Escalating Dose Study in Subjects With Relapsed or Refractory B Cell Non-Hodgkin Lymphoma, Chronic Lymphocytic Leukemia, and Waldenstrom's Macroglobulinemia

• Establish recommended Phase 2 dose, after completing dose escalation in Part 1 and evaluating accumulated safety,PK,and PD data from the dose escalation phase (Part1) [ Time Frame: Completion of Part 1 dose escalation phase of study ] [ Designated as safety issue: No ]
  After completion of observation for dose limiting toxicities in Part 1 of the study, the accumulated safety, PK, and PD data from Part 1 will be evaluated by the investigators and Sponsor to select a preliminary RP2D for administration to additional subjects to be enrolled into 1 of 3 independent and non-randomized diagnosis-specific expansion cohorts in Part 2 of the study
• evaluate the Pharmacokinetic parameters of AVL-292 [ Time Frame: First 28 days of dosing ] [ Designated as safety issue: No ]
  Serial blood sampling to enable PK characterization of AVL-292 will be performed for the Cycle1 Day 1 (C1D1) and Cycle 1Day 15 dose administrations. Additional samples will be obtained on C1D8 and C1D22.A non-compartmental model will be evaluated for all subjects.
• evaluate the Pharmacodynamics of AVL-292 by measurement of free Btk [ Time Frame: First 28 days of dosing ] [ Designated as safety issue: No ]
  The PD activity of AVL-292 will be studied with a quantitative assay using a covalent probe to directly assess free Btk in PBMC lysates.
• Characterize preliminary anti-tumor efficacy of AVL-292 in relapsed and/or refractory B-NHL, CLL and WM [ Time Frame: After completion of 28 day cycle of treatment ] [ Designated as safety issue: No ]
  Efficay response assessments will be formally assessed within 7 days preceding C2D1, C3D1, C5D1, C7D1, and EOT

The purpose of this study is to evaluate the safety and tolerability of AVL-292 as monotherapy in subjects with relapsed or refractory B cell non-Hodgkin lymphoma (B-NHL), chronic lymphocytic leukemia (CLL) or Waldenstrom's macroglobulinemia (WM).

Bruton's tyrosine kinase (Btk) is non-receptor tyrosine kinase with restricted cellular expression largely limited to B-lymphocytes, monocytes, and mast cells or basophils. Btk is a critical component of the B cell receptor (BCR) signaling network and is crucial for B cell development. Investigation has revealed that some B cell lymphomas and CLL depend on BCR signaling, suggesting that interruption of such signaling could be a promising therapeutic opportunity in B-NHL, CLL and WM.

• B Cell Non-Hodgkin's Lymphoma
• Chronic Lymphocytic Leukemia
• Waldenstrom Macroglobulinemia

Inclusion Criteria:

• Women and men ≥18 years of age
• Body weight ≥50 kg.
• Confirmed diagnosis of B cellNon-Hodgkin Lymphoma(according to World Health Organization [WHO] classification)including Chronic Lymphocytic Leukemia/Small cell Lymphocytic Leukemia (International Workshop),or Waldenstrom's Macroglobulinemia(Second International Workshop)
• Have failed ≥1 previous treatment for B-NHL/CLL/WM, and have relapsed or refractory disease following last prior treatment.
• Eastern Cooperative Oncology Group performance status of ≤ 2 and a life expectancy of at least 3 months.
• Ability to swallow oral capsules without difficulty
• Has recovered from adverse toxic effects of prior therapies

• Meet the following clinical laboratory requirements:

  • Creatinine ≤ 1.5 × upper limit of normal (ULN)
  • Total bilirubin ≤ 1.5 x ULN
  • AST and ALT ≤ 3 × ULN
  • Platelet count ≥ 50,000/µL (non-hodgkin & Waldenstrom's)
  • Platelet count ≥ 30,000/µL (chronic lymphocytic leukemia)
  • Absolute Neutrophil count ≥ 1000/µL

Exclusion Criteria:

• Prior allogeneic bone marrow transplant
• Autologous stem cell transplant within 3 months of screening
• Active central nervous system involvement
• Subjects with autoimmune hemolytic anemia or immune thrombocytopenia
• Prior treatment with a Btk inhibitor
• Active uncontrolled infection
• History of malabsorption
• Uncontrolled illness, i.e cardiac, endocrine, respiratory, etc.
• History of myocardial infarction, acute coronary syndromes, coronary angioplasty and/or stenting with in the previous 6 months
• History of another currently active cancer
• History of major surgery within 4 weeks or minor surgery within 1 week
• Other medical or psychiatric illness or organ dysfunction
• HIV positive
• Positive for Hepatitis B surface antigen or Hepatitis C-virus