Open-label Study to Evaluate the Safety, PK, and PD of MEK Inhibitor GSK1120212 in Subjects With Relapsed or Refractory Leukemias
Condition: Cancer
MeSH terms: Leukemia
Intervention: GSK1120212; GSK1120212
Intervention description: Starting dose based on GSK protocol MEK111054 and then dose escalation based on Dose Limiting Toxicities per protocol.; Dose will be maximum tolerated dose based on Phase I results.
Intervention MeSH terms: Trametinib
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 97.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Oncology, GSK1120212, MEK inhibitor, hematological malignancies, AML; CMML; MDS

Summary:

      MEK111759 is a dose-escalation, Phase I/II, open-label study to determine the recommended
      dose and regimen for the orally administered MEK inhibitor GSK1120212 in subjects with
      relapsed or refractory leukemias. The recommended dose and regimen will be selected based on
      the safety, pharmacokinetic, and pharmacodynamic profiles. This study will identify the
      maximum tolerated and recommended Phase II doses using a dose-escalation procedure. Dose
      escalations will continue based on predefined parameters until a maximum tolerated dose is
      established. In Phase II, the clinical efficacy of GSK1120212 in subjects with relapsed or
      refractory leukaemias (AML, MDS or CMML) will be determined.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Phase I

          -  Written informed consent provided.

          -  18 years old or older.

          -  Subjects must have relapsed/refractory leukemias for which no standard therapies are
             anticipated to result in a durable remission. Subjects with poor-risk myelodysplasia
             (MDS) and chronic melomonocytic leukemia (CMML) are also eligible. Relapsed/refractory
             leukemias include acute non-lymphocytic leukemia (AML), acute lymphocytic leukemia
             (ALL), chronic lymphocytic leukemia (CLL), or chronic myelogenous leukemia (CML) in
             blast crisis. Subjects with agnogenic myeloid metaplasia (AMM) are also eligible.
             Subjects with a haematological malignancy associated with human immunodeficiency virus
             (HIV) infection or solid organ transplant are NOT eligible.

          -  Subjects who have previously received an autologous stem cell transplant are allowed
             if a minimum of three months has elapsed from the time of transplant (T0) and the
             subject has recovered from transplant-associated toxicities prior to the first dose of
             GSK1120212.

          -  Subjects with a history of allogeneic stem cell transplant are eligible for study
             participation provided the following eligibility criteria are met: transplant was
             greater than 100 days prior to study enrolment, subject has not taken
             immunosuppressive medications (per protocol) for at least 1 month, no signs or
             symptoms of graft versus host disease other than Grade 1 skin involvement, no active
             infection, subject meets the remainder of the eligibility criteria outlined in this
             protocol.

          -  Eastern Cooperative Oncology Group (ECOG) performance status of less than or equal to
             2.

          -  Life expectancy of at least four weeks.

          -  Able to swallow and retain oral medication.

          -  Male subjects must agree to use one of the contraception methods listed in the
             protocol.

          -  Female subjects must be of non-childbearing potential as listed in the protocol or
             using a contraception method listed in the protocol.

          -  Calcium Phosphate Product less than or equal to 4.0 mmol (squared)/L (squared) or 50mg
             (squared)/dL (squared).

          -  Subjects must have adequate organ function as specified in the protocol.

          -  Phase II

          -  Confirmed diagnosis of one of the following: Relapsed or refractory acute myeloid
             leukemia (AML), Secondary AML including AML arising from antecedent hematologic
             diseases (e.g., myelodysplastic syndrome, myeloproliferative disorders, or
             therapyrelated AML), CMML, or MDS.

        Cohorts 1: RAS Positive AML/MDS Cohort 2: Wild Type AML/MDS/CMML Cohort 3: RAS Positive
        CMML

        Exclusion Criteria:

          -  Phase I

          -  Currently receiving cancer therapy as specified in the protocol.

          -  Received corticosteroids or imatinib within 24h of GSK1120212 administration.

          -  Received gemtuzumab ozogamicin (myelotarg) within two weeks of GSK1120212
             adminstration.

          -  Received an investigational anti-cancer drug within four weeks or five half-lives,
             whichever is shorter of GSK1120212 administration, as specified in the protocol.

          -  Received major surgery, radiotherapy, or immunotherapy within four weeks of GSK1120212
             administration.

          -  Received chemotherapy regimens with delayed toxicity within the last four weeks (six
             weeks for prior nitrosourea or mitomycin C). Received chemotherapy regimens given
             continuously or on a weekly basis with limited potential for delayed toxicity within
             the last two weeks.

          -  Received a MEK inhibitor.

          -  Current use of a prohibited medication per protocol.

          -  Current use of warfarin. Low molecular weight heparin and prophylactic low-dose
             warfarin are permitted per protocol.

          -  Presence of active gastrointestinal disease or other condition that will interfere
             significantly with the absorption, distribution, metabolism, or excretion of drugs.

          -  History of RVO.

          -  Visible retinal pathology as assessed by ophthalmologic exam that is considered a risk
             factor for retinal vein thrombosis.

          -  Intraocular pressure greater than 21mm Hg as measured by tonography.

          -  Psychological, familial, sociological, or geographical conditions that do not permit
             compliance with the protocol.

          -  Condition that in the investigator's opinion would jeopardize compliance with the
             protocol.

          -  Symptomatic or untreated central nervous system involvement by the hematologic
             malignancy, including primary CNS lymphoma. Subjects who were previously treated for
             CNS involvement, and are asymptomatic without anti-epileptic medications for at least
             two months are eligible.

          -  Evidence of severe or uncontrolled systemic diseases (e.g., unstable or uncompensated
             respiratory, hepatic, renal, or cardiac disease).

          -  Unresolved toxicity greater than Grade 1 from previous anti-cancer therapy except
             alopecia (if applicable) unless agreed to by a GSK Medical Monitor and the
             investigator.

          -  QTc interval greater than 480 msecs.

          -  History of acute coronary syndromes (including unstable angina), coronary angioplasty
             or stenting within the past 24 weeks.

          -  Class II, III, or IV heart failure as defined by the New York Heart Association (NYHA)
             functional classification system.

          -  Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs
             chemically related to the study drug, dimethyl sulfoxide (DMSO), or excipients (See
             Section 3.10). (To date there are no known FDA approved drugs chemically related to
             GSK1120212).

          -  Pregnant or lactating female.

          -  Unwillingness or inability to follow the procedures outlined in the protocol.