Clinical trial NCT01476137 (phase 1, status: completed)
Conditions: cancer
ICD codes: C05.2, C10.0, C16.0, C16.4, C17.0, C17.1, C17.2
Drugs: gsk1120212, gsk2110183
SMILES: CN1C(=O)C(C)=C2N(C(=O)N(C3CC3)C(=O)C2=C1NC1=CC=C(I)C=C1F)C1=CC(NC(C)=O)=CC=C1, CN1N=CC(Cl)=C1C1=C(Cl)SC(=C1)C(=O)N[C@H](CN)CC1=CC=CC(F)=C1
Eligibility criteria:

        Inclusion Criteria for Part 1:

          -  Male or female, at least 18 years of age at the time of signing informed consent form
             and capable of giving written informed consent, which includes willingness to comply
             with the requirements and restrictions listed in the consent form.

          -  Histologically or cytologically confirmed diagnosis of a solid tumor malignancy with
             one of the following characteristics that is not responsive to standard therapies or
             for which there is no approved or curative therapy or for subjects which refuse
             standard therapy: breast cancer, colorectal cancer, pancreatic cancer, endometrial
             cancer, non-small cell lung cancer, ovarian cancer, melanoma, renal cell carcinoma,
             head and neck cancer, prostate cancer, gastric cancer, hepatocellular cancer, or
             bladder cancer.

          -  At Screening, archived tissue must be requested. If archived tissue is not available,
             a fresh biopsy is required.

          -  Subjects diagnosed previously with Type 2 diabetes must have been diagnosed at least 6
             months prior to enrollment.

          -  All prior treatment-related toxicities must be less than or equal to Grade 1 according
             to NCI-CTCAE (version 4.0) at the time of treatment allocation, or are less than or
             equal to Grade 2 and stable for 4 weeks or longer at the time of screening evaluation.

          -  Adequate organ system function: absolute neutrophil count (ANC) greater than or equal
             to 1.5X10^9/L, hemoglobin greater than or equal to 9g/dL, , platelets greater than or
             equal to 75X10^9/L, PT/INR and PTT less than or equal to 1.5Xupper limit of normal
             (ULN); total bilirubin less than or equal to 1.5XULN, AST and ALT less than or equal
             to 2.5XULN, albumin greater than or equal to 2.5g/dL; creatinine less than 2.5mg/dL or
             calculated or 24-hour urine creatining clearance greater than or equal to 30mL/min;
             fasting serum glucose less than 126mg/dL (7mmol/L), HbA1C less than or equal to 8% and
             cardiac ejection fraction greater than or equal to the lower limit of normal (LLN) by
             echocardiography.

          -  Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.

          -  All subjects enrolled in the serial PK cohorts must agree to serial PK sampling.

          -  Must agree to collection of samples for evaluation of circulating free DNA (cfDNA).

          -  Able to swallow and retain orally administered medication.

          -  Women of childbearing potential and men with reproductive potential must be willing to
             practice acceptable methods of birth control. Additionally, women of childbearing
             potential must have a negative serum pregnancy test within 14 days prior to the first
             dose of study medication.

        Inclusion Criteria for Part 2A only:

          -  As listed for Part 1 with the exception of criterion 2 which should be replaced with
             the following:

        Histologically confirmed diagnosis of secretory multiple myeloma (must have measurable M
        protein in serum or urine) with at least one of the following: serum M protein greater than
        or equal to 1g/dL, urine M protein greater than or equal to 200mg/24hours, serum Free Light
        Chain (FLC) assay- involved FLC level greater than or equal to 10mg/dL and an abnormal
        serum FLC ratio (<0.26 or >1.65), biopsy-proven plasmacytoma within 28 days of screening
        visit.

          -  Adequate organ system function, defined as ANC greater than or equal to 1X10^9/L,
             hemoglobin greater than or equal to 8g/dL, platelets greater than or equal to
             50X10^9/L, PT/INR and PTT less than or equal to 1.5XULN, total bilirubin less than or
             equal to 1.5XULN, AST and ALT less than or equal to 2.5XULN, albumin greater than or
             equal to 2.5g/dL, creatinine less than or equal to 2.5mg/dL or calculated or 24-hour
             urine creatinine clearance greater than or equal to 30mL/min; fasting serum glucose
             less than 126mg/dL, HbA1C less than or equal to 8%, calcium less than or equal to
             12.5mg/dL (3.126mmol/L), cardiac ejection fraction greater than or equal to LLN by
             echocardiography.

          -  Subjects with a history of autologous stem cell transplant, provided these eligibility
             criteria are met: transplant was > 100 days prior to study enrollment, no active
             infection, subject meets remainder of eligibility criteria outlined in the protocol.

          -  Only those subjects with proteasome inhibitor-refractory multiple myeloma may be
             enrolled (Part 2A). Refractory is defined as failure to respond to last proteasome
             inhibitor therapy or progression within 60 days after stopping last proteasome
             inhibitor therapy.

          -  Subjects must agree to pre-, and in some cases, post-dose bone marrow aspirates and
             biopsies.

          -  Subjects with prior exposure to an AKT inhibitor or MEK inhibitor are not eligible.
             Perifosine is not considered an AKT inhibitor.

        Inclusion Criteria for Part 2B only:

          -  As listed for Part 1, with the exception of criterion 2 which should be replaced with
             the following:

        Histologically or cytologically confirmed diagnosis of:

          1. endometrial cancer with less than or equal to 2 prior cytotoxic chemotherapies in the
             relapsed or metastatic setting. For the purposes of this study, targeted agents like
             bevacizumab are not considered cytotoxic chemotherapy.

             OR

          2. ER-/PR-/HER2- breast cancer in the locally advanced or metastatic setting that has
             been previously treated with an anthracycline and taxane in any setting, greater than
             or equal to 2 but less than or equal to 5 prior therapies with cytotoxic agents in the
             metastatic setting. For purposes of this study, targeted agents like bevacizumab are
             not considered cytotoxic chemotherapy.

        Note: central confirmation of ER and/or PgR and/or HER2 negativity is not required for
        eligibility, but documentation of the local result must be available in the source
        document.

          -  Subjects must have measurable disease per RECIST version 1.1.

          -  A select subset of subjects must agree to pre- and post-dose tumor biopsies.

          -  Subjects with prior exposure to an AKT inhibitor or MEK inhibitor are not eligible.
             Perifosine is not considered an AKT inhibitor.

        Subjects with alternative tumor histologies and/or molecular profiles (eg KRAS mutant
        colorectal cancer) may be enrolled in Part 2B cohorts if emerging data suggest they would
        be likely to respond to therapy.

        Exclusion Criteria:

          -  Chemotherapy, radiotherapy, immunotherapy or other anti-cancer therapy including
             investigational drugs within 14 days prior to the first dose of any one of the
             investigational drugs described in this study.

          -  History of an allogenic stem cell transplant. Subjects with a history of an autologous
             stem cell transplant are NOT excluded from Part 2A if they meet Part 2A inclusion
             criteria.

          -  Current use of prohibited medication during treatment with GSK1120212 and/ or GSK
             2110183.

          -  History of Type 1 diabetes.

          -  Anticoagulants are permitted only if the subject meets PTT and INR entry criteria.
             Their use must be monitored in accordance with local institutional practice.

          -  Presence of active gastrointestinal disease or other condition that could affect
             gastrointestinal absorption (eg, malabsorption syndrome) or predispose subject to
             gastrointestinal ulceration.

          -  Evidence of mucosal or internal bleeding.

          -  Any major surgery within the last 4 weeks.

          -  Any serious or unstable pre-existing medical, psychiatric, or other condition
             (including lab abnormalities) that could interfere with the subject's safety or
             providing informed consent.

          -  Known active infection requiring parenteral or oral anti-infective treatment.

          -  Evidence of severe or uncontrolled systemic diseases (eg, unstable or uncompensated
             respiratory, hepatic, renal or cardiac disease, unstable hypertension).

          -  Subjects with brain metastases are excluded if their brain metastases are:
             symptomatic, treated (surgery, radiation therapy) but not clinically and
             radiologically stable one month after therapy (as assessed by at least 2 distinct
             contrast enhanced MRI or CT scans over at least a one month period) OR asymptomatic
             and untreated but > 1 cm in the longest dimension.

        Subjects with small (less than or equal to 1cm in the longest dimension), asymptomatic
        brain metastases that do not need immediate therapy can be enrolled. Subjects with solid
        tumors on a stable (ie, unchanged) dose of corticosteroids for more than one month, or
        those who have been off corticosteroids for at least 2 weeks can be enrolled. Subjects must
        also be off of enzyme-inducing anticonvulsants for more than 4 weeks.

          -  Subjects with leptomeningeal disease are excluded.

          -  QTcF interval greater than or equal to 470msecs.

          -  Subjects with bundle branch block (BBB) or pacemaker.

          -  Other clinically significant ECG abnormalities including 2nd degree (Type II) or 3rd
             degree atrioventricular (AV) block.

          -  History of myocardial infarction, acute coronary syndromes (including unstable
             angina), coronary angioplasty, or stenting or bypass grafting within 6 months of
             Screening.

          -  Class II, III or IV heart failure as defined by the New York Heart Association (NYHA)
             functional classification system.

          -  Known hypersensitivity to any of the components of the study treatment.

          -  Pregnant or lactating female.

          -  Any malignancy related to HIV or solid organ transplant; history of known HIV, history
             of known HBV surface antigen positivity (subjects with documented laboratory evidence
             of HBV clearance may be enrolled) or positive HCV antibody.

          -  History or current evidence/ risk of retinal vein occlusion (RVO) or central serous
             retinopathy (CSR): history of RVO or CSR, or predisposing factors to RVO or CSR at the
             time of screening (eg, uncontrolled glaucoma or ocular hypertension, uncontrolled
             systemic disease such as hypertension, diabetes mellitus, or history of hyperviscosity
             or hypercoagulability syndromes); visible retinal pathology as assessed by ophthalmic
             exam that is considered a risk factor for RVO or CSR, such as evidence of new optic
             disc cupping, evidence of new visual field defects, intraocular pressure (IOP) >
             24mmHg.