A Dose-finding Study of the Bromodomain (Brd) Inhibitor OTX015/ Birabresib (MK-8628) in Hematologic Malignancies (MK-8628-001)

Inclusion Criteria

• Histologically or cytologically proven acute leukemias (AML or ALL) or hematologic malignancies (DLBCL or MM) using standard diagnosis criteria. Acute leukemia includes de novo and secondary to a pre-existing myelodysplastic syndrome, according to the World Health Organization 2008 classification. For DLBCL, an archived formaldehyde-fixed paraffin-embedded block must be available.
• Has failed all standard therapies or for whom standard treatments are contra-indicated:
• Acute leukemia participants: 60 years old in first relapse with a disease-free interval (DFI) 90 days; participants with B-cell ALL: Philadelphia chromosome positive (Ph+) must have received ≥2 lines of therapy, including 2 bcr-abl tyrosine-kinase (TK) inhibitors (among imatinib, nilotinib and dasatinib), or only 1 line including 1 TK inhibitor, if the relapse/refractoriness is associated with the detection of a resistance mutation to these inhibitors
• DLBCL participants: Failed 2 standard lines of therapy (≥1 containing an anti-CD20 monoclonal antibody), or for whom such treatment is contra-indicated
• MM participants: Adequately exposed to at least one alkylating agent, one corticosteroid, one immunomodulatory drug (IMiD) and bortezomib, or for whom such treatments are contra-indicated.
• For participants with evaluable disease:
• Advanced leukemia participants must have >5% bone marrow blasts at study entry, without alternative causality (e.g. bone marrow regeneration)
• DLBCL participants must have ≥1 non-irradiated tumor mass ≥15 mm (long axis of lymph node) or ≥10 mm (short axis of lymph node or extranodal lesions) on spiral computed tomography (CT)-scan.
• MM participants must have ≥1 of the following: serum monoclonal component >1 g/dL (IgG), or >0.5 g/dL (IgA), or Bence-Jones (BJ) proteinuria >200 mg/24h, or measurable plasmacytoma (not previously irradiated).
• Life expectancy ≥3 months.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2.
• Off previous therapy ≥3 weeks prior to first study drug administration with full recovery from any previous toxicities, except 1) hydroxyurea single agent of in combination (e.g. + 6-Mercaptopurine [6MP]) to control hyperleukocytosis, which should be stopped for ≥48 hours, and 2) rituximab, which should be stopped for ≥3 weeks.
• Recovery from the non-hematologic toxic effects of prior treatment to grade ≤1, according to National Cancer Institute Common Toxicity Criteria (NCI-CTC) classification, except alopecia.
• Adequate bone marrow function.
• Adequate calculated creatinine clearance.
• Adequate liver function tests.
• Complete baseline disease assessment workup prior to first study drug administration.

Exclusion Criteria

• History of prior malignancy other than those previously treated with a curative intent >3 years ago and without relapse (any tumor) or basal cell skin cancer, in situ cervical cancer, superficial bladder cancer, or high grade intestinal polyps treated adequately, regardless of the DFI.
• Pregnant or lactating women or women of childbearing potential not using adequate contraception. Male participants not using adequate contraception.
• Peripheral cytopenias (i.e. auto-immune hemolytic anemia or thrombocytopenia).
• Acute promyelocytic leukemia or with clinically uncontrolled (i.e. with bleeding) disseminated intravascular coagulation (DIC).
• Chronic graft versus host disease (GVHD) or on immunosuppressive therapy for the control of GVHD.
• Uncontrolled leptomeningeal disease.
• Other tumor location necessitating an urgent therapeutic intervention (palliative care, surgery or radiation therapy), such as spinal cord compression, other compressive mass, uncontrolled painful lesion, bone fracture, etc.
• Unable to swallow oral medications, or has gastrointestinal condition (e.g. malabsorption, resection) deemed to jeopardize intestinal absorption.
• Other serious illness or medical conditions, which, in the investigator's opinion could hamper