Dose Escalation Study of GSK2820151 in Subjects With Advanced or Recurrent Solid Tumors
Condition: Cancer; Neoplasms
Intervention: GSK2820151
Intervention description: GSK2820151 is provided as capsules containing 1 mg, 5 mg, 10 mg, 50 mg, or 100 mg of GSK2820151 as free base equivalent to be administered orally. The dosing regimen is as follows: Week 1 - once daily on days 1, 3, 4, and 5; Week 2 - once daily on days 1, 2, 3, 4, 5; and Weeks 3 and beyond - once daily continuously.
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 5.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Cancer; Safety; GSK2820151; Dose escalation; Tolerability; Pharmacodynamics; Pharmacokinetics

Summary:

      The study drug, GSK2820151, is a Bromodomain (BRD) and Extra-Terminal (BET) inhibitor arising
      from a distinct structural class. GSK2820151 potently inhibits tumor growth in vitro and in
      vivo in animal models. This first time in human (FTIH), open-label, dose escalation study is
      to assess the safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary clinical
      activity of GSK2820151 in subjects with advanced or recurrent solid tumors. The objective is
      to determine the safety, tolerability and maximum tolerated dose (MTD) of GSK2820151 in
      subjects 18 years or older with advanced or recurrent solid tumors. Eligible subjects with
      advanced or recurrent solid tumors will be enrolled in the dosing cohorts until MTD is
      established. All subjects will receive study drug. Subjects may continue treatment in the
      study until disease progression, unacceptable toxicity, or withdrawal of consent. The
      duration of study will depend on recruitment rates and the timing of subjects' duration on
      study (withdrawal rates due to toxicity or progression). It is anticipated that approximately
      30 to 50 subjects will be enrolled.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Written informed consent provided

          -  Males and females 18 years old and greater

          -  Diagnosis of advanced or recurrent, histologically or cytologically confirmed, solid
             malignancy that is either metastatic or unresectable. At time of enrollment, subjects
             either refuse standard curative or palliative therapy, are not candidates for standard
             curative or palliative therapy, have a disease for which no non-investigational
             therapy exists, OR have progressed on prior therapy (up to three lines of prior
             cytotoxic agents are permitted).

          -  Subjects with solid tumors, with the exception of castration-resistant prostate cancer
             (CRPC), must demonstrate measurable disease, per Response Evaluation Criteria in Solid
             Tumors (RECIST) v1.1.

          -  All prior treatment- related toxicities must be National Cancer Institute- Common
             Terminology Criteria for Adverse Events (NCI-CTCAE) v4.03 <=Grade 1 (except alopecia
             [permissible at any Grade] and peripheral neuropathy [which must be <= Grade 2]) at
             the time of treatment allocation.

          -  Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0 to 1.

          -  Adequate organ function defined as follows: System and Laboratory Values: Hematologic
             - Absolute neutrophil count (ANC) >=1.5 X 10^9/liter (L), Hemoglobin >=9 grams
             (g)/deciliter (dL) (subjects that required transfusion or growth factor need to
             demonstrate stable hemoglobin for 7 days of 9 g/dL), Platelets >=100 X 10^9/L,
             prothrombin time (PT)/ international normalized ratio (INR) and partial thromboplastin
             time (PTT) - <=1.5 X upper limit of normal (ULN); Hepatic - Albumin >=2.5 g/dL, Total
             bilirubin <=1.5 X ULN (isolated bilirubin >1.5 X ULN is acceptable if bilirubin is
             fractionated and direct bilirubin <35% or subject has a diagnosis of Gilbert's
             syndrome), Alanine aminotransferase (ALT) <=2.5 x ULN OR <5 x ULN is acceptable for
             subjects with documented liver metastases/tumor infiltration; Renal - Creatinine <=1.5
             X ULN OR Creatinine clearance [either directly measured or calculated by
             Cockcroft-Gault formula] >=40 milliliter (mL)/minute (min); Cardiac - Ejection
             fraction >=50% by echocardiogram or multigated acquisition scan (MUGA), Troponin (T)
             <=ULN, Potassium >=Lower limit of normal (LLN) and <=ULN, Magnesium >=LLN

          -  Able to swallow and retain orally administered medication.

          -  A female subject is eligible to participate if she is of: Non-childbearing potential
             defined as pre-menopausal females with a documented tubal ligation, hysteroscopic
             tubal occlusion procedure with follow-up confirmation of bilateral tubal occlusion,
             hysterectomy, or documented bilateral tubal oophorectomy; or postmenopausal defined as
             12 months of spontaneous amenorrhea [in questionable cases a blood sample with
             simultaneous follicle stimulating hormone (FSH) >40 units (U)/mL and estradiol <40
             picograms (pg)/mL (<140 picomoles (pmol)/L) 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 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 enrollment. For most forms of HRT, at least 2 to 4 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 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 GSK2820151 or at least 28 days (whichever is longer) following
             the last dose of study treatment.

          -  Male subjects with female partners of child bearing potential 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 on study medication
             must continue to use condoms for 7 days after stopping study medication

        Exclusion Criteria:

          -  Primary malignancy of the central nervous system or malignancies related to human
             immunodeficiency virus (HIV) or solid organ transplant.

          -  More than three prior lines of cytotoxic therapy.

          -  Recent prior therapy, defined as follows: 1) Any investigational or Food and Drug
             Administration (FDA)-approved anti-cancer drug within 14 days or 5 half-lives,
             whichever is longer, prior to the first dose of GSK2820151. Any nitrosoureas or
             mitomycin C within 42 days prior to the first dose of GSK2820151. Prior therapy with
             monoclonal antibodies is permitted so long as 14 days have elapsed since therapy and
             all therapy-related toxicity has resolved to Grade 1 or less. Note that an
             investigational drug is defined as a drug without an approved oncologic indication.

             2) Any radiotherapy within 14 days or major surgery within 28 days prior to the first
             dose of GSK2820151.

             3) Anti-androgen therapies for prostate cancer, such as bicalutamide, must be stopped
             4 weeks prior to enrollment. Second-line hormone therapies such as enzalutamide,
             abiraterone, or orteronel should be stopped 2 weeks prior to enrolment. Subjects with
             prostate cancer should remain on luteinizing hormone releasing hormone (LHRH) agonists
             or antagonists. Subjects with prostate cancer may also remain on low-dose prednisone
             or prednisolone (up to 10 milligrams [mg]/day) and still be eligible for this study.

             4) In addition, any therapy-related toxicity must have resolved to Grade 1 or less,
             with the exception of alopecia (acceptable at any Grade) and peripheral neuropathy
             (which must be Grade 2 or less prior to enrollment).

          -  Therapeutic anticoagulation (e.g., warfarin, heparin) must be discontinued and
             coagulation parameters must be normalized prior to the first dose of GSK2820151. Low
             dose (prophylactic) low molecular weight heparin (LMWH) is permitted. In addition, INR
             must be monitored in accordance with local institutional practices.

          -  Current use of a prohibited medication or planned use of any forbidden medications
             during treatment with GSK2820151.

          -  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),
             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 leptomeningeal or brain metastases or spinal cord
             compression. NOTE: Subjects previously treated for these conditions that have had
             stable central nervous system (CNS) disease (verified with consecutive imaging
             studies) for >1 months, are asymptomatic and off corticosteroids, or are on stable
             dose of corticosteroids for at least 1 month prior to study Day 1 are permitted.
             Stability of brain metastases must be confirmed with imaging. Subject treated with
             gamma knife therapy can be enrolled 2 weeks post-procedure as long as there are no
             post-procedure complications/stable. In addition, subjects treated or currently taking
             enzyme-inducing anticonvulsant (EIAC) are allowed on study.

          -  Cardiac abnormalities as evidenced by any of the following: History of or current
             "untreated" clinically significant uncontrolled arrhythmias, Clinically significant
             conduction abnormalities or arrhythmias, 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.
             Subjects with a history of stent placement requiring ongoing antithrombotic therapy
             (e.g., clopidogrel, prasugrel) will not be permitted to enroll.

          -  Any of the following electrocardiogram (ECG) findings: Baseline QTcF >=450 millisecond
             (msec). NOTE: Any clinically significant ECG assessments should be reviewed by the
             site cardiologist prior to study entry.

          -  Any of the following liver findings: ALT >2.5xULN, ALT > 5xULN with liver
             metastases/tumor infiltration, Bilirubin >1.5xULN (isolated bilirubin >1.5xULN is
             acceptable if bilirubin is fractionated and direct bilirubin <35%), Current active
             liver or biliary disease (with the exception of Gilbert's syndrome or asymptomatic
             gallstones, liver metastases or otherwise stable chronic liver disease per
             investigator assessment). NOTE: Stable chronic liver disease should generally be
             defined by the absence of ascites, encephalopathy, coagulopathy, hypoalbuminaemia,
             esophageal or gastric varices, persistent jaundice or cirrhosis

          -  Presence of hepatitis B surface antigen (HBsAg) or positive hepatitis C antibody test
             result at screening or within 3 months prior to first dose of study treatment. History
             of known HIV infection. NOTE: Subjects with positive Hepatitis C antibody due to prior
             resolved disease can be enrolled only if a confirmatory negative Hepatitis C
             ribonucleic acid (RNA) polymerase chain reaction (PCR) is obtained.

          -  Any serious known immediate or delayed hypersensitivity reaction(s) to GSK2820151 or
             idiosyncrasy to drugs chemically related to the investigational drug.

          -  Hemoptysis >1 teaspoon in 24 hours within the last 28 days.

          -  History of major gastrointestinal bleeding within the last 6 months.

          -  Any clinically significant gastrointestinal (GI) abnormalities that may alter
             absorption such as malabsorption syndrome or major resection of the stomach and/or
             bowels.