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Carcinoma, MidlinePhase 1NCT01587703

A Study to Investigate the Safety, Pharmacokinetics, Pharmacodynamics, and Clinical Activity of GSK525762 in Subjects With NUT Midline Carcinoma (NMC) and Other Cancers

A Phase 1 study testing GSK525762 in people with Carcinoma, Midline, run by GlaxoSmithKline at 17 sites in 7 countries.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial 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… Read more about this study

Who is it for?
Ages 16 years and older
Conditions the study is for
Carcinoma, Midline
What is being tested?
GSK525762
Type of treatment
Pill or oral medicine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
196 participants
Where
17 sitesin 7 countries
Study dates
28 Mar 2012to 29 Jul 2019
Phase
Phase 1
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 16 years and older
  • All sexes
  • No healthy volunteers
  • Child, Adult, Older adult

Who may be able to join

  • 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.
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  • 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.

Who cannot join

  • 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.
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  • 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.

Trial locations and contacts

17 sites in 7 countries.

17 sites in 7 countries

United States5 sites

  • GSK Investigational Site

    Baltimore, Maryland, 21231-2410

  • GSK Investigational Site

    Boston, Massachusetts, 02215

  • GSK Investigational Site

    Houston, Texas, 77030

  • GSK Investigational Site

    Nashville, Tennessee, 37232

  • GSK Investigational Site

    Philadelphia, Pennsylvania, 19104

Other trials in United States

France3 sites

  • GSK Investigational Site

    Bordeaux, 33076

  • GSK Investigational Site

    Lyon, 69373

  • GSK Investigational Site

    Paris, 75248

Other trials in France

Spain3 sites

  • GSK Investigational Site

    Barcelona, 08035

  • GSK Investigational Site

    Madrid, 28040

  • GSK Investigational Site

    Málaga, 29010

Other trials in Spain

South Korea2 sites

  • GSK Investigational Site

    Seoul, 03080

  • GSK Investigational Site

    Seoul, 03722

Other trials in South Korea

United Kingdom2 sites

  • GSK Investigational Site

    Newcastle upon Tyne, NE7 7DN

  • GSK Investigational Site

    Sutton, Surrey, SM2 5PT

Other trials in United Kingdom

Australia1 site

  • GSK Investigational Site

    Clayton, Victoria, 3168

Other trials in Australia

Netherlands1 site

  • GSK Investigational Site

    Amsterdam, 1066 CX

Other trials in Netherlands

About this study

Official title: A Phase I/II Open-Label, Dose Escalation Study to Investigate the Safety, Pharmacokinetics, Pharmacodynamics, and Clinical Activity of GSK525762 in Subjects With NUT Midline Carcinoma (NMC) and Other Cancers

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.

Being tested
GSK525762
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
Medical subject headings
Carcinoma, Small Cell Lung Carcinoma, Multiple Myeloma, Neuroblastoma, Neoplasms

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • GSK525762Drug

    Begin at Dose Level 1 and increase up to 2 fold

Study groups in NCT01587703
Study groupRoleWhat they receive
Single and Repeat Dose finding cohortExperimentalAll subjects will follow a 3+3 dose escalation design for GSK525762 and the dose will be escalated based on all available data, including PK data and the safety profile of prior cohorts, as well as the recommended dose from the Neuenschwander- Continuous Reassessment Method (N-CRM) design.
Receives: Drug: GSK525762
Expansion CohortExperimentalUp to 150 additional subjects with NMC and other solid tumors may be enrolled in expansion cohorts. The recommended Phase 2 (Part 2) dose (RP2D) of GSK525762 will be determined based on the MTD or biologically active dose (example: clinical response), the safety profile and available pharmacodynamic data generated from all subjects in Parts 1
Receives: Drug: GSK525762
Besylate Sub studyExperimentalTablet and amorphous tablet in one of the two sequences (ABCD or BACD). Where Treatment A: RP2D/MTD as amorphous free-base tablet + low dose stable isotope in solution, fasted Treatment B: RP2D/MTD as besylate tablet + low dose stable isotope in solution, fasted. Treatment C: half to one-third of RP2D/MTD as besylate tablet + low dose stable isotope in solution, fasted. Treatment D: RP2D/MTD as besylate tablet, fed
Receives: Drug: GSK525762

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)-Part 1 QD

    An AE is any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An SAE is any untoward medical occurrence that, at any dose: results in death; is life-threatening; requires hospitalization or prolongation of existing hospitalization; results in disability/incapacity; is a congenital anomaly/birth defect; important medical events that may require medical or surgical intervention to prevent one of the outcomes mentioned; events of possible study treatment-induced liver injury with hyperbilirubinemia; any new primary cancers; significant cardiac dysfunction; Grade 4 laboratory abnormalities; and drug related hepatobiliary event leading to permanent discontinuation of study treatment. All Treated Population comprised of all participants who received at least one dose of study treatment.

    Measured: Median of 1.38 months of drug exposure

  2. Number of Participants With AEs and SAEs-Part 1 BID

    An AE is any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An SAE is any untoward medical occurrence that, at any dose: results in death; is life-threatening; requires hospitalization or prolongation of existing hospitalization; results in disability/incapacity; is a congenital anomaly/birth defect; important medical events that may require medical or surgical intervention to prevent one of the outcomes mentioned; events of possible study treatment-induced liver injury with hyperbilirubinemia; any new primary cancers; significant cardiac dysfunction; Grade 4 laboratory abnormalities; and drug related hepatobiliary event leading to permanent discontinuation of study treatment

    Measured: Median of 1.41 months of drug exposure

  3. Number of Participants With AEs and SAEs-Part 2

    An AE is any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An SAE is any untoward medical occurrence that, at any dose: results in death; is life-threatening; requires hospitalization or prolongation of existing hospitalization; results in disability/incapacity; is a congenital anomaly/birth defect; important medical events that may require medical or surgical intervention to prevent one of the outcomes mentioned; events of possible study treatment-induced liver injury with hyperbilirubinemia; any new primary cancers; significant cardiac dysfunction; Grade 4 laboratory abnormalities; and drug related hepatobiliary event leading to permanent discontinuation of study treatment.

    Measured: Median of 1.41 months of drug exposure

  4. Number of Participants With Dose Reductions or Delays-Part 1 QD

    The number of participants who had any dose reductions or delays is presented.

    Measured: Median of 1.38 months of drug exposure

  5. Number of Participants With Dose Reductions or Delays-Part 1 BID

    The number of participants who had any dose reductions or delays is presented.

    Measured: Median of 1.41 months of drug exposure

  6. Number of Participants With Dose Reductions or Delays-Part 2

    The number of participants who had any dose reductions or delays is presented.

    Measured: Median of 1.41 months of drug exposure

  7. Number of Participants With Dose Reductions or Delays-Besylate Sub-study

    The number of participants who had any dose reductions or delays is presented.

    Measured: Median of 1.87 months of drug exposure

  8. Number of Participants Withdrawn Due to Toxicities-Part 1 QD

    Number of participants withdrawn due to toxicities is presented.

    Measured: Median of 1.38 months of drug exposure

  9. Number of Participants Withdrawn Due to Toxicities-Part 1 BID

    Number of participants withdrawn due to toxicities is presented.

    Measured: Median of 1.41 months of drug exposure

  10. Number of Participants Withdrawn Due to Toxicities-Part 2

    Number of participants withdrawn due to toxicities is presented.

    Measured: Median of 1.41 months of drug exposure

  11. Number of Participants Withdrawn Due to Toxicities-Besylate Sub-study

    Number of participants withdrawn due to toxicities is presented.

    Measured: Median of 1.87 months of drug exposure

  12. Number of Participants With Grade Change From Baseline in Clinical Chemistry Data-Part 1 QD

    Blood samples were collected for the analysis of: glucose, albumin, alkaline phosphatase (ALP), alanine aminotransferase (ALT), amylase, aspartate aminotransferase (AST), direct bilirubin (Dir bil), bilirubin, N-Terminal proB-type natriuretic peptide (NT-BNP), calcium, cholesterol, creatine kinase (CK), chloride, carbon dioxide (CO2), creatinine, gamma glutamyl transferase (GGT), high and low density lipoprotein (HDL and LDL), insulin, potassium, lactate dehydrogenase (LDH), lipase, magnesium, protein, sodium, thyroxine, testosterone, triglycerides, troponin I and T, urate and urea. Grading was done according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.0. Grade 1: mild; Grade 2: moderate; Grade 3: severe or medically significant; Grade 4: life-threatening consequences; Grade 5: death. Baseline is the most recent, non-missing value prior to or on first study treatment dose date. Data for worst case post-Baseline is presented.

    Measured: Baseline (pre-dose Week1 Day1) and median of 1.38 months of drug exposure

  13. Number of Participants With Grade Change From Baseline in Clinical Chemistry Data-Part 1 BID

    Blood samples were collected for the analysis of clinical chemistry parameters: glucose, albumin, ALP, ALT, amylase, AST, Dir bil, bilirubin, NT-BNP, calcium, cholesterol, CK, chloride, CO2, creatinine, GGT, HDL and LDL cholesterol, insulin, potassium, LDH, lipase, magnesium, protein, sodium, thyroxine, testosterone, triglycerides, troponin I and T, urate and urea. Laboratory parameters were graded according to NCI-CTCAE version 4.0. Grade 1: mild; Grade 2: moderate; Grade 3: severe or medically significant; Grade 4: life-threatening consequences; Grade 5: death. Baseline is the most recent, non-missing value prior to or on the first study treatment dose date. Data for worst-case post-Baseline is presented.

    Measured: Baseline (pre-dose Week1 Day1) and median of 1.41 months of drug exposure

  14. Number of Participants With Grade Change From Baseline in Clinical Chemistry Data-Part 2

    Blood samples were collected for the analysis of clinical chemistry parameters: glucose, albumin, ALP, ALT, amylase, AST, Dir bil, bilirubin, NT-BNP, calcium, cholesterol, CK, chloride, CO2, creatinine, GGT, HDL and LDL cholesterol, insulin, potassium, LDH, lipase, magnesium, protein, sodium, thyroxine, testosterone, triglycerides (triglyc), troponin I and T, urate and urea. Laboratory parameters were graded according to NCI-CTCAE version 4.0. Grade 1: mild; Grade 2: moderate; Grade 3: severe or medically significant; Grade 4: life-threatening consequences; Grade 5: death. Baseline is the most recent, non-missing value prior to or on the first study treatment dose date. Data for worst-case post-Baseline is presented.

    Measured: Baseline (pre-dose Week1 Day1) and median of 1.41 months of drug exposure

  15. Number of Participants With Grade Change From Baseline in Clinical Chemistry Data-Besylate Sub-study

    Blood samples were collected for the analysis of clinical chemistry parameters: glucose, albumin, ALP, ALT, amylase, AST, Dir bil, bilirubin, NT-BNP, calcium, cholesterol, CK, chloride, CO2, creatinine, GGT, HDL and LDL cholesterol, insulin, potassium, LDH, lipase, magnesium, protein, sodium, thyroxine, testosterone, triglycerides, troponin I and T, urate and urea. Laboratory parameters were graded according to NCI-CTCAE version 4.0. Grade 1: mild; Grade 2: moderate; Grade 3: severe or medically significant; Grade 4: life-threatening consequences; Grade 5: death. Baseline is the most recent, non-missing value prior to or on the first study treatment dose date. Data for worst case post-Baseline is presented.

    Measured: Baseline (pre-dose Week1 Day1) and median of 1.87 months of drug exposure

  16. Number of Participants With Grade Change From Baseline in Hematology Data-Part 1 QD

    Blood samples were collected for the analysis of hematology parameters: activated partial thromboplastin time (aPTT), platelet count, red blood cell count (RBC), white blood cell count (WBC), prothrombin international normalized ratio (INR), prothrombin time (PT), fibrinogen (Fib), hemoglobin, neutrophils, lymphocytes, monocytes, eosinophils and basophils. Laboratory parameters were graded according to NCI-CTCAE version 4.0. Grade 1: mild; Grade 2: moderate; Grade 3: severe or medically significant; Grade 4: life-threatening consequences; Grade 5: death. Baseline is the most recent, non-missing value prior to or on the first study treatment dose date. Data for worst case post-Baseline is presented.

    Measured: Baseline (pre-dose Week1 Day1) and median of 1.38 months of drug exposure

  17. Number of Participants With Grade Change From Baseline in Hematology Data-Part 1 BID

    Blood samples were collected for the analysis of hematology parameters: aPTT, platelet count, RBC, WBC, INR, PT, Fib, hemoglobin, neutrophils, lymphocytes, monocytes, eosinophils and basophils. Laboratory parameters were graded according to NCI-CTCAE version 4.0. Grade 1: mild; Grade 2: moderate; Grade 3: severe or medically significant; Grade 4: life-threatening consequences; Grade 5: death. Baseline is the most recent, non-missing value prior to or on the first study treatment dose date. Data for worst case post-Baseline is presented.

    Measured: Baseline (pre-dose Week1 Day1) and median of 1.41 months of drug exposure

  18. Number of Participants With Grade Change From Baseline in Hematology Data-Part 2

    Blood samples were collected for the analysis of hematology parameters: aPTT, platelet count, RBC, WBC, INR, PT, Fib, hemoglobin, neutrophils, lymphocytes, monocytes, eosinophils and basophils. Laboratory parameters were graded according to NCI-CTCAE version 4.0. Grade 1: mild; Grade 2: moderate; Grade 3: severe or medically significant; Grade 4: life-threatening consequences; Grade 5: death. Baseline is the most recent, non-missing value prior to or on the first study treatment dose date. Data for worst case post-Baseline is presented.

    Measured: Baseline (pre-dose Week1 Day1) and median of 1.41 months of drug exposure

  19. Number of Participants With Grade Change From Baseline in Hematology Data-Besylate Sub-study

    Blood samples were collected for the analysis of hematology parameters: aPTT, platelet count, RBC, WBC, INR, PT, Fib, hemoglobin, neutrophils, lymphocytes, monocytes, eosinophils and basophils. Laboratory parameters were graded according to NCI-CTCAE version 4.0. Grade 1: mild; Grade 2: moderate; Grade 3: severe or medically significant; Grade 4: life-threatening consequences; Grade 5: death. Baseline is the most recent, non-missing value prior to or on the first study treatment dose date. Data for worst case post-Baseline is presented.

    Measured: Baseline (pre-dose Week1 Day1) and median of 1.87 months of drug exposure

  20. Number of Participants With Maximum Urinalysis Change From Baseline-Part 1 QD

    Urine samples were collected for the analysis of following urine parameters: potential of hydrogen (pH), glucose, protein, occult blood, ketones, specific gravity, erythrocytes and leukocytes. Baseline is the most recent, non-missing value prior to or on the first study treatment dose date. Only parameters and time points with non-zero values for any increase have been presented.

    Measured: Baseline (pre-dose Week1 Day1) and Weeks 5, 9, 17, 25, 33, 41, 49 and discharge/progression (disc/prog)

  21. Number of Participants With Maximum Urinalysis Change From Baseline Data-Part 1 BID

    Urine samples were collected for the analysis of following urine parameters: pH, glucose, protein, occult blood, ketones, specific gravity, erythrocytes and leukocytes. Baseline is the most recent, non-missing value prior to or on the first study treatment dose date. Only parameters and time points with non-zero values for any increase have been presented.

    Measured: Baseline (pre-dose Week1 Day1) and Weeks 5,9,17 and discharge/progression

  22. Number of Participants With Maximum Urinalysis Change From Baseline-Part 2

    Urine samples were collected for the analysis of following urine parameters: pH, glucose, protein, blood, ketones, specific gravity, erythrocytes and leukocytes. Baseline is the most recent, non-missing value prior to or on the first study treatment dose date. Only parameters and time points with non-zero values for any increase have been presented.

    Measured: Baseline (pre-dose Week1 Day1), Weeks 5,9,13,25,37, 49, 73, 85 and discharge/progression

  23. Number of Participants With Maximum Urinalysis Change From Baseline-Besylate Sub-study

    Urine samples were collected for the analysis of following urine parameters: pH, glucose, protein, occult blood, ketones, specific gravity, erythrocytes and leukocytes. Baseline is the most recent, non-missing value prior to or on the first study treatment dose date. Only parameters and time points with non-zero values for any increase have been presented.

    Measured: Baseline (pre-dose Week1 Day1), Weeks 5,9,17,25 and disc/prog

  24. Number of Participants With Changes in Pulse Rate From Baseline-Part 1 QD

    Pulse rate was measured in a supine or semi-recumbent position after at least 5 minutes rest for the participant. The clinical concern range for pulse rate is <60 beats per minute and >100 beats per minute. Participants were counted twice if the participant "Decreased to <60" and "Increased to >100" post-baseline. Baseline is the most recent, non-missing value from a central laboratory prior to or on the first study treatment dose date. Data for worst case post-Baseline is presented

    Measured: Baseline (pre-dose Week1 Day1) and median of 1.38 months of drug exposure

  25. Number of Participants With Changes in Pulse Rate From Baseline-Part 1 BID

    Pulse rate was measured in a supine or semi-recumbent position after at least 5 minutes rest for the participant. Baseline is the most recent, non-missing value from a central laboratory prior to or on the first study treatment dose date. Data for worst case post-Baseline is presented.

    Measured: Baseline (pre-dose Week1 Day1) and median of 1.41 months of drug exposure

  26. Number of Participants With Changes in Pulse Rate From Baseline-Part 2

    Pulse rate was measured in a supine or semi-recumbent position after at least 5 minutes rest for the participant. The clinical concern range for pulse rate is <60 beats per minute and >100 beats per minute. Baseline is the most recent, non-missing value from a central laboratory prior to or on the first study treatment dose date. Data for worst case post-Baseline is presented. Participants were counted twice if the participant "Decreased to <60" and "Increased to >100" post-baseline.

    Measured: Baseline (pre-dose Week1 Day1) and median of 1.41 months of drug exposure

  27. Number of Participants With Changes in Pulse Rate From Baseline-Besylate Sub-study

    Pulse rate was measured in a supine or semi-recumbent position after at least 5 minutes rest for the participant. The clinical concern range for pulse rate is <60 beats per minute and >100 beats per minute. Baseline is the most recent, non-missing value from a central laboratory prior to or on the first study treatment dose date. Data for worst case post-Baseline is presented.

    Measured: Baseline (pre-dose Week1 Day1) and median of 1.87 months of drug exposure

  28. Number of Participants With Increase in Blood Pressure From Baseline-Part 1 QD

    Systolic blood pressure (SBP) and diastolic blood pressure (DBP) was measured in a supine or semi-recumbent position after at least 5 minutes rest for the participant. Grading of SBP and DBP were done using NCI-CTCAE version 4.0 where, SBP (millimeters of mercury): Grade 0 (<120), Grade 1 (120-139), Grade 2 (140-159), Grade 3/4 (>=160) and DBP: Grade 0 (<80), Grade 1 (80-89), Grade 2 (90-99), Grade 3/4 (>=100). An increase is defined as an increase in CTCAE grade relative to baseline grade. Baseline is the most recent, non-missing value from a central laboratory prior to or on the first study treatment dose date. Data for worst case post-Baseline is presented

    Measured: Baseline (pre-dose Week1 Day1) and median of 1.38 months of drug exposure

  29. Number of Participants With Increase in Blood Pressure From Baseline-Part 1 BID

    SBP and DBP were measured in a supine or semi-recumbent position after at least 5 minutes rest for the participant. Grading of SBP and DBP were done using NCI-CTCAE version 4.0 where, SBP (millimeters of mercury): Grade 0 (<120), Grade 1 (120-139), Grade 2 (140-159), Grade 3/4 (>=160) and DBP: Grade 0 (<80), Grade 1 (80-89), Grade 2 (90-99), Grade 3/4 (>=100). An increase is defined as an increase in CTCAE grade relative to baseline grade. Baseline is the most recent, non-missing value from a central laboratory prior to or on the first study treatment dose date. Data for worst case post-Baseline is presented

    Measured: Baseline (pre-dose Week1 Day1) and median of 1.41 months of drug exposure

  30. Number of Participants With Changes in Blood Pressure From Baseline-Part 2

    SBP and DBP were measured in a supine or semi-recumbent position after at least 5 minutes rest for the participant. Grading of SBP and DBP were done using NCI-CTCAE version 4.0 where, SBP (millimeters of mercury): Grade 0 (<120), Grade 1 (120-139), Grade 2 (140-159), Grade 3/4 (>=160) and DBP: Grade 0 (<80), Grade 1 (80-89), Grade 2 (90-99), Grade 3/4 (>=100). An increase is defined as an increase in CTCAE grade relative to baseline grade. Baseline is the most recent, non-missing value from a central laboratory prior to or on the first study treatment dose date. Data for worst case post-Baseline is presented.

    Measured: Baseline (pre-dose Week1 Day1) and median of 1.41 months of drug exposure

  31. Number of Participants With Increase in Blood Pressure From Baseline-Besylate Sub-study

    SBP and DBP were measured in a supine or semi-recumbent position after at least 5 minutes rest for the participant. Grading of SBP and DBP were done using NCI-CTCAE version 4.0 where, SBP (millimeters of mercury): Grade 0 (<120), Grade 1 (120-139), Grade 2 (140-159), Grade 3/4 (>=160) and DBP: Grade 0 (<80), Grade 1 (80-89), Grade 2 (90-99), Grade 3/4 (>=100). An increase is defined as an increase in CTCAE grade relative to baseline grade. Baseline is the most recent, non-missing value from a central laboratory prior to or on the first study treatment dose date. Data for worst case post-Baseline is presented.

    Measured: Baseline (pre-dose Week1 Day1) and median of 1.87 months of drug exposure

  32. Number of Participants With Changes in Temperature From Baseline-Part 1 QD

    Temperature was measured in a supine or semi-recumbent position after at least 5 minutes rest for the participant. The clinical concern range for temperature is <=35 degree Celsius and >=38 degree Celsius. Baseline is the most recent, non-missing value from a central laboratory prior to or on the first study treatment dose date. Data for worst case post-Baseline is presented.

    Measured: Baseline (pre-dose Week1 Day1) and median of 1.38 months of drug exposure

  33. Number of Participants With Changes in Temperature From Baseline-Part 1 BID

    Temperature was measured in a supine or semi-recumbent position after at least 5 minutes rest for the participant. The clinical concern range for temperature is <=35 degree Celsius and >=38 degree Celsius. Baseline is the most recent, non-missing value from a central laboratory prior to or on the first study treatment dose date. Data for worst case post-Baseline is presented.

    Measured: Baseline (pre-dose Week1 Day1) and median of 1.41 months of drug exposure

  34. Number of Participants With Changes in Temperature From Baseline-Part 2

    Temperature was measured in a supine or semi-recumbent position after at least 5 minutes rest for the participant. The clinical concern range for temperature is <=35 degree Celsius and >=38 degree Celsius. Baseline is the most recent, non-missing value from a central laboratory prior to or on the first study treatment dose date. Data for worst case post-Baseline is presented.

    Measured: Baseline (pre-dose Week1 Day1) and median of 1.41 months of drug exposure

  35. Number of Participants With Changes in Temperature From Baseline-Besylate Sub-study

    Temperature was measured in a supine or semi-recumbent position after at least 5 minutes rest for the participant. The clinical concern range for temperature is <=35 degree Celsius and >=38 degree Celsius. Baseline is the most recent, non-missing value from a central laboratory prior to or on the first study treatment dose date. Data for worst case post-Baseline is presented.

    Measured: Baseline (pre-dose Week1 Day1) and median of 1.87 months of drug exposure

  36. Overall Response Rate-Part 1 QD

    Overall response rate is defined as the percentage of participants who achieved a confirmed complete response (CR) or partial response (PR) from the start of treatment until disease progression or the start of new anticancer therapy, among participants who received at least 1 dose of treatment. Overall response rate was determined by the investigator according to Response Evaluation Criteria in Solid Tumors (RECIST version (v) 1.1). CR=Disappearance of all target lesions. Any pathological lymph nodes must be <10 millimeters (mm) in the short axis. PR=At least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the Baseline sum of the diameters.

    Measured: Median of 1.38 months of drug exposure

  37. Overall Response Rate-Part 1 BID

    Overall response rate is defined as the percentage of participants who achieved a confirmed CR or PR from the start of treatment until disease progression or the start of new anticancer therapy, among participants who received at least 1 dose of treatment. Overall response rate was determined by the investigator according to RECIST v 1.1. CR=Disappearance of all target lesions. Any pathological lymph nodes must be <10 mm in the short axis. PR=At least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the Baseline sum of the diameters.

    Measured: Median of 1.41 months of drug exposure

  38. Overall Response Rate-Part 2

    Overall response rate is defined as the percentage of participants who achieved a confirmed CR or PR from the start of treatment until disease progression or the start of new anticancer therapy, among participants who received at least 1 dose of treatment. Overall response rate was determined by the investigator according to RECIST v 1.1. CR=Disappearance of all target lesions. Any pathological lymph nodes must be <10 mm in the short axis. PR=At least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the Baseline sum of the diameters.

    Measured: Median of 1.41 months of drug exposure

  39. Overall Response Rate-Besylate Sub-study

    Overall response rate is defined as the percentage of participants who achieved a confirmed CR or PR from the start of treatment until disease progression or the start of new anticancer therapy, among participants who received at least 1 dose of treatment. Overall response rate was determined by the investigator according to RECIST v 1.1. CR=Disappearance of all target lesions. Any pathological lymph nodes must be <10 mm in the short axis. PR=At least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the Baseline sum of the diameters.

    Measured: Median of 1.87 months of drug exposure

  40. Number of Participants With Prostate Specific Antigen (PSA)50 Response-Part 1 QD

    PSA 50 response rate is defined as the response rate that a PSA reduction from Baseline >=50% is observed at 12 weeks and beyond (must be confirmed by a second value). The number of participants with PSA >=50% reduction is presented along with 95% confidence intervals.

    Measured: Median of 1.38 months of drug exposure

  41. Number of Participants With PSA50 Response Rate-Part 1 BID

    PSA 50 Response rate is defined as the response rate that a PSA reduction from Baseline >=50% is observed at 12 weeks and beyond (must be confirmed by a second value). The number of participants with PSA >=50% reduction is presented along with 95% confidence intervals.

    Measured: Median of 1.41 months of drug exposure

  42. Number of Participants With PSA50 Response-Part 2

    PSA 50 response rate is defined as the response rate that a PSA reduction from Baseline >=50% is observed at 12 weeks and beyond (must be confirmed by a second value). The number of participants with PSA >=50% reduction is presented along with 95% confidence intervals.

    Measured: Median of 1.41 months of drug exposure

  43. Number of Participants With PSA50 Response-Besylate Sub-study

    PSA 50 Response rate is defined as the response rate that a PSA reduction from Baseline >=50% is observed at 12 weeks and beyond (must be confirmed by a second value). The number of participants with PSA >=50% reduction is presented along with 95% confidence intervals.

    Measured: Median of 1.87 months of drug exposure

  44. Area Under the Concentration-time Curve (AUC) From Time Zero to 24 Hours(AUC[0 to 24]); AUC From Time 0 to Last Quantifiable Concentration (AUC [0 to t]) and AUC Extrapolated to Infinity (AUC[0 to Inf]) of GSK525762-Besylate Sub-study

    Blood samples for pharmacokinetic analysis of GSK525762 were collected at the indicated time points. Besylate sub-study pharmacokinetic (PK) Parameter Population consisted of all participants in the PK Parameter Population who participated in the besylate substudy.

    Measured: Week1 Day1, Day3 and Week2 Day1 (pre-dose,0.25,0.5,1,1.5,2,3,4,6,8,24,48 hours post-dose)

  45. Maximum Observed Concentration (Cmax) of GSK525762-Besylate Sub-study

    Blood samples for pharmacokinetic analysis of GSK525762 were collected at the indicated time points.

    Measured: Week1 Day1, Day3 and Week2 Day1 (pre-dose,0.25,0.5,1,1.5,2,3,4,6,8,24,48 hours post-dose)

  46. Apparent Terminal Phase Elimination Rate Constant (Lambda z) for GSK525762-Besylate Sub-study

    Blood samples for pharmacokinetic analysis of GSK525762 were collected at the indicated time points.

    Measured: Week1 Day1, Day3 and Week2 Day1 (pre-dose,0.25,0.5,1,1.5,2,3,4,6,8,24,48 hours post-dose)

  47. Time to Reach Cmax (Tmax) for GSK525762-Besylate Sub-study

    Blood samples for pharmacokinetic analysis of GSK525762 were collected at the indicated time points.

    Measured: Week1 Day1, Day3 and Week2 Day1 (pre-dose,0.25,0.5,1,1.5,2,3,4,6,8,24,48 hours post-dose)

  48. Number of Participants With Non-serious AEs and SAEs-Besylate Sub-study

    An AE is any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An SAE is any untoward medical occurrence that, at any dose: results in death; is life-threatening; requires hospitalization or prolongation of existing hospitalization; results in disability/incapacity; is a congenital anomaly/birth defect; important medical events that may require medical or surgical intervention to prevent one of the outcomes mentioned; events of possible study treatment-induced liver injury with hyperbilirubinemia; any new primary cancers; significant cardiac dysfunction; Grade 4 laboratory abnormalities; and drug related hepatobiliary event leading to permanent discontinuation of study treatment

    Measured: Median of 1.87 months of drug exposure

Secondary outcomes (32)

  1. Number of Participants With Increase in QT Interval Corrected for Heart Rate According to Fridericia's Formula (QTcF)-Part 1 QD

    Electrocardiogram (ECG) measurements were done using an automated 12-lead ECG machine. QTc parameters were graded according to NCI-CTCAE version 4.0. Grade 0 (<450 milliseconds [msec]), Grade 1 (450-480 msec), Grade 2 (481-500 msec), Grade 3 (>=501 msec). An increase is defined as an increase in CTCAE grade relative to Baseline grade. Baseline is the most recent, non-missing value prior to or on the first study treatment dose date. Number of participants with increase in QTcF at worst-case post Baseline is reported.

    Measured: Median of 1.38 months of drug exposure

  2. Number of Participants With Increase in QTcF-Part 1 BID

    ECG measurements were done using an automated 12-lead ECG machine. QTc parameters were graded according to NCI-CTCAE version 4.0. Grade 0 (<450 milliseconds [msec]), Grade 1 (450-480 msec), Grade 2 (481-500 msec), Grade 3 (>=501 msec). An increase is defined as an increase in CTCAE grade relative to Baseline grade. Baseline is the most recent, non-missing value prior to or on the first study treatment dose date. Number of participants with increase in QTcF at worst-case post Baseline is reported.

    Measured: Median of 1.41 months of drug exposure

  3. Number of Participants With Increase in QTcF-Part 2

    ECG measurements were done using an automated 12-lead ECG machine. QTc parameters were graded according to NCI-CTCAE version 4.0. Grade 0 (<450 milliseconds [msec]), Grade 1 (450-480 msec), Grade 2 (481-500 msec), Grade 3 (>=501 msec). An increase is defined as an increase in CTCAE grade relative to Baseline grade. Baseline is the most recent, non-missing value prior to or on the first study treatment dose date. Number of participants with increase in QTcF at worst-case post Baseline is reported.

    Measured: Median of 1.41 months of drug exposure

  4. Number of Participants With Increase in QTcF-Besylate Sub-study

    ECG measurements were done using 12-lead ECG machine that automatically calculated the heart rate and measured PR, QRS, QT and QTcF intervals. QTc parameters were graded according to NCI-CTCAE version 4.0. Grade 0 (<450 milliseconds [msec]), Grade 1 (450-480 msec), Grade 2 (481-500 msec), Grade 3 (>=501 msec). An increase is defined as an increase in CTCAE grade relative to Baseline grade. Baseline is the most recent, non-missing value prior to or on the first study treatment dose date. Number of participants with increase in QTcF at worst-case post Baseline is reported.

    Measured: Median of 1.87 months of drug exposure

  5. Progression Free Survival-Part 1 QD

    Progression free survival is defined as the interval of time (in months) between the date of first dose and the earlier of the date of disease progression and date of death due to any cause. Confidence intervals were estimated using Brookmeyer Crowley method.

    Measured: Median of 1.38 months of drug exposure

  6. Progression Free Survival-Part 1 BID

    Progression free survival is defined as the interval of time (in months) between the date of first dose and the earlier of the date of disease progression and date of death due to any cause. Confidence intervals were estimated using Brookmeyer Crowley method.

    Measured: Median of 1.41 months of drug exposure

  7. Progression Free Survival-Part 2

    Progression free survival is defined as the interval of time (in months) between the date of first dose and the earlier of the date of disease progression and the date of death due to any cause. Confidence intervals were estimated using Brookmeyer Crowley method.

    Measured: Median of 1.41 months of drug exposure

  8. Progression Free Survival-Besylate Sub-study

    Progression free survival is defined as the interval of time (in months) between the date of first dose and the earlier of the date of disease progression and the date of death due to any cause. Confidence intervals were estimated using Brookmeyer Crowley method.

    Measured: Median of 1.87 months of drug exposure

  9. Time to Response-Part 1 QD

    Time to response is defined, for participants with a confirmed CR or PR, as the time from first dose to the first documented evidence of CR or PR. Time to response is not derived for participants with incomplete response dates. Confidence intervals were estimated using Brookmeyer Crowley method.

    Measured: Median of 1.38 months of drug exposure

  10. Time to Response-Part 1 BID

    Time to response is defined, for participants with a confirmed CR or PR, as the time from first dose to the first documented evidence of CR or PR. Time to response is not derived for participants with incomplete response dates. Confidence intervals were estimated using Brookmeyer Crowley method.

    Measured: Median of 1.41 months of drug exposure

  11. Time to Response-Part 2

    Time to response is defined, for participants with a confirmed CR or PR, as the time from first dose to the first documented evidence of CR or PR. Time to response is not derived for participants with incomplete response dates. Confidence intervals were estimated using Brookmeyer Crowley method.

    Measured: Median of 1.41 months of drug exposure

  12. Time to Response-Besylate Sub-study

    Time to response is defined, for participants with a confirmed CR or PR, as the time from first dose to the first documented evidence of CR or PR. Time to response is not derived for participants with incomplete response dates. Confidence intervals were estimated using Brookmeyer Crowley method.

    Measured: Median of 1.87 months of drug exposure

  13. Duration of Response-Part 1 QD

    Duration of response is defined as the time from first documented evidence of CR or PR until disease progression or death due to any cause among participants who achieve a confirmed CR or PR. Duration of response is not derived for participants with incomplete response dates. Confidence intervals were estimated using Brookmeyer Crowley method.

    Measured: Median of 1.38 months of drug exposure

  14. Duration of Response-Part 1 BID

    Duration of response is defined as the time from first documented evidence of CR or PR until disease progression or death due to any cause among participants who achieve a confirmed CR or PR. Duration of response is not derived for participants with incomplete response dates. Confidence intervals were estimated using Brookmeyer Crowley method.

    Measured: Median of 1.41 months of drug exposure

  15. Duration of Response-Part 2

    Duration of response is defined as the time from first documented evidence of CR or PR until disease progression or death due to any cause among participants who achieve a confirmed CR or PR. Duration of response is not derived for participants with incomplete response dates. Confidence intervals were estimated using Brookmeyer Crowley method.

    Measured: Median of 1.41 months of drug exposure

  16. Duration of Response-Besylate Sub-study

    Duration of response is defined as the time from first documented evidence of CR or PR until disease progression or death due to any cause among participants who achieve a confirmed CR or PR. Duration of response is not derived for participants with incomplete response dates. Confidence intervals were estimated using Brookmeyer Crowley method.

    Measured: Median of 1.87 months of drug exposure

  17. Overall Survival-Part 1 QD

    Overall survival is defined as the interval of time (in months) between the date of first dose and the date of death due to any cause. The median overall survival is presented along with 95% confidence interval. Confidence intervals were estimated using Brookmeyer Crowley method.

    Measured: Median of 1.38 months of drug exposure

  18. Overall Survival-Part 1 BID

    Overall survival is defined as the interval of time (in months) between the date of first dose and the date of death due to any cause. The median overall survival is presented along with 95% confidence interval. Confidence intervals were estimated using Brookmeyer Crowley method.

    Measured: Median of 1.41 months of drug exposure

  19. Overall Survival-Part 2

    Overall survival is defined as the interval of time (in months) between the date of first dose and the date of death due to any cause. The median overall survival is presented along with 95% confidence interval. Confidence intervals were estimated using Brookmeyer Crowley method.

    Measured: Median of 1.41 months of drug exposure

  20. Overall Survival-Besylate Sub-study

    Overall survival is defined as the interval of time (in months) between the date of first dose and the date of death due to any cause. The median overall survival is presented along with 95% confidence interval. Confidence intervals were estimated using Brookmeyer Crowley method.

    Measured: Median of 1.87 months of drug exposure

  21. AUC (0 to t), AUC (0 to 24) and AUC (0 to Inf) of GSK525762-Part 1 QD

    Blood samples were collected at the indicated time points for pharmacokinetic analysis of GSK525762. PK parameter population comprised of all participants in the PK Concentration Population (all participants in the All Treated Population for whom a blood sample for pharmacokinetics is obtained and analyzed) for whom a PK parameter has been obtained.

    Measured: pre-dose,0.25,0.5,1,2,4,8,12,24 and 48 hours post-dose at Week1 Day1 and Week 3 Day 4

  22. Maximum Observed Concentration for GSK525762-Part 1 QD

    Blood samples were collected at the indicated time points for pharmacokinetic analysis of GSK525762.

    Measured: pre-dose,0.25,0.5,1,2,4,8,12,24 and 48 hours post-dose at Week1 Day1 and Week 3 Day 4

  23. Lambda z for GSK525762-Part 1 QD

    Blood samples were collected at the indicated time points for pharmacokinetic analysis of GSK525762.

    Measured: pre-dose,0.25,0.5,1,2,4,8,12,24 and 48 hours post-dose at Week1 Day1 and Week 3 Day 4

  24. Tmax for GSK525762-Part 1 QD

    Blood samples were collected at the indicated time points for pharmacokinetic analysis of GSK525762.

    Measured: pre-dose,0.25,0.5,1,2,4,8,12,24 and 48 hours post-dose at Week1 Day1 and Week 3 Day 4

  25. Apparent Clearance of GSK525762-Part 1 QD

    Blood samples were collected at the indicated time points for pharmacokinetic analysis of GSK525762.

    Measured: pre-dose,0.25,0.5,1,2,4,8,12,24 and 48 hours post-dose at Week1 Day1 and Week 3 Day 4

  26. Volume of Distribution of GSK525762-Part 1 QD

    Blood samples were collected at the indicated time points for pharmacokinetic analysis of GSK525762.

    Measured: pre-dose,0.25,0.5,1,2,4,8,12,24 and 48 hours post-dose at Week1 Day1 and Week 3 Day 4

  27. AUC (0 to Inf), AUC (0 to 24) and AUC (0 to t) of GSK525762-Part 1 BID

    Blood samples were collected at indicated time points post ante-meridiem (AM) and post-meridiem (PM) dose for pharmacokinetic analysis of GSK525762.

    Measured: pre-dose,0.25,0.5,1,2,4,8,12 hours post-AM dose at Week1Day1 and Week3 Day 4; Week1 Day5(0.5, 3 hours post-AM dose); pre-dose, 0.25,0.5,1,2,4,8,12, 36 hours post-PM dose at Week1Day1 and Week3 Day4

  28. Maximum Observed Concentration of GSK525762-Part 1 BID

    Blood samples were collected at indicated time points post ante-meridiem (AM) and post-meridiem (PM) dose for pharmacokinetic analysis of GSK525762.

    Measured: pre-dose,0.25,0.5,1,2,4,8,12 hours post-AM dose at Week1Day1 and Week3 Day 4; Week1 Day5(0.5, 3 hours post-AM dose); pre-dose, 0.25,0.5,1,2,4,8,12, 36 hours post-PM dose at Week1Day1 and Week3 Day4

  29. Lambda z for GSK525762-Part 1 BID

    Blood samples were collected at indicated time points post ante-meridiem (AM) and post-meridiem (PM) dose for pharmacokinetic analysis of GSK525762.

    Measured: pre-dose,0.25,0.5,1,2,4,8,12 hours post-AM dose at Week1Day1 and Week3 Day 4; Week1 Day5(0.5, 3 hours post-AM dose); pre-dose, 0.25,0.5,1,2,4,8,12, 36 hours post-PM dose at Week1Day1 and Week3 Day4

  30. Tmax for GSK525762-Part 1 BID

    Blood samples were collected at indicated time points post ante-meridiem (AM) and post-meridiem (PM) dose for pharmacokinetic analysis of GSK525762.

    Measured: pre-dose,0.25,0.5,1,2,4,8,12 hours post-AM dose at Week1Day1 and Week3 Day 4; Week1 Day5(0.5, 3 hours post-AM dose); pre-dose, 0.25,0.5,1,2,4,8,12, 36 hours post-PM dose at Week1Day1 and Week3 Day4

  31. Apparent Clearance of GSK525762-Part 1 BID

    Blood samples were collected at indicated time points post ante-meridiem (AM) and post-meridiem (PM) dose for pharmacokinetic analysis of GSK525762.

    Measured: pre-dose,0.25,0.5,1,2,4,8,12 hours post-AM dose at Week1Day1 and Week3 Day 4; Week1 Day5(0.5, 3 hours post-AM dose); pre-dose, 0.25,0.5,1,2,4,8,12, 36 hours post-PM dose at Week1Day1 and Week3 Day4

  32. Volume of Distribution of GSK525762-Part 1 BID

    Blood samples were collected at indicated time points post ante-meridiem (AM) and post-meridiem (PM) dose for pharmacokinetic analysis of GSK525762.

    Measured: pre-dose,0.25,0.5,1,2,4,8,12 hours post-AM dose at Week1Day1 and Week3 Day 4; Week1 Day5(0.5, 3 hours post-AM dose); pre-dose, 0.25,0.5,1,2,4,8,12, 36 hours post-PM dose at Week1Day1 and Week3 Day4

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted30 Apr 2012 (estimated)
  2. Study start28 Mar 2012
  3. Primary completion13 Apr 2018
  4. Study completion29 Jul 2019

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1
Primary purpose
Treatment
Allocation
Non-randomised
Intervention model
Single group
Masking
None (open label)
Enrolment
196 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01587703
Sponsor's protocol ID
115521
Other IDs
2014-004982-25, 2014
Status last verified
Mar 2020
First submitted
3 Apr 2012
Last updated
16 Mar 2020

Publications

  • Piha-Paul SA, Hann CL, French CA, Cousin S, Brana I, Cassier PA, Moreno V, de Bono JS, Harward SD, Ferron-Brady G, Barbash O, Wyce A, Wu Y, Horner T, Annan M, Parr NJ, Prinjha RK, Carpenter CL, Hilton J, Hong DS, Haas NB, Markowski MC, Dhar A, O'Dwyer PJ, Shapiro GI. Phase 1 Study of Molibresib (GSK525762), a Bromodomain and Extra-Terminal Domain Protein Inhibitor, in NUT Carcinoma and Other Solid Tumors. JNCI Cancer Spectr. 2019 Nov 6;4(2):pkz093. doi: 10.1093/jncics/pkz093. eCollection 2020 Apr.

    PubMed 32328561

  • Cousin S, Blay JY, Garcia IB, de Bono JS, Le Tourneau C, Moreno V, Trigo J, Hann CL, Azad AA, Im SA, Cassier PA, French CA, Italiano A, Keedy VL, Plummer R, Sablin MP, Hemming ML, Ferron-Brady G, Wyce A, Khaled A, Datta A, Foley SW, McCabe MT, Wu Y, Horner T, Kremer BE, Dhar A, O'Dwyer PJ, Shapiro GI, Piha-Paul SA. Safety, pharmacokinetic, pharmacodynamic and clinical activity of molibresib for the treatment of nuclear protein in testis carcinoma and other cancers: Results of a Phase I/II open-label, dose escalation study. Int J Cancer. 2022 Mar 15;150(6):993-1006. doi: 10.1002/ijc.33861. Epub 2021 Nov 26.

    PubMed 34724226

  • Krishnatry AS, Voelkner A, Dhar A, Prohn M, Ferron-Brady G. Population pharmacokinetic modeling of molibresib and its active metabolites in patients with solid tumors: A semimechanistic autoinduction model. CPT Pharmacometrics Syst Pharmacol. 2021 Jul;10(7):709-722. doi: 10.1002/psp4.12639. Epub 2021 Jun 4.

    PubMed 33955700

  • Parikh SA, French CA, Costello BA, Marks RS, Dronca RS, Nerby CL, Roden AC, Peddareddigari VG, Hilton J, Shapiro GI, Molina JR. NUT midline carcinoma: an aggressive intrathoracic neoplasm. J Thorac Oncol. 2013 Oct;8(10):1335-8. doi: 10.1097/JTO.0b013e3182a00f41.

    PubMed 24457244

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing GSK525762 in people with Carcinoma, Midline, run by GlaxoSmithKline at 17 sites in 7 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 14 inclusion and 12 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 16 Mar 2020. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 17 sites in United States, France, Spain, South Korea, United Kingdom and 2 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 16 Mar 2020). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)-Part 1 QD (time frame: Median of 1.38 months of drug exposure). The study lists 48 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01587703, which also lists 4 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 16 Mar 2020.

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