintenance therapy is considered one line of therapy)
• Acute myeloid leukemia
• Acute lymphoblastic leukemia
• Diffuse large B-cell lymphoma
• Hodgkin lymphoma
• Mantle cell lymphoma
• Mature T- and NK-cell neoplasms restricted to the following WHO-defined entities:

• T-cell prolymphocytic leukemia
• T-cell large granular lymphocytic leukemia
• Aggressive NK-cell leukemia
• Adult T-cell leukemia/lymphoma
• Extranodal NK/T-cell lymphoma (nasal type)
• Mycosis fungoides
• Sézary syndrome
• Primary CD30-positive T-cell lymphoproliferative disorders
• Primary cutaneous anaplastic large cell lymphoma
• Primary cutaneous gamma-delta T-cell lymphoma
• Peripheral T-cell lymphoma (not otherwise specified)
• Angioimmunoblastic T-cell lymphoma
• Anaplastic large cell lymphoma (ALK-positive/ALK-negative)
• Grade 3B follicular lymphoma
• Relapsed following or progressed during standard therapy
• Meeting the following criteria:

• Standard intensive therapy is not feasible
• Current disease state for which there is no standard effective therapy
• Refused standard therapy where no curative option exists
• Measurable disease, defined as the following:

• Myeloma: measurable serum monoclonal protein > 1 g/dL for IgG, or > 0.5 g/dL for IgA, IgM or IgD, or difference between involved and uninvolved free light chain levels in serum > 100 mg/L
• Lymphoma: must have ≥ 1 lesion measurable by CT (longest diameter ≥ 15 mm)
• Acute leukemia: ≥ 20% blasts in bone marrow or in peripheral blood (≥ 200/mL blasts in peripheral blood)
• No HIV-associated lymphoma

PATIENT CHARACTERISTICS:

• WHO performance status 0-2
• Absolute neutrophil count ≥ 1,500/mm³
• Platelet count ≥ 75,000/mm³ (if bone marrow impairment, ≥ 20,000/mm^3)
• Hemoglobin > 80 g/L (if considered to be caused by the underlying hematologic malignancy or bone marrow impairment, > 80 g/L after transfusion)
• Bilirubin ≤ 1.5 times upper limit of normal (ULN) (if suspected hemolysis, direct bilirubin ≤ 1.5 times ULN)
• ALT ≤ 2.5 times ULN
• Calculated creatinine clearance > 30 mL/min
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception during and for 12 months after completion of study treatment
• Willing and capable to comply with an oral regimen
• Capable of understanding information given by the investigator on the trial
• Able to adhere and remain in geographic proximity to allow proper staging, treatment, and followup
• No other non-hematologic malignancy within the past 5 years, except adequately treated cervical carcinoma in situ or localized nonmelanoma skin cancer
• No known chronic hepatitis B or C infection or known HIV infection
• No serious underlying medical condition (at the judgment of the investigator) which would impair the ability of the patient to participate in the trial, including any of the following:

• Active autoimmune disease
• Uncontrolled diabetes
• Ongoing or active infection
• Symptomatic congestive heart failure
• Unstable angina pectoris
• Cardiac arrhythmia
• Psychiatric disorder
• No myocardial infarction within the past 6 months
• No polyneuropathy > grade 1 significantly interfering with activities of daily living or painful polyneuropathy
• No known hypersensitivity to trial drugs or hypersensitivity to any other component of the trial drugs

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics
• No more than 4 prior lines of chemotherapeutic regimens (induction chemotherapy followed by high-dose chemotherapy and autologous stem cell transplant with or without maintenance therapy is considered one line of therapy)
• More than 30 days since prior treatment in a clinical trial
• More than 30 days since prior and no concurrent chemotherapy or biologic agents

• For patients with acute leukemia, hydroxyurea may be given up to 48 hours before first administration of the trial treatment, and low dose cytarabine (up to 20 mg/m^2) and mitoxantrone up to 20 mg up to 14 days before first dosing
• At least 1 week since prior and no concurrent CYP3A4 modulators
• No concurrent other experimental drugs
• No concurrent radiotherapy
• No concurrent antineoplastic therapy with chemotherapeutic or biologic agents