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

NCT01587703 | Completed Phase 1 Results

• 2 other identifiers: 1155212014-004982-25
• Study Type: interventional
• Target: 196
• Locations: 7 countries
• Sites: 17

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.

Conditions

Carcinoma, Midline

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

Outcome Measures

Primary Outcomes (48)

• 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.

  Median of 1.38 months of drug exposure

• 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

  Median of 1.41 months of drug exposure

• 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.

  Median of 1.41 months of drug exposure

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

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

  Median of 1.38 months of drug exposure

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

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

  Median of 1.41 months of drug exposure

• Number of Participants With Dose Reductions or Delays-Part 2

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

  Median of 1.41 months of drug exposure

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

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

  Median of 1.87 months of drug exposure

• Number of Participants Withdrawn Due to Toxicities-Part 1 QD

  Number of participants withdrawn due to toxicities is presented.

  Median of 1.38 months of drug exposure

• Number of Participants Withdrawn Due to Toxicities-Part 1 BID

  Number of participants withdrawn due to toxicities is presented.

  Median of 1.41 months of drug exposure

• Number of Participants Withdrawn Due to Toxicities-Part 2

  Number of participants withdrawn due to toxicities is presented.

  Median of 1.41 months of drug exposure

• Number of Participants Withdrawn Due to Toxicities-Besylate Sub-study

  Number of participants withdrawn due to toxicities is presented.

  Median of 1.87 months of drug exposure

• 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.

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

• 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.

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

• 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.

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

• 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.

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

• 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.

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

• 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.

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

• 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.

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

• 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.

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

• 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.

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

• 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.

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

• 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.

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

• 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.

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

• 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

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

• 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.

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

• 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.

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

• 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.

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

• 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

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

• 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

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

• 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.

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

• 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.

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

• 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.

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

• 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.

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

• 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.

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

• 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.

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

• 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.

  Median of 1.38 months of drug exposure

• 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.

  Median of 1.41 months of drug exposure

• 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.

  Median of 1.41 months of drug exposure

• 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.

  Median of 1.87 months of drug exposure

• 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.

  Median of 1.38 months of drug exposure

• 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.

  Median of 1.41 months of drug exposure

• 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.

  Median of 1.41 months of drug exposure

• 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.

  Median of 1.87 months of drug exposure

• 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.

  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)

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

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

  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)

• 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.

  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)

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

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

  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)

• 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

  Median of 1.87 months of drug exposure

Secondary Outcomes (32)

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

  Median of 1.38 months of drug exposure

• Number of Participants With Increase in QTcF-Part 1 BID

  Median of 1.41 months of drug exposure

• Number of Participants With Increase in QTcF-Part 2

  Median of 1.41 months of drug exposure

• Number of Participants With Increase in QTcF-Besylate Sub-study

  Median of 1.87 months of drug exposure

• Progression Free Survival-Part 1 QD

  Median of 1.38 months of drug exposure

Study Arms (3)

Single and Repeat Dose finding cohort

EXPERIMENTAL

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.

Drug: GSK525762

Expansion Cohort

EXPERIMENTAL

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

Drug: GSK525762

Besylate Sub study

EXPERIMENTAL

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

Drug: GSK525762

Interventions

GSK525762 DRUG

Begin at Dose Level 1 and increase up to 2 fold

Besylate Sub study; Expansion Cohort; Single and Repeat Dose finding cohort

Eligibility Criteria

• Age: 16 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• GlaxoSmithKline: lead

Study Sites (17)

GSK Investigational Site

Baltimore, Maryland, 21231-2410, United States

Location

GSK Investigational Site

Boston, Massachusetts, 02215, United States

Location

GSK Investigational Site

Philadelphia, Pennsylvania, 19104, United States

Location

GSK Investigational Site

Nashville, Tennessee, 37232, United States

Location

GSK Investigational Site

Houston, Texas, 77030, United States

Location

GSK Investigational Site

Clayton, Victoria, 3168, Australia

Location

GSK Investigational Site

Bordeaux, 33076, France

Location

GSK Investigational Site

Lyon, 69373, France

Location

GSK Investigational Site

Paris, 75248, France

Location

GSK Investigational Site

Amsterdam, 1066 CX, Netherlands

Location

GSK Investigational Site

Seoul, 03080, South Korea

Location

GSK Investigational Site

Seoul, 03722, South Korea

Location

GSK Investigational Site

Barcelona, 08035, Spain

Location

GSK Investigational Site

Madrid, 28040, Spain

Location

GSK Investigational Site

Málaga, 29010, Spain

Location

GSK Investigational Site

Sutton, Surrey, SM2 5PT, United Kingdom

Location

GSK Investigational Site

Newcastle upon Tyne, NE7 7DN, United Kingdom

Location

Related Publications (4)

• 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.

  PMID: 32328561 BACKGROUND

• 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.

  PMID: 34724226 DERIVED

• 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.

  PMID: 33955700 DERIVED

• 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.

  PMID: 24457244 DERIVED

MeSH Terms

Conditions

Carcinoma; Small Cell Lung Carcinoma; Multiple Myeloma; Neuroblastoma; Neoplasms

Interventions

molibresib

Condition Hierarchy (Ancestors)

Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Lung Diseases; Respiratory Tract Diseases; Neoplasms, Plasma Cell; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Paraproteinemias; Blood Protein Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Hemorrhagic Disorders; Lymphoproliferative Disorders; Immunoproliferative Disorders; Immune System Diseases; Neuroectodermal Tumors, Primitive, Peripheral; Neuroectodermal Tumors, Primitive; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue

Results Point of Contact

• Title: GSK Response Center
• Organization: GlaxoSmithKline

GSKClinicalSupportHD@gsk.com

866-435-7343

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 3, 2012
• First Posted: April 30, 2012
• Study Start: March 28, 2012
• Primary Completion: April 13, 2018
• Study Completion: July 29, 2019
• Last Updated: March 16, 2020
• Results First Posted: March 16, 2020

Record last verified: 2020-03

Locations

FR (3); US (5); ES (3); GB (2); NL (1); KR (2); AU (1)