A Dose Escalation Study to Investigate the Safety, Pharmacokinetics (PK), Pharmacodynamics (PD) and Clinical Activity of GSK525762 in Subjects With Relapsed, Refractory Hematologic Malignancies
Condition: Neoplasms
MeSH terms: Hematologic Neoplasms
Intervention: GSK525762
Intervention description: GSK525762 1 mg, 10 mg and 30 mg will be supplied as white to off-white, amorphous free base and white to slightly colored crystalline besylate tablets, round, biconvex tablets with no markings. GSK525762 will be administered with 240 milliliter (mL) water.
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 111.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: leukemia; Acute myeloid leukemia; BET inhibitor; lymphoma; Myelodysplastic syndromes; Oncology; multiple myeloma; GSK525762

Summary:

      This is an open-label repeat dose, multicenter, 2-part study to determine the maximum
      tolerated dose (MTD) and the recommended Phase 2 dose (RP2D) for GSK525762 given once-daily
      (QD) orally. Part 1 of the study is a dose escalation phase to select the recommended Part 2
      dose (RP2D) based on the safety, PK, and PD profiles observed after oral administration of
      GSK525762. Eligible subjects with select relapsed refractory hematological malignancies
      (acute myeloid leukemia [AML], non-Hodgkin's Lymphoma [NHL]and multiple myeloma [MM]), will
      be enrolled in the QD and/or BID dosing cohorts until a MTD is established. Subjects may
      continue treatment in the study until disease progression, unacceptable toxicity, or
      withdrawal of consent. . Upon determination of the MTD, twice daily (BID) dosing cohorts may
      be opened to collect additional safety data and evaluate the preliminary efficacy of
      GSK525762 administered BID. Part 2 will explore clinical activity at the MTD or RP2D;
      separate expansion cohorts will be planned for acute myeloid leukemia (AML), non-Hodgkin's
      Lymphoma (NHL, including an exploratory sub-cohort of subjects with myc and B-Cell Leukemia
      (BCL)2 and/or BCL6 rearrangements/overexpression [double- and triple-hit lymphoma]), and
      multiple myeloma (MM). This is the first study of this agent to be conducted in subjects with
      these relapsed and/or refractory hematological malignancies for which no standard therapies
      are anticipated to result in a durable remission.
    

Eligibility criteria:

        Inclusion criteria

          -  Written informed consent provided.

          -  Males and females 18 years old or older.

          -  In Part 1 and, Part 2, subjects must have AML, MM, or NHL. Subjects with AML, are
             eligible if they • have relapsed and/or refractory disease, OR are>=65 years of age
             and not candidates for or have refused standard chemotherapy. Subjects with multiple
             myeloma are eligible if they have progressed despite therapy with an alkylating agent,
             proteasome inhibitor, and immunomodulatory agent, either as individual regimens or in
             combination. Subjects with NHL are eligible if they have received at least two prior
             lines of systemic therapy, including at least one line of immunochemotherapy with an
             anti-CD20 antibody (if their tumor expresses CD20).

        In Part 2, the NHL cohort will separately enrol subjects with double- and triple hit
        lymphoma, so that a minimum of 10 subjects with this subset of disease will be enrolled. To
        be eligible for this sub-cohort, tumor sample from the subject must demonstrate
        rearrangement and/or overexpression of MYC and either BCL2 and/or BCL6 genes. Evaluation of
        double- or triple-hit status may be performed via appropriate local testing, and the
        determination of double- or triple-hit diagnosis will be at the discretion of the
        investigator and GSK Medical Monitor.

          -  Subjects with a prior history of stem cell transplant (autologous and/or allogeneic)
             are allowed if

               -  At least 3 months has elapsed from the time of transplant and

               -  the subject has recovered from transplant-associated toxicities prior to the
                  first dose of GSK525762, and For subjects with a prior history of allogeneic
                  transplant,

               -  the subject has been off systemic immunosuppressive medications (including but
                  not limited to: cyclosporine, tacrolimus, mycophenolate mofetil, or
                  corticosteroids) for at least 1 month prior to the first dose of GSK525762.
                  Topical steroids are permitted

               -  there are no signs or symptoms of graft versus host disease, other than Grade 1
                  skin involvement.

          -  Eastern Cooperative Oncology Group (ECOG) performance status of <=1.

          -  Subject must be stable enough to be expected to complete dosing through the DLT
             observation period as assessed by the investigator.

          -  Able to swallow and retain orally administered medication and does not have any
             clinically significant gastrointestinal abnormalities that may alter absorption such
             as malabsorption syndrome or major resection of the stomach or bowels.

          -  A female subject is eligible to participate if she is of: Non-childbearing potential
             defined as pre-menopausal females with a documented tubal ligation or hysterectomy; or
             postmenopausal defined as 12 months of spontaneous amenorrhea [in questionable cases,
             a blood sample with simultaneous follicle stimulating hormone (FSH) > 40
             milli-International units per milliliter and estradiol < 40 picograms per milliliter
             (< 140 picomole per liter) is confirmatory]. Females on hormone replacement therapy
             (HRT) and whose menopausal status is in doubt will be required to use one of the
             contraception methods defined in protocol if they wish to continue their HRT during
             the study. Otherwise, they must discontinue HRT to allow confirmation of
             post-menopausal status prior to study enrolment. For most forms of HRT, at least two
             to four weeks will elapse between the cessation of therapy and the blood draw; this
             interval depends on the type and dosage of HRT. Following confirmation of their
             post-menopausal status, they can resume use of HRT during the study without use of a
             contraceptive method; Child-bearing potential and agrees to use one of the
             contraception methods for an appropriate period of time (as determined by the product
             label or investigator) prior to the start of dosing to sufficiently minimize the risk
             of pregnancy at that point. Female subjects must agree to use contraception until at
             least 7 months after the last dose of study medication; Negative serum pregnancy test
             <= 7 days prior to first study drug dose; Female subjects who are lactating must
             discontinue nursing prior to the first dose of study treatment and must refrain from
             nursing throughout the treatment period and for 5 half-lives of GSK525762 or at least
             28 days (whichever is longer) following the last dose of study treatment.

          -  Male subjects must agree to use one of the methods of contraception specified. This
             method must be used from the time of the first dose of study medication until 16 weeks
             after the last dose of study medication. In addition, male subjects whose partners are
             or become pregnant must continue to use condoms for 7 days after stopping study
             medications.

          -  Adequate organ system function.

          -  Ability to comply with dietary and tobacco/alcohol abstinence requirements.

        Exclusion Criteria

          -  Haematological malignancy associated with human immunodeficiency virus (HIV) infection
             or solid organ transplant or history of known Hepatitis B Antigen or positive
             Hepatitis C antibody (confirmed by Recombinant ImmunoBlot Assay [RIBA], if available
             or alternately confirmed by Hepatitis C Virus [HCV] Ribonucleic acid [RNA]).

          -  History or concurrent malignancy of solid tumours, except for below. Exception:
             Subjects who have been disease-free for 5 years, or subjects with a history of
             completely resected non-melanoma skin cancer or successfully treated in situ carcinoma
             are eligible. Subjects with second malignancies that are indolent or definitively
             treated may be enrolled even if less than 5 years have elapsed since treatment.
             Consult the GSK Medical Monitor if unsure whether second malignancies meet
             requirements specified above.

          -  Currently receiving cancer therapy (chemotherapy, radiation therapy, immuno- therapy,
             biologic therapy, hormonal therapy, surgery, and/or tumour embolization).The following
             are allowed: Hydroxyurea for proliferative disease, Corticosteroids, Use of
             hematopoetic growth factors is permitted at the discretion of the investigator
             according to published guidelines (e.g., National Comprehensive Cancer Network (NCCN),
             American Society of Clinical Oncology (ASCO), American Society of Hematology (ASH),
             etc.). The following are NOT allowed: Investigational anti cancer drug within 2 weeks
             prior to the first dose of GSK525762; Major surgery, radiotherapy, or immunotherapy
             within 4 weeks of GSK525762 Chemotherapy regimens with delayed toxicity within the
             last 4 weeks. Chemotherapy regimens given continuously or on a weekly basis with
             limited potential for delayed toxicity within the last 2 weeks.

        Nitrosourea or mitomycin C within the last 6 weeks

          -  Evidence of severe of uncontrolled infection.

          -  Use of anticoagulants (e.g., warfarin, heparin) at therapeutic levels within 7 days
             prior to the first dose of GSK525762. Low dose (prophylactic) low molecular weight
             heparin (LMWH) is permitted. In addition, INR must be monitored in accordance with
             local institutional practices, as appropriate.

          -  Current use of a prohibited medication or requires any of these medications during
             treatment with the investigational drugs. This includes excluding current medications
             known or suspected to be associated QT prolongation. In addition, any subject who is
             expected to require a QT prolonging medication while on trial should not be enrolled.

          -  Evidence of severe or uncontrolled systemic diseases (e.g., unstable or uncompensated
             respiratory, hepatic, renal, cardiac disease, or clinically significant bleeding
             episodes). Any serious and/or unstable pre-existing medical (aside from malignancy
             exception above), psychiatric disorder, or other conditions that could interfere with
             subject's safety, obtaining informed consent or compliance to the study procedures, in
             the opinion of the investigator.

          -  Symptomatic or untreated Central nervous system (CNS) disease, Subjects with a history
             of CNS disease (leukemia, lymphoma or myeloma) are permitted to enrol if they have
             previously received appropriate therapy and CNS remission has been documented. Subject
             with primary CNS lymphoma (defined as isolated CNS lymphoma without systemic
             involvement) are excluded from study.

          -  Cardiac abnormalities as evidenced by any of the following: History or current
             clinically significant uncontrolled arrhythmias or hypertension; Clinically
             significant conduction abnormalities or arrhythmias, subjects with Bundle Branch
             Block; Presence of cardiac pacemaker; History or evidence of current >=Class II
             congestive heart failure as defined by New York Heart Association (NYHA); History of
             acute coronary syndromes (including unstable angina and myocardial infarction),
             coronary angioplasty, or stenting within the past 3 months.

          -  Any of the following ECG findings or assessments including: Baseline QTcF interval
             >=450 milliseconds; Clinically significant ECG assessments should be reviewed by the
             site cardiologist prior to study entry.

          -  GSK525762 is a benzodiazepine class molecule. Any serious known immediate or delayed
             hypersensitivity reaction(s) to GSK525762 or idiosyncrasy to drugs chemically related
             to the investigational drug.

          -  Evidence of hemoptysis within the last 7 days.

          -  History of major gastrointestinal bleeding within the last 3 months or any evidence of
             active gastrointestinal bleeding excludes the subject.

          -  Presence of gastrointestinal disease that would significantly affect compound
             absorption.