A Dose-finding Study of the Bromodomain (Brd) Inhibitor OTX015/ Birabresib (MK-8628) in Hematologic Malignancies (MK-8628-001)
Condition: Acute Myeloid Leukemia; Diffuse Large B-cell Lymphoma; Acute Lymphoblastic Leukemia; Multiple Myeloma
MeSH terms: Leukemia; Multiple Myeloma; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Lymphoma, Large B-Cell, Diffuse
Intervention: OTX015/Birabresib
Intervention description: OTX015/Birabresib 10 mg, 20 mg, or 40 mg capsules administered orally
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 141.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      The primary purpose of this study was to determine the recommended dose (RD) of birabresib
      (MK-8628) /OTX015 for further phase II studies, in participants with acute leukemia (AL)
      including acute myeloid leukemia (AML; de novo and secondary to a myelodysplastic syndrome)
      and acute lymphoblastic leukemia (ALL) or other hematologic malignancies (OHM) including
      diffuse large B cell lymphoma (DLBCL) and multiple myeloma (MM). The first phase of the study
      will be a dose escalation phase to determine the Phase II RD using dose-limiting toxicities
      (DLTs). Once the RD is determined, participants will be enrolled in an expansion phase at the
      RD to determine preliminary efficacy in AL and OHM cohorts. Participants received therapy in
      21-day cycles until disease progression, intolerable toxicity, or treatment interruption for
      >2 weeks due to toxicity.
    

Eligibility criteria:

        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 second relapse or relapsing after
                  allogeneic stem cell transplantation (aSCT) regardless of number of relapses; >60
                  years old in first relapse with a disease-free interval (DFI) <12 months or
                  further relapse; irrespective of age, in participants relapsing after aSCT, the
                  time elapsed since aSCT should be >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 understanding of the study by the participants, participant's compliance
             to study treatment, participant's safety or interpretation of study results. These
             conditions include (but are not restricted to):

               1. Congestive heart failure or angina pectoris except if medically controlled.
                  Previous history of myocardial infarction within 1 year of study entry,
                  uncontrolled hypertension or arrhythmias.

               2. Existence of significant neurologic or psychiatric disorders impairing the
                  ability to obtain consent.

               3. Uncontrolled infection.

               4. Known human immunodeficiency virus (HIV) positivity

          -  Concurrent treatment with other experimental therapies or participation in another
             clinical trial within 30 days prior to first study drug administration.

          -  Concurrent treatment or treatment within 30 days prior to first study drug
             administration with any other anticancer therapy, except hydroxyurea (+/- 6MP) to
             control hyperleukocytosis.

          -  Concomitant treatment with corticosteroids except if chronic treatment with ≤30 mg of
             methylprednisolone daily or equivalent dose of other corticosteroids.