• Safety [ Designated as safety issue: Yes ]
  
• Maximum tolerated dose (Phase I) [ Designated as safety issue: Yes ]
  
• Progression-free survival (Phase II) [ Designated as safety issue: No ]
  
• Objective response rate (Phase II) [ Designated as safety issue: No ]
  
• Time to tumor progression (Phase II) [ Designated as safety issue: No ]
  
• Overall survival (Phase II) [ Designated as safety issue: No ]
  
• Duration of overall survival (Phase II) [ Designated as safety issue: No ]
  
• ECOG performance status (Phase II) [ Designated as safety issue: No ]
  
• Response to treatment (Phase II) [ Designated as safety issue: No ]
  

OBJECTIVES:

• Determine the maximum tolerated dose of ABT-263 in patients with relapsed or refractory T-cell or B-cell lymphoid malignancy. (Phase I)
• Determine the dose-limiting toxicity of this drug in these patients. (Phase I)
• Determine the pharmacokinetic profile of this drug in these patients. (Phase I)
• Determine the effect of food on bioavailability of this drug in these patients. (Phase I)
• Determine the safety of this drug in these patients.
• Determine, preliminarily, the efficacy of this drug in these patients. (Phase II)

OUTLINE: This is a multicenter, phase I, dose-escalation study followed by an open-label, phase II study.

• Phase I: Patients receive oral ABT-263 once daily on days -3 and 1-14 of course 1 and on days 1-14 of all subsequent courses. Courses repeat every 21 days for up to 1 year in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of ABT-263 until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which at least 2 of 6 patients experience dose-limiting toxicity.

Blood samples are acquired periodically during study treatment. Samples are examined for pharmacokinetics and proteomics.

• Phase II: Patients receive oral ABT-263 at the MTD determined in phase I. Core-needle biopsies are acquired prior to treatment, at the time of relapse, and after completion of study treatment. Samples are examined by immunohistochemistry and fluorescent in situ hybridization (FISH) for pharmacogenetic and chromosomal translocation analyses.

After completion of study treatment, patients are followed at 21 and 30 days.

PROJECTED ACCRUAL: A total of 80 patients will be accrued for this study.

DISEASE CHARACTERISTICS:

• Histologically confirmed B- or T-cell lymphoid malignancies meeting the following criteria*:

  • Refractory OR progressive disease
  • Received at least 1 prior chemotherapy treatment for a lymphoid malignancy

• No prior or concurrent diagnosis of the following*:

  • Post-transplant lymphoproliferative disease
  • Burkitt's-like lymphoma
  • Lymphoblastic lymphoma/leukemia
  • Multiple myeloma
  • HIV-associated lymphoma

• Histologically confirmed follicular lymphoma meeting the following criteria**:

  • No more than 4 prior conventional chemotherapy regimens

  • Measurable disease or lesions with ≥ 1 disease site meeting the following criteria:

    • Measurable disease with cytologically and/or histologically confirmed neoplastic nature of solitary lesions
    • Lesions that can be accurately measured in ≥ 1 dimension with the longest diameter ≥ 10 mm

• At least 1 of the following available for pharmacodynamic analyses**:

  • Core-needle biopsy of malignant lymph node obtained at screening
  • Bone marrow aspirate or core obtained at screening (positive for lymphoma)
  • Archived tumor tissue with no intervening treatment since biopsy (e.g., from debulking, tissue obtained at relapse, or bone marrow sample)
• Must have documented brain imaging by MRI or CT scan negative for subdural or epidural hematoma ≤ 28 days prior to study treatment when clinically indicated (e.g., patients over the age of 70 years)
• No prior or concurrent cancer-related CNS disease (lymphoid or nonlymphoid) NOTE: *Phase I

NOTE: **Phase II

PATIENT CHARACTERISTICS:

• ECOG performance status 0-2
• Absolute neutrophil count ≥ 1,000/mm³
• Platelet count ≥ 100,000/mm³
• Hemoglobin ≥ 9.0 g/dL
• Creatinine ≤ 1.5 mg/dL OR creatinine clearance ≥ 50 mL/min
• AST and ALT ≤ 1.5 times upper limit of normal (ULN) (2.5 times ULN for patients with hepatic involvement)
• Bilirubin ≤ 1.5 times ULN (unless Gilbert's syndrome is present)
• aPTT, PT, and INR normal
• No nonchemotherapy-induced, thrombocytopenic-associated bleeding within the past year
• No underlying predisposition to bleeding
• Not currently exhibiting signs of bleeding

• No history of platelet autoantibodies or autoimmune phenomena, including the following:

  • Immune thrombocytopenic purpura
  • Autoimmune hemolytic anemia
• No active peptic ulcer disease or other hemorrhagic esophagitis/gastritis

• No significant history of disease in any of the following body systems that, in the opinion of the investigator, would adversely affect study participation:

  • Cardiac
  • Renal
  • Neurologic
  • Psychiatric
  • Endocrinologic
  • Metabolic
  • Immunologic
  • Hepatic
• No other prior or concurrent malignancy except adequately treated basal cell or squamous cell skin cancer, carcinoma in situ of the cervix, or nonpulmonary malignancy (e.g., localized prostate cancer) confined and surgically resected from which the patient has been disease free for ≥ 3 years

• No other clinically significant uncontrolled conditions, including, but not limited to, the following:

  • Active systemic fungal infection
  • Fever and neutropenia within the past week
• No HIV positivity
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics
• More than 3 days since prior consumption of grapefruit or grapefruit products
• More than 3 months since prior rituximab therapy, except for patients who have objective disease progression after rituximab treatment (Phase II)
• More than 7 days since prior steroid therapy
• More than 28 days since prior selective serotonin reuptake inhibitor antidepressants (e.g., fluoxetine)

• More than 28 days since prior and no other concurrent anticancer therapy, including the following:

  • Chemotherapy
  • Immunotherapy
  • Radiotherapy
  • Hormonal therapy
  • Biologic therapy
  • Other investigational therapy
• No prior or concurrent allogeneic or autologous stem cell transplantation
• No concurrent anticoagulation therapy or other drugs that affect platelet function
• No concurrent surgery

• No concurrent use of the following medications:

  • Anticoagulants (e.g., warfarin, clopidogrel bisulfate, acetylsalicylic acid, ibuprofen, tirofiban)
  • CYP2C8 inhibitors (e.g., glitazones and statins)
  • CYP2C9 inhibitors (e.g., quinidine, metronidazole, phenytoin, tolbutamide)
  • CYP3A inhibitors (e.g., ketoconazole, clarithromycin)
  • Disulfiram
  • Selective serotonin reuptake inhibitor antidepressants (e.g., fluoxetine, citalopram hydrobromide)