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

• ClinicalTrials.gov Identifier: NCT01587703
• Recruitment Status: Completed
• First Posted: April 30, 2012
• Results First Posted: March 16, 2020
• Last Update Posted: March 16, 2020
• Sponsor: GlaxoSmithKline
• Information provided by (Responsible Party): GlaxoSmithKline

Tracking Information

• First Submitted Date: April 3, 2012
• First Posted Date: April 30, 2012
• Results First Submitted Date: April 12, 2019
• Results First Posted Date: March 16, 2020
• Last Update Posted Date: March 16, 2020
• Actual Study Start Date: March 28, 2012
• Actual Primary Completion Date: April 13, 2018 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: March 13, 2020)

• 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 ]
  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.
• Number of Participants With AEs and SAEs-Part 1 BID [ Time Frame: Median of 1.41 months of drug exposure ]
  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
• Number of Participants With AEs and SAEs-Part 2 [ Time Frame: Median of 1.41 months of drug exposure ]
  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.
• Number of Participants With Dose Reductions or Delays-Part 1 QD [ Time Frame: Median of 1.38 months of drug exposure ]
  The number of participants who had any dose reductions or delays is presented.
• Number of Participants With Dose Reductions or Delays-Part 1 BID [ Time Frame: Median of 1.41 months of drug exposure ]
  The number of participants who had any dose reductions or delays is presented.
• Number of Participants With Dose Reductions or Delays-Part 2 [ Time Frame: Median of 1.41 months of drug exposure ]
  The number of participants who had any dose reductions or delays is presented.
• Number of Participants With Dose Reductions or Delays-Besylate Sub-study [ Time Frame: Median of 1.87 months of drug exposure ]
  The number of participants who had any dose reductions or delays is presented.
• Number of Participants Withdrawn Due to Toxicities-Part 1 QD [ Time Frame: Median of 1.38 months of drug exposure ]
  Number of participants withdrawn due to toxicities is presented.
• Number of Participants Withdrawn Due to Toxicities-Part 1 BID [ Time Frame: Median of 1.41 months of drug exposure ]
  Number of participants withdrawn due to toxicities is presented.
• Number of Participants Withdrawn Due to Toxicities-Part 2 [ Time Frame: Median of 1.41 months of drug exposure ]
  Number of participants withdrawn due to toxicities is presented.
• Number of Participants Withdrawn Due to Toxicities-Besylate Sub-study [ Time Frame: Median of 1.87 months of drug exposure ]
  Number of participants withdrawn due to toxicities is presented.
• Number of Participants With Grade Change From Baseline in Clinical Chemistry Data-Part 1 QD [ Time Frame: Baseline (pre-dose Week1 Day1) and median of 1.38 months of drug exposure ]
  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.
• Number of Participants With Grade Change From Baseline in Clinical Chemistry Data-Part 1 BID [ Time Frame: Baseline (pre-dose Week1 Day1) and median of 1.41 months of drug exposure ]
  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.
• Number of Participants With Grade Change From Baseline in Clinical Chemistry Data-Part 2 [ Time Frame: Baseline (pre-dose Week1 Day1) and median of 1.41 months of drug exposure ]
  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.
• Number of Participants With Grade Change From Baseline in Clinical Chemistry Data-Besylate Sub-study [ Time Frame: Baseline (pre-dose Week1 Day1) and median of 1.87 months of drug exposure ]
  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.
• Number of Participants With Grade Change From Baseline in Hematology Data-Part 1 QD [ Time Frame: Baseline (pre-dose Week1 Day1) and median of 1.38 months of drug exposure ]
  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.
• Number of Participants With Grade Change From Baseline in Hematology Data-Part 1 BID [ Time Frame: Baseline (pre-dose Week1 Day1) and median of 1.41 months of drug exposure ]
  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.
• Number of Participants With Grade Change From Baseline in Hematology Data-Part 2 [ Time Frame: Baseline (pre-dose Week1 Day1) and median of 1.41 months of drug exposure ]
  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.
• Number of Participants With Grade Change From Baseline in Hematology Data-Besylate Sub-study [ Time Frame: Baseline (pre-dose Week1 Day1) and median of 1.87 months of drug exposure ]
  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.
• Number of Participants With Maximum Urinalysis Change From Baseline-Part 1 QD [ Time Frame: Baseline (pre-dose Week1 Day1) and Weeks 5, 9, 17, 25, 33, 41, 49 and discharge/progression (disc/prog) ]
  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.
• Number of Participants With Maximum Urinalysis Change From Baseline Data-Part 1 BID [ Time Frame: Baseline (pre-dose Week1 Day1) and Weeks 5,9,17 and discharge/progression ]
  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.
• Number of Participants With Maximum Urinalysis Change From Baseline-Part 2 [ Time Frame: Baseline (pre-dose Week1 Day1), Weeks 5,9,13,25,37, 49, 73, 85 and discharge/progression ]
  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.
• Number of Participants With Maximum Urinalysis Change From Baseline-Besylate Sub-study [ Time Frame: Baseline (pre-dose Week1 Day1), Weeks 5,9,17,25 and disc/prog ]
  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.
• Number of Participants With Changes in Pulse Rate From Baseline-Part 1 QD [ Time Frame: Baseline (pre-dose Week1 Day1) and median of 1.38 months of drug exposure ]
  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
• Number of Participants With Changes in Pulse Rate From Baseline-Part 1 BID [ Time Frame: Baseline (pre-dose Week1 Day1) and median of 1.41 months of drug exposure ]
  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.
• Number of Participants With Changes in Pulse Rate From Baseline-Part 2 [ Time Frame: Baseline (pre-dose Week1 Day1) and median of 1.41 months of drug exposure ]
  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.
• Number of Participants With Changes in Pulse Rate From Baseline-Besylate Sub-study [ Time Frame: Baseline (pre-dose Week1 Day1) and median of 1.87 months of drug exposure ]
  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.
• Number of Participants With Increase in Blood Pressure From Baseline-Part 1 QD [ Time Frame: Baseline (pre-dose Week1 Day1) and median of 1.38 months of drug exposure ]
  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
• Number of Participants With Increase in Blood Pressure From Baseline-Part 1 BID [ Time Frame: Baseline (pre-dose Week1 Day1) and median of 1.41 months of drug exposure ]
  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
• Number of Participants With Changes in Blood Pressure From Baseline-Part 2 [ Time Frame: Baseline (pre-dose Week1 Day1) and median of 1.41 months of drug exposure ]
  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.
• Number of Participants With Increase in Blood Pressure From Baseline-Besylate Sub-study [ Time Frame: Baseline (pre-dose Week1 Day1) and median of 1.87 months of drug exposure ]
  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.
• Number of Participants With Changes in Temperature From Baseline-Part 1 QD [ Time Frame: Baseline (pre-dose Week1 Day1) and median of 1.38 months of drug exposure ]
  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.
• Number of Participants With Changes in Temperature From Baseline-Part 1 BID [ Time Frame: Baseline (pre-dose Week1 Day1) and median of 1.41 months of drug exposure ]
  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.
• Number of Participants With Changes in Temperature From Baseline-Part 2 [ Time Frame: Baseline (pre-dose Week1 Day1) and median of 1.41 months of drug exposure ]
  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.
• Number of Participants With Changes in Temperature From Baseline-Besylate Sub-study [ Time Frame: Baseline (pre-dose Week1 Day1) and median of 1.87 months of drug exposure ]
  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.
• Overall Response Rate-Part 1 QD [ Time Frame: Median of 1.38 months of drug exposure ]
  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.
• Overall Response Rate-Part 1 BID [ Time Frame: Median of 1.41 months of drug exposure ]
  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.
• Overall Response Rate-Part 2 [ Time Frame: Median of 1.41 months of drug exposure ]
  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.
• Overall Response Rate-Besylate Sub-study [ Time Frame: Median of 1.87 months of drug exposure ]
  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.
• Number of Participants With Prostate Specific Antigen (PSA)50 Response-Part 1 QD [ Time Frame: Median of 1.38 months of drug exposure ]
  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.
• Number of Participants With PSA50 Response Rate-Part 1 BID [ Time Frame: Median of 1.41 months of drug exposure ]
  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.
• Number of Participants With PSA50 Response-Part 2 [ Time Frame: Median of 1.41 months of drug exposure ]
  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.
• Number of Participants With PSA50 Response-Besylate Sub-study [ Time Frame: Median of 1.87 months of drug exposure ]
  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.
• 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 [ Time Frame: 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) ]
  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.
• Maximum Observed Concentration (Cmax) of GSK525762-Besylate Sub-study [ Time Frame: 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) ]
  Blood samples for pharmacokinetic analysis of GSK525762 were collected at the indicated time points.
• Apparent Terminal Phase Elimination Rate Constant (Lambda z) for GSK525762-Besylate Sub-study [ Time Frame: 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) ]
  Blood samples for pharmacokinetic analysis of GSK525762 were collected at the indicated time points.
• Time to Reach Cmax (Tmax) for GSK525762-Besylate Sub-study [ Time Frame: 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) ]
  Blood samples for pharmacokinetic analysis of GSK525762 were collected at the indicated time points.
• Number of Participants With Non-serious AEs and SAEs-Besylate Sub-study [ Time Frame: Median of 1.87 months of drug exposure ]
  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

Original Primary Outcome Measures (submitted: April 26, 2012)

• Dose limiting toxicities within first 6 weeks [ Time Frame: 7 Weeks ]
  MTD
• Overall response rate (RR) by RECIST 1.1 [ Time Frame: 7 Weeks ]
  To evaluate the clinical activity of GSK525762 in subjects with NUT Midline Carcinoma (NMC).
• AEs, SAEs, dose reductions or delays, withdrawals due to toxicities and changes in safety assessments (e.g., laboratory parameters, vital signs, ECG, cardiotoxicity, gastrointestinal, etc) [ Time Frame: Changes pre-dose to 7 weeks ]
  Safety and Tolerability

Current Secondary Outcome Measures (submitted: March 13, 2020)

• Number of Participants With Increase in QT Interval Corrected for Heart Rate According to Fridericia's Formula (QTcF)-Part 1 QD [ Time Frame: Median of 1.38 months of drug exposure ]
  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.
• Number of Participants With Increase in QTcF-Part 1 BID [ Time Frame: Median of 1.41 months of drug exposure ]
  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.
• Number of Participants With Increase in QTcF-Part 2 [ Time Frame: Median of 1.41 months of drug exposure ]
  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.
• Number of Participants With Increase in QTcF-Besylate Sub-study [ Time Frame: Median of 1.87 months of drug exposure ]
  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.
• Progression Free Survival-Part 1 QD [ Time Frame: Median of 1.38 months of drug exposure ]
  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.
• Progression Free Survival-Part 1 BID [ Time Frame: Median of 1.41 months of drug exposure ]
  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.
• Progression Free Survival-Part 2 [ Time Frame: Median of 1.41 months of drug exposure ]
  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.
• Progression Free Survival-Besylate Sub-study [ Time Frame: Median of 1.87 months of drug exposure ]
  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.
• Time to Response-Part 1 QD [ Time Frame: Median of 1.38 months of drug exposure ]
  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.
• Time to Response-Part 1 BID [ Time Frame: Median of 1.41 months of drug exposure ]
  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.
• Time to Response-Part 2 [ Time Frame: Median of 1.41 months of drug exposure ]
  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.
• Time to Response-Besylate Sub-study [ Time Frame: Median of 1.87 months of drug exposure ]
  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.
• Duration of Response-Part 1 QD [ Time Frame: Median of 1.38 months of drug exposure ]
  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.
• Duration of Response-Part 1 BID [ Time Frame: Median of 1.41 months of drug exposure ]
  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.
• Duration of Response-Part 2 [ Time Frame: Median of 1.41 months of drug exposure ]
  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.
• Duration of Response-Besylate Sub-study [ Time Frame: Median of 1.87 months of drug exposure ]
  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.
• Overall Survival-Part 1 QD [ Time Frame: Median of 1.38 months of drug exposure ]
  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.
• Overall Survival-Part 1 BID [ Time Frame: Median of 1.41 months of drug exposure ]
  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.
• Overall Survival-Part 2 [ Time Frame: Median of 1.41 months of drug exposure ]
  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.
• Overall Survival-Besylate Sub-study [ Time Frame: Median of 1.87 months of drug exposure ]
  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.
• AUC (0 to t), AUC (0 to 24) and AUC (0 to Inf) of GSK525762-Part 1 QD [ Time Frame: 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 ]
  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.
• Maximum Observed Concentration for GSK525762-Part 1 QD [ Time Frame: 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 ]
  Blood samples were collected at the indicated time points for pharmacokinetic analysis of GSK525762.
• Lambda z for GSK525762-Part 1 QD [ Time Frame: 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 ]
  Blood samples were collected at the indicated time points for pharmacokinetic analysis of GSK525762.
• Tmax for GSK525762-Part 1 QD [ Time Frame: 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 ]
  Blood samples were collected at the indicated time points for pharmacokinetic analysis of GSK525762.
• Apparent Clearance of GSK525762-Part 1 QD [ Time Frame: 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 ]
  Blood samples were collected at the indicated time points for pharmacokinetic analysis of GSK525762.
• Volume of Distribution of GSK525762-Part 1 QD [ Time Frame: 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 ]
  Blood samples were collected at the indicated time points for pharmacokinetic analysis of GSK525762.
• AUC (0 to Inf), AUC (0 to 24) and AUC (0 to t) of GSK525762-Part 1 BID [ Time Frame: 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 ]
  Blood samples were collected at indicated time points post ante-meridiem (AM) and post-meridiem (PM) dose for pharmacokinetic analysis of GSK525762.
• Maximum Observed Concentration of GSK525762-Part 1 BID [ Time Frame: 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 ]
  Blood samples were collected at indicated time points post ante-meridiem (AM) and post-meridiem (PM) dose for pharmacokinetic analysis of GSK525762.
• Lambda z for GSK525762-Part 1 BID [ Time Frame: 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 ]
  Blood samples were collected at indicated time points post ante-meridiem (AM) and post-meridiem (PM) dose for pharmacokinetic analysis of GSK525762.
• Tmax for GSK525762-Part 1 BID [ Time Frame: 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 ]
  Blood samples were collected at indicated time points post ante-meridiem (AM) and post-meridiem (PM) dose for pharmacokinetic analysis of GSK525762.
• Apparent Clearance of GSK525762-Part 1 BID [ Time Frame: 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 ]
  Blood samples were collected at indicated time points post ante-meridiem (AM) and post-meridiem (PM) dose for pharmacokinetic analysis of GSK525762.
• Volume of Distribution of GSK525762-Part 1 BID [ Time Frame: 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 ]
  Blood samples were collected at indicated time points post ante-meridiem (AM) and post-meridiem (PM) dose for pharmacokinetic analysis of GSK525762.

Original Secondary Outcome Measures (submitted: April 26, 2012)

• Cmax (maximum observed concentrations) (0, 0.5, 1, 2, 4, 8, 24, 48 hours post dose), 8 timepoints up to 6 weeks [ Time Frame: Week 1, Week 4, Week 6 ]
  PK parameter values for GSK525762 following single and repeat-dose oral administration. (0, 0.5, 1, 2, 4, 8, 24, 48 hours post dose), 8 timepoints up to 6 weeks
• AUC (area under concentration-time curve) (0-48 hours post dose); AUC (0-infinity for single dose); AUC (0-tau at steady state) [ Time Frame: 7 Weeks ]
  PK parameter values for GSK525762 following single and repeat-dose oral administration. (0-48 hours post dose); AUC (0-infinity for single dose); AUC (0-tau at steady state)

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Study to Investigate the Safety, Pharmacokinetics, Pharmacodynamics, and Clinical Activity of GSK525762 in Subjects With NUT Midline Carcinoma (NMC) and Other Cancers
• 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
• Brief 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.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 1
• Study Design: Allocation: Non-Randomized; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Carcinoma, Midline

Intervention

Drug: GSK525762

Begin at Dose Level 1 and increase up to 2 fold

Study Arms

• Experimental: Single and Repeat Dose finding cohort
  All 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.
  Intervention: Drug: GSK525762
• Experimental: Expansion Cohort
  Up 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
  Intervention: Drug: GSK525762
• Experimental: Besylate Sub study
  Tablet 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
  Intervention: Drug: GSK525762

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.
• 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.
• 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.
• 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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: March 13, 2020): 196
• Original Estimated Enrollment (submitted: April 26, 2012): 60
• Actual Study Completion Date: July 29, 2019
• Actual Primary Completion Date: April 13, 2018 (Final data collection date for primary outcome measure)

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 16 Years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, France, Korea, Republic of, Netherlands, Spain, United Kingdom, United States
• Removed Location Countries: Canada

Administrative Information

• NCT Number: NCT01587703
• Other Study ID Numbers: 115521; 2014-004982-25 ( EudraCT Number )
• Has Data Monitoring Committee: Not Provided
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: GlaxoSmithKline
• Original Responsible Party: Same as current
• Current Study Sponsor: GlaxoSmithKline
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: GSK Clinical Trials; GlaxoSmithKline

• PRS Account: GlaxoSmithKline
• Verification Date: March 2020