A Study to Investigate the Safety, Pharmacokinetics, Pharmacodynamics, and Clinical Activity of GSK525762 in Subjects With NUT Midline Carcinoma (NMC) and Other Cancers
Condition: Carcinoma, Midline
MeSH terms: Carcinoma
Intervention: GSK525762
Intervention description: Begin at Dose Level 1 and increase up to 2 fold
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 196.0
Sex: All
Minimum age: 16 Years
Healthy volunteers: No
Keywords: BRD3; GSK525762; NUT Midline Carcinoma; MYCN-amplified Solid Tumor; BRD4; BET inhibitor; bromodomains; NMC; Colorectal C ancer; Small Cell Lung Cancer; Multiple Myeloma; Neuroblastoma; Oncology

Summary:

      This study is divided into two parts; Part 1 of the study is a dose escalation phase to
      select the recommended dose for Part 2 based on the safety, pharmacokinetic, and
      pharmacodynamic profiles observed after oral administration of GSK525762 in the following
      subjects: NMC, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), colorectal
      cancer (CRC), neuroblastoma (NB), castration resistant prostate cancer (CRPC), triple
      negative breast cancer (TNBC), estrogen receptor positive (ER positive) breast cancer, and
      MYCN driven solid tumor subjects. Part 2 of the study will explore the safety, tolerability,
      pharmacokinetics, pharmacodynamics, and clinical activity of the recommended dose from Part 1
      in cohorts comprised of NMC, small cell lung cancer (SCLC), castration resistant prostate
      cancer (CRPC), triple negative breast cancer (TNBC), and estrogen receptor positive (ER
      positive) breast cancer subjects. Approximately 60 subjects will be enrolled in the Part 1
      and approximately 150 subjects will be enrolled in Part 2. A sub-study will be opened in Part
      1 to approximately 10-12 subjects in the United States to investigate the relative
      bioavailability of the besylate tablet compared to the amorphous free-base tablet at the
      maximum tolerated dose (MTD) or recommended phase 2 dosing (RP2D), the effect of high-fat
      high-calorie meal on the bioavailability of the besylate tablet at the MTD or RP2D and the
      dose proportionality of 2 doses of GSK525762 administered as besylate tablet.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Male or female 16 years or older, at the time of signing the informed consent.

          -  Capable of giving written informed consent, which includes compliance with the
             requirements and restrictions listed in the consent form. If the subject is less than
             18 years old, an Assent form and parental/guardian Consent form (replacing "you will"
             with "your child will" will be required).

          -  Diagnosis of one of the following: Part 1 Only: NUT Midline Carcinoma based on ectopic
             expression of NUT protein as determined by IHC and/or detection of NUT gene
             translocation as determined by FISH. Subjects may be treatment naïve or have had prior
             therapy; SCLC, CRC, NB, TNBC, ER positive BC, CRPC, NSCLC and any other solid tumor
             which has been confirmed by clinical testing to be MYCN amplified (defined as a MYCN
             gene copy number gain of >=5). Subjects should have tumor progression after receiving
             at least one prior standard/approved chemotherapy, or where there is no approved
             therapy, or where standard therapy is refused. Part 2 only: NUT Midline Carcinoma as
             diagnosed by the Central Laboratory. Subjects may be treatment naïve or have had prior
             therapy. SCLC, CRPC, TNBC and ER+BC .

          -  Subjects with solid tumors, with the exception of CRPC, must demonstrate measurable
             disease, per RECIST v1.1. NOTE: Subjects with NMC that do not meet the RECIST v1.1
             criteria for measurable disease, but have evaluable disease may be considered for
             enrollment after discussion with the GSK medical monitor..

          -  All prior treatment- related toxicities must be CTCAE (Version 4.0) <=Grade 1 (except
             alopecia and peripheral neuropathy) at the time of treatment allocation [NCI-CTCAE,
             2009].

          -  ECOG Performance Status score of 0 or 2 for subjects with NMC; 0-1 for subjects with
             other tumor types.

          -  Adequate organ function as follows: Hematologic system: Absolute neutrophil count
             (ANC), Lab values - >=1.5 X 10^9/L; Hematologic system: Hemoglobin, Lab values - >=9.5
             grams/deciliter (g/dL) (subjects that required transfusion or growth factor need to
             demonstrate stable haemoglobin for 7 days of 9.5 g/ g/dL); Hematologic system:
             Platelets, Lab values - >=100 X 10^9/Liter [L] ); Hematologic system: Prothrombin time
             /International normalized ratio and partial thromboplastin time, Lab values - <=1.5 X
             upper limit of normal (ULN). Renal system: Creatinine, lab values - <=1.5 X ULN; or
             Renal system: Calculated creatinine clearance [calculated by Cockcroft Gault formula],
             lab values - >=50 milliliter (mL)/minute (min); or Renal system: 24-hour urine
             creatinine clearance>=50 mL/min; Hepatic system: 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)
             and aspartate aminotransferase (AST) >=2.5 x ULN. Cardiac system: Ejection fraction,
             lab values - >=lower limit of normal (LLN) by Echocardiogram (ECHO) (minimum of 50%);
             Cardiac system: Troponin ( T), lab values - <=ULN; Cardiac system: Potassium, lab
             values - >=LLN and <=ULN; Cardiac system: Magnesium, lab values - >=LLN. Thyroid
             system: thyroid stimulating hormone, lab values >=LLN and <=to ULN. Reproductive
             /endocrine system: testosterone <50 nanogram (ng)/dL (only for subject with CRPC)

          -  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) greater than 40
             milli international unit/mL and estradiol less than 40 pg/mL (less than 140 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 postmenopausal 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 (described in the protocol) 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 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 least 16
             weeks after the last dose of study medication. In addition, male subjects whose
             partners are or become pregnant while on study medication must continue to use condoms
             for 7 days after stopping study medications.

          -  Specific eligibility criteria for Part 2 CRPC expansion cohort: Histologically or
             cytologically confirmed diagnosis of prostate adenocarcinoma, surgically castrated or
             continuously medically castrated (for >=8 weeks prior to pre-screening).

          -  Specific eligibility criteria for Part 2 CRPC expansion cohort: Persistent disease
             with evidence of disease progression following standard therapy(ies) including prior
             treatment with androgen/androgen receptor directed therapy, including enzalutamide
             and/or abiraterone

          -  Specific eligibility criteria for Part 2 CRPC expansion cohort: Ongoing androgen
             deprivation therapy with a serum testosterone level <1.7 nanomoles/L or <50 ng/dL.

          -  Specific eligibility criteria for Part 2 CRPC expansion cohort: Prostate-Specific
             Antigen (PSA) levels >=2.0 ng/mL. Note: If PSA level has been obtained within 14 days
             of Screening, this test does not need to be repeated and the result previously
             obtained may be used for the Screening value.

        Exclusion Criteria:

          -  Primary malignancy of the central nervous system or malignancies related to human
             immunodeficiency virus or solid organ transplant. History of known HIV. History of
             known Hepatitis B surface antigen or positive Hepatitis C antibody (confirmed by
             RIBA).

          -  Prior treatments usage as defined: A) Use of an investigational anti-cancer drug
             within 14 days or 5 half-lives, whichever is longer, prior to the first dose of the
             investigational products:; B) A minimum of 14 days between termination of the
             investigational drug and administration of GSK525762; C) Any therapy related
             toxicities must also have resolved to Grade 1 or less. Note that an investigational
             drug is defined as a drug without an approved oncologic indication; D) Chemotherapy,
             radiotherapy, anti-neoplastic antibody or targeted therapy or immunotherapy within 14
             days, major surgery within 28 days (or 42 days for prior nitrosoureas or mitomycin C)
             prior to the first dose of the investigational product. Anti-androgen (e.g.,
             bicalutamide) therapies for prostate cancer 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 enrollment. 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 mg/day) and still be eligible for this study.

          -  Current 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.

          -  Current use of a prohibited medication or requires any of these medications during
             treatment with the investigational drugs (details will be available in the protocol).
             This includes excluding current medications known or suspected to be associated QT
             prolongation. In addition, any subject who may 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 leptomeningeal or brain metastases or spinal cord
             compression. NOTE: Subjects previously treated for these conditions that have had
             stable central nervous system disease (verified with consecutive imaging studies) for
             >1 month, 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 the
             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 are allowed on study.

          -  Cardiac abnormalities as evidenced by any of the following: History or current
             "untreated" clinically significant uncontrolled arrhythmias; 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: Baseline QTcF interval >=450 millisecond (msec);
             Any 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.

          -  Hemoptysis >1 teaspoon in 24 hours within the last 28 days.

          -  History of major gastrointestinal bleeding within the last 6 months. Any evidence of
             active gastrointestinal bleeding excludes the subject.

          -  Besylate Sub-Study only: unable or unwilling to eat the FDA recommended high-fat
             high-calorie breakfast (two eggs fried in butter, two strips of bacon, 4 ounce [oz])
             of hash brown potatoes and 8 oz of whole milk) within the recommended 30 minutes.