A Phase 1 Study Evaluating the Safety and Pharmacokinetics of ABT-199 in Subjects With Relapsed or Refractory Chronic Lymphocytic Leukemia and Non-Hodgkin Lymphoma

• Determination of dose limiting toxicity (DLT), maximum tolerated dose (MTD), recommended phase two dose (RPTD), and lead-in period regimen [ Time Frame: Lead-in period (if applicable) plus 3 weeks of study drug administration at the designated cohort dose (continuous dosing) ] [ Designated as safety issue: Yes ]
  Protocol-defined events, which can not be attributed by the investigator to a clearly identifiable cause such as tumor progression, concurrent illness, or concomitant medication, will be considered a DLT. Dose limiting toxicities of tumor lysis syndrome observed during the lead-in period will be attributed to the lead-in period.
• Pharmacokinetic profile evaluation [ Time Frame: After first dose (single dose followed by 6 days off drug) and at Weeks 6, 8, 12, 16, 20, and 24 (continuous dosing) ] [ Designated as safety issue: No ]
  Blood and urine samples for pharmocokinetic analysis of ABT-199 will be collected at designated time points
• Safety assessment [ Time Frame: First 3 weeks of study drug administration and every 4 weeks thereafter (continuous dosing for an anticipated maximum duration of 9 months) ] [ Designated as safety issue: Yes ]
  Adverse event monitoring, vital signs, physical examination, lymphocyte enumeration, 12-lead ECG, 2D echocardiogram/multiple gaited acquisition scan (MUGA), and laboratory assessments

• Determination of dose limiting toxicity (DLT) and maximum tolerated dose (MTD) [ Time Frame: First 3 weeks of study drug administration (continuous dosing) ] [ Designated as safety issue: Yes ]
  Protocol-defined events, which can not be attributed by the investigator to a clearly identifiable cause such as tumor progression, intercurrent illness, or concomitant medication, will be considered a DLT
• Pharmacokinetic profile evaluation [ Time Frame: First 3 weeks of study drug administration and at Weeks 6, 12, 16 and 24 (continuous dosing) ] [ Designated as safety issue: No ]
  Blood and urine samples for pharmocokinetic analysis of ABT-199 will be collected at designated time points

• Preliminary efficacy assessment [ Time Frame: First 3 weeks of study drug administration and every 4 weeks thereafter (continuous dosing for an anticipated maximum duration of 9 months) ] [ Designated as safety issue: No ]
  Tumor response or clinical disease progression
• Food Effect [ Time Frame: Week 1 Day -7 (single dose), Week 1 Day 1, and Week 6 Day 1 ] [ Designated as safety issue: No ]
  Effect of food on ABT-199 pharmacokinetic profile (Arm B subjects only)
• Biomarkers and pharmacogenetics [ Time Frame: Screening, Week 1 Day -7, Week 1 Day -6, Week 1 Day 1, Week 6 Day 1, Week 24 Day 1, time of relapse and Final visit. Timepoints vary by disease type, assay performed and whether dose escalation or expanded safety portion of the study. ] [ Designated as safety issue: No ]
  Various biomarkers are being collected to determine if they can be used to measure the status of a disease and/or the effects of treatments.
• Minimal residual disease collection [ Time Frame: At least 2 months after the CR, CRi criteria for tumor response are first met. Every 12 weeks thereafter, until MRD negativity has been achieved (in peripheral blood). ] [ Designated as safety issue: No ]
  MRD assessed in the peripheral blood and/or bone marrow (BM) either by flow cytometry or real-time PCR, will be measured in CLL subjects achieving CR/CRi.

• Preliminary efficacy assessment [ Time Frame: First 3 weeks of study drug administrations and every 4 weeks thereafter (continuous dosing for an anticipated maximum duration of 9 months) ] [ Designated as safety issue: No ]
  Tumor response or clinical disease progression
• Safety assessment [ Time Frame: First 3 weeks of study drug administrations and every 4 weeks thereafter (continuous dosing for an anticipated maximum duration of 9 months) ] [ Designated as safety issue: Yes ]
  Adverse event monitoring, vital signs, physical examination, lymphocyte enumeration, 12-lead ECG, 2D echocardiogram/multiple gaited acquisition scan (MUGA), and laboratory assessments

This is a Phase 1, open-label, multicenter study evaluating the safety and pharmacokinetics profile of ABT-199 under a once daily dosing schedule in approximately 130 subjects with relapsed or refractory chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL). Two arms will be implemented for dose escalation: Arm A, CLL/small lymphocytic lymphoma (SLL) subjects, and Arm B, NHL subjects. Arm A is designed to enroll approximately 78 subjects with relapsed or refractory CLL or SLL and Arm B is designed to enroll approximately 52 subjects with relapsed or refractory NHL. Approximately 42 subjects will be enrolled in Arm A and approximately 28 subjects will be enrolled in Arm B during the dose escalation portion of the study, with the objective of defining dose limiting toxicities (DLTs) and the maximum tolerated dose (MTD). Once the MTD is declared for the arm, approximately 36 additional CLL/SLL subjects and approximately 24 additional NHL subjects (with a potential to enroll a sub-set of 12 subjects with mantle cell lymphoma) will be enrolled in an expanded safety portion of the study at the recommended phase 2 dose (RPTD) and schedule. In addition, subjects in the Arm B (NHL) dose escalation of the study will be evaluated for the food effect of ABT-199.

Interventional Study Design - Primary Purpose: Determination of safety and tolerability

• Chronic Lymphocytic Leukemia
• Non-Hodgkin Lymphoma

• Experimental: Arm A (CLL/SLL subjects)
  Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) subjects
  Intervention: Drug: ABT-199
• Experimental: Arm B (NHL subjects)
  Non-Hodgkin lymphoma (NHL) subjects
  Intervention: Drug: ABT-199

Inclusion Criteria:

• Subject must be at least 18 years of age.

• Subject must have either:

  • (Arm A) relapsed or refractory CLL/SLL and require treatment in the opinion of the Investigator. Subject must have relapsed following or be refractory to standard treatments such as fludarabine based regimens (F, FC, FR, FCR) or alkylator (chlorambucil, bendamustine) based regimens. In addition, there are no other curative options, and the subject has exhausted options that would be considered standard of care, or
  • (Arm B) relapsed or refractory NHL and require treatment in the opinion of the Investigator. Subject must have histologically documented diagnosis of NHL as defined in the World Health Organization classification scheme, except as noted in the exclusion criteria. Subject must have relapsed following or be refractory to standard treatments such as R-CHOP, R-CVP, or fludarabine based regimens. In addition, there are no other curative options, and the subject has exhausted options that would be considered standard of care. Subjects with other lymphoproliferative diseases can be considered in consultation with the Abbott medical monitor.
• Subject has an Eastern Cooperative Oncology Group (ECOG) performance score less than or equal to 1.
• Subject must have adequate bone marrow independent of growth factor support per local laboratory reference range at Screening.
• Subject must have adequate coagulation, renal, and hepatic function, per laboratory reference range at Screening.

Exclusion Criteria:

• CLL subject has undergone an allogeneic or autologous stem cell transplant or NHL subject has undergone an allogeneic stem cell transplant or has been diagnosed with Post-Transplant Lymphoproliferative Disease, Burkitt's lymphoma, Burkitt-like lymphoma, or lymphoblastic lymphoma/leukemia.
• Subject has tested positive for HIV (due to potential drug-drug interactions between anti-retroviral medications and ABT-199, as well as anticipated ABT-199 mechanism based lymphopenia that may potentially increase the risk of opportunistic infections and potential drug-drug interactions with certain anti-infective agents).
• Subject has a cardiovascular disability status of New York Heart Association Class greater or equal to 2. Class 2 is defined as cardiac disease in which patients are comfortable at rest but ordinary physical activity, results in fatigue, palpitations, dyspnea or anginal pain.
• Subject has a significant history of renal, neurologic, psychiatric, endocrinologic, metabolic, immunologic, cardiovascular, or hepatic disease that in the opinion of the Investigator would adversely affect his/her participating in this study.