Study of BMN 673, a PARP Inhibitor, in Patients With Advanced Hematological Malignancies

Inclusion criteria

• 18 years of age or older.
• Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1
• Arm 1 AML/MDS: Must have available tissue
• Arm 2 CLL/MCL: Must have available tissue
• Have adequate organ function as defined below:

• Serum aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ≤ 2.5 X upper limit of normal (ULN);
• Total serum bilirubin ≤ 1.5 X ULN;
• Able to take oral medications
• Recovered from acute toxicity of prior treatment
• Willing and able to provide written, signed informed consent after the nature of the study has been explained, and prior to any research-related procedures.
• If sexually active, must be willing to use an acceptable method of contraception during therapy and for 30 days after the last dose of BMN 673.
• If female of childbearing potential, must have a negative serum pregnancy test at screening and be willing to have additional pregnancy tests during the study.
• Willing and able to comply with all study procedures.

Exclusion criteria

• Acute promyelocytic leukemia, APL [AML with t(15;17)(q22;q12), PML-RARA and variants].
• Disease-specific exclusion criteria:

a. AML: i. Marrow cellularity < 25% ii. Circulating blasts > 50,000/mm3 b. MCL and CLL: i. Platelet count < 50,000/mm3 ii. Neutrophil count < 1000/mm3

• Autologous bone marrow transplant < 6 months before Cycle 1 Day 1
• Prior allogeneic bone marrow transplant < 6 months before Cycle 1 Day 1 and/or with the presence of graft versus host disease (GVHD)
• Prior treatment:

• AML: anti-leukemia treatment within 14 days before Cycle 1 Day 1; hydroxyurea treatment within 7 days before Cycle 1 Day 1.
• CLL, MCL or MDS: anti-lymphoma/leukemia treatment within 28 days before Cycle 1 Day 1;
• CLL/MCL patients who have received transfusion, hematopoietic growth factors within 7 days before Cycle 1 Day 1.
• Symptomatic central nervous system (CNS) involvement.
• Known to have human immunodeficiency virus (HIV) or active hepatitis C virus (HCV) or hepatitis B virus (HBV).
• Major surgery within 28 days before Cycle 1, Day 1.
• Active peptic ulcer disease.
• Active gastrointestinal tract disease with malabsorption syndrome.
• Requirement for IV alimentation.
• Prior surgical procedures affecting absorption.
• Uncontrolled inflammatory bowel disease (eg, Crohn's disease, ulcerative colitis).
• Myocardial infarction within 6 months before Cycle 1 Day 1, symptomatic congestive heart failure (New York Heart Association > class II), unstable angina, or unstable cardiac arrhythmia requiring medication.
• Breastfeeding at screening or planning to become pregnant (self or partner) at any time during study participation.
• Use of any investigational product or investigational medical device within 28 days before Cycle 1, Day 1.
• Concurrent disease or condition that would interfere with study participation or safety, such as:

• CLL/MCL patients with active, clinically significant infection requiring the use of parenteral anti-microbial agents, or grade > 2 infection by NCI CTCAE (v4.03) within 14 days before Cycle 1, Day 1(AML/MDS patients with controlled infection are eligible for the study with no specific time requirement prior to Cycle 1, Day 1);
• Clinically significant bleeding diathesis or coagulopathy, including known platelet function disorders;
• Non-healing wound, ulcer, or bone fracture.
• Patients who have received prior treatment with a PARP inhibitor are not eligible for Part 2 of the study (expansion), but are eligible for Part 1 (dose escalation) of the study.