A Phase I, Dose-finding Study of the Bromodomain (Brd) Inhibitor OTX015 in Haematological Malignancies

Inclusion Criteria:

• Signed informed consent prior to beginning protocol specific procedures. Patients registered for this trial must be treated and followed at the participating centers.
• Histologically or cytologically proven hematological malignancy, or confirmed multiple myeloma using standard diagnosis criteria. For the dose finding part, any refractory/relapsing hematological malignancy will be accepted. For the expansion cohorts, only patients with selected hematological malignancies will be enrolled : acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), DLBCL and MM) and/or other diseases, as decided by the SMC after closure of the dose finding part.

• Patient having failed all standard therapies or for whom standard treatment are contra-indicated:

  • For acute leukemia: patients < 60 years old in second relapse or relapsing > 90 days after allogeneic stem cell transplantation; patients> 60 years old in first relapse with a disease-free interval (DFI) < 12 months; Patients with Philadelphia chromosome positive (Ph+) and/or bcr-abl+ B-cell ALL must have received at least two lines of therapy, including 2 bcr-abl tyrosine-kinase (TK) inhibitors (among imatinib, nilotinib and dasatinib), or only one line including one TK inhibitor, if the relapse/refractoriness is associated with the detection of a resistance mutation to these inhibitors.
  • For MM: patients adequately exposed to at least one alkylating agent, one corticosteroid, one immunomodulatory drug (IMiD) and bortezomib,
  • For lymphomas : Patients having failed 2 standard lines of therapy (at least one containing an anti-CD20 antibody if B-cell lymphoma), or for whom such treatment is contra-indicated.

• Patients with evaluable disease

  • AL patients must have > 5% bone marrow blasts at study entry, without alternative causality (e.g. bone marrow regeneration)
  • Lymphoma patients must have at least one non-irradiated tumor mass > 15 mm (long axis of lymph node) or > 10 mm (short axis of lymph node or extranodal lesions) on spiral CT-scan.
  • Patients with MM must have at least one of the following: serum monoclonal component > 1g/dL (IgG), or > 0.5g/dL (IgA), or Bence-Jones (BJ) proteinuria > 200mg/24h, or measurable plasmacytoma (not previously irradiated).
• Patients > 18 years old.
• Life expectancy of at least 3 months
• ECOG performance status of 0 to 2
• Off previous therapy for at least 3 weeks, or 5 half-lives of previously administered drug, whichever is longer, prior to first study treatment administration, except hydroxyurea given to control hyperleukocytosis that should be stopped 48 hours prior to start study medication.
• Recovery from the non-hematological toxic effects of prior treatment to grade < 1, or baseline value, according to NCI-CTC classification, except alopecia.

• Bone marrow function:

  • For patients with acute leukemia: No limitation
  • For patients with other hematological malignancies: Neutrophils > 1.0 x 10e9 /L and platelets > 50 x 10e9 /L (without transfusion),
• Calculated creatinine clearance > 60 mL/min (Cockroft & Gault formula, or MDRD formula for patients aged > 65 years). For patients with MM, a creatinine clearance > 30mL/min is accepted).
• Adequate LFTs: Total bilirubin < the institutional upper normal limits (UNL); ALAT/ASAT and AP < 3 x UNL (or < 5 x UNL in case of liver involvement).
• Serum albumin > 28g/L
• Complete baseline disease assessment workup prior to first study treatment administration.

Exclusion Criteria:

• History of prior malignancy other than those previously treated with a curative intent more than 5 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 disease-free interval.
• Pregnant or lactating women or women of childbearing potential not using adequate contraception. Male patients not using adequate contraception.
• Patients with peripheral cytopenias (i.e. auto-immune hemolytic anemia or thrombocytopenia)
• Patients with acute promyelocytic leukemia or with uncontrolled disseminated intravascular coagulation
• MM patients with POEMS syndrome or plasma cell leukemia.
• Patient with 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..)
• Uncontrolled disease-related metabolic disorder (e.g. hypercalcemia)
• Patients unable to swallow oral medications, or patients with 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 patient, patient's compliance to study treatment, patient'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 from 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 HIV positivity
• Concurrent treatment with other experimental therapies or participation in another clinical trial within 21 days prior to first study treatment administration, or 5 half-lives of previously administered drugs, whichever is longer.
• Concurrent treatment or within 21 days prior to first study treatment administration with any other anticancer therapy, except hydroxyurea to reduced hyperleukocytosis.
• Concomitant treatment with corticosteroids except if chronic treatment with corticosteroids < 20 mg of methylprednisolone daily or equivalent.