Clinical trial NCT01587703: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
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
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2012-04-30
Enrollment: 196
Sex: ALL
Minimum age (years): 16
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.


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.

Primary outcomes:
measure: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)-Part 1 QD
timeFrame: Median of 1.38 months of drug exposure
measure: Number of Participants With AEs and SAEs-Part 1 BID
timeFrame: Median of 1.41 months of drug exposure
measure: Number of Participants With AEs and SAEs-Part 2
timeFrame: Median of 1.41 months of drug exposure
measure: Number of Participants With Dose Reductions or Delays-Part 1 QD
timeFrame: Median of 1.38 months of drug exposure
measure: Number of Participants With Dose Reductions or Delays-Part 1 BID
timeFrame: Median of 1.41 months of drug exposure
measure: Number of Participants With Dose Reductions or Delays-Part 2
timeFrame: Median of 1.41 months of drug exposure
measure: Number of Participants With Dose Reductions or Delays-Besylate Sub-study
timeFrame: Median of 1.87 months of drug exposure
measure: Number of Participants Withdrawn Due to Toxicities-Part 1 QD
timeFrame: Median of 1.38 months of drug exposure
measure: Number of Participants Withdrawn Due to Toxicities-Part 1 BID
timeFrame: Median of 1.41 months of drug exposure
measure: Number of Participants Withdrawn Due to Toxicities-Part 2
timeFrame: Median of 1.41 months of drug exposure
measure: Number of Participants Withdrawn Due to Toxicities-Besylate Sub-study
timeFrame: Median of 1.87 months of drug exposure
measure: Number of Participants With Grade Change From Baseline in Clinical Chemistry Data-Part 1 QD
timeFrame: Baseline (pre-dose Week1 Day1) and median of 1.38 months of drug exposure
measure: Number of Participants With Grade Change From Baseline in Clinical Chemistry Data-Part 1 BID
timeFrame: Baseline (pre-dose Week1 Day1) and median of 1.41 months of drug exposure
measure: Number of Participants With Grade Change From Baseline in Clinical Chemistry Data-Part 2
timeFrame: Baseline (pre-dose Week1 Day1) and median of 1.41 months of drug exposure
measure: Number of Participants With Grade Change From Baseline in Clinical Chemistry Data-Besylate Sub-study
timeFrame: Baseline (pre-dose Week1 Day1) and median of 1.87 months of drug exposure
measure: Number of Participants With Grade Change From Baseline in Hematology Data-Part 1 QD
timeFrame: Baseline (pre-dose Week1 Day1) and median of 1.38 months of drug exposure
measure: Number of Participants With Grade Change From Baseline in Hematology Data-Part 1 BID
timeFrame: Baseline (pre-dose Week1 Day1) and median of 1.41 months of drug exposure
measure: Number of Participants With Grade Change From Baseline in Hematology Data-Part 2
timeFrame: Baseline (pre-dose Week1 Day1) and median of 1.41 months of drug exposure
measure: Number of Participants With Grade Change From Baseline in Hematology Data-Besylate Sub-study
timeFrame: Baseline (pre-dose Week1 Day1) and median of 1.87 months of drug exposure
measure: Number of Participants With Maximum Urinalysis Change From Baseline-Part 1 QD
timeFrame: Baseline (pre-dose Week1 Day1) and Weeks 5, 9, 17, 25, 33, 41, 49 and discharge/progression (disc/prog)
measure: Number of Participants With Maximum Urinalysis Change From Baseline Data-Part 1 BID
timeFrame: Baseline (pre-dose Week1 Day1) and Weeks 5,9,17 and discharge/progression
measure: Number of Participants With Maximum Urinalysis Change From Baseline-Part 2
timeFrame: Baseline (pre-dose Week1 Day1), Weeks 5,9,13,25,37, 49, 73, 85 and discharge/progression
measure: Number of Participants With Maximum Urinalysis Change From Baseline-Besylate Sub-study
timeFrame: Baseline (pre-dose Week1 Day1), Weeks 5,9,17,25 and disc/prog
measure: Number of Participants With Changes in Pulse Rate From Baseline-Part 1 QD
timeFrame: Baseline (pre-dose Week1 Day1) and median of 1.38 months of drug exposure
measure: Number of Participants With Changes in Pulse Rate From Baseline-Part 1 BID
timeFrame: Baseline (pre-dose Week1 Day1) and median of 1.41 months of drug exposure
measure: Number of Participants With Changes in Pulse Rate From Baseline-Part 2
timeFrame: Baseline (pre-dose Week1 Day1) and median of 1.41 months of drug exposure
measure: Number of Participants With Changes in Pulse Rate From Baseline-Besylate Sub-study
timeFrame: Baseline (pre-dose Week1 Day1) and median of 1.87 months of drug exposure
measure: Number of Participants With Increase in Blood Pressure From Baseline-Part 1 QD
timeFrame: Baseline (pre-dose Week1 Day1) and median of 1.38 months of drug exposure
measure: Number of Participants With Increase in Blood Pressure From Baseline-Part 1 BID
timeFrame: Baseline (pre-dose Week1 Day1) and median of 1.41 months of drug exposure
measure: Number of Participants With Changes in Blood Pressure From Baseline-Part 2
timeFrame: Baseline (pre-dose Week1 Day1) and median of 1.41 months of drug exposure
measure: Number of Participants With Increase in Blood Pressure From Baseline-Besylate Sub-study
timeFrame: Baseline (pre-dose Week1 Day1) and median of 1.87 months of drug exposure
measure: Number of Participants With Changes in Temperature From Baseline-Part 1 QD
timeFrame: Baseline (pre-dose Week1 Day1) and median of 1.38 months of drug exposure
measure: Number of Participants With Changes in Temperature From Baseline-Part 1 BID
timeFrame: Baseline (pre-dose Week1 Day1) and median of 1.41 months of drug exposure
measure: Number of Participants With Changes in Temperature From Baseline-Part 2
timeFrame: Baseline (pre-dose Week1 Day1) and median of 1.41 months of drug exposure
measure: Number of Participants With Changes in Temperature From Baseline-Besylate Sub-study
timeFrame: Baseline (pre-dose Week1 Day1) and median of 1.87 months of drug exposure
measure: Overall Response Rate-Part 1 QD
timeFrame: Median of 1.38 months of drug exposure
measure: Overall Response Rate-Part 1 BID
timeFrame: Median of 1.41 months of drug exposure
measure: Overall Response Rate-Part 2
timeFrame: Median of 1.41 months of drug exposure
measure: Overall Response Rate-Besylate Sub-study
timeFrame: Median of 1.87 months of drug exposure
measure: Number of Participants With Prostate Specific Antigen (PSA)50 Response-Part 1 QD
timeFrame: Median of 1.38 months of drug exposure
measure: Number of Participants With PSA50 Response Rate-Part 1 BID
timeFrame: Median of 1.41 months of drug exposure
measure: Number of Participants With PSA50 Response-Part 2
timeFrame: Median of 1.41 months of drug exposure
measure: Number of Participants With PSA50 Response-Besylate Sub-study
timeFrame: Median of 1.87 months of drug exposure
measure: 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
timeFrame: 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)
measure: Maximum Observed Concentration (Cmax) of GSK525762-Besylate Sub-study
timeFrame: 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)
measure: Apparent Terminal Phase Elimination Rate Constant (Lambda z) for GSK525762-Besylate Sub-study
timeFrame: 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)
measure: Time to Reach Cmax (Tmax) for GSK525762-Besylate Sub-study
timeFrame: 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)
measure: Number of Participants With Non-serious AEs and SAEs-Besylate Sub-study
timeFrame: Median of 1.87 months of drug exposure
Secondary outcomes:
measure: Number of Participants With Increase in QT Interval Corrected for Heart Rate According to Fridericia's Formula (QTcF)-Part 1 QD
timeFrame: Median of 1.38 months of drug exposure
measure: Number of Participants With Increase in QTcF-Part 1 BID
timeFrame: Median of 1.41 months of drug exposure
measure: Number of Participants With Increase in QTcF-Part 2
timeFrame: Median of 1.41 months of drug exposure
measure: Number of Participants With Increase in QTcF-Besylate Sub-study
timeFrame: Median of 1.87 months of drug exposure
measure: Progression Free Survival-Part 1 QD
timeFrame: Median of 1.38 months of drug exposure
measure: Progression Free Survival-Part 1 BID
timeFrame: Median of 1.41 months of drug exposure
measure: Progression Free Survival-Part 2
timeFrame: Median of 1.41 months of drug exposure
measure: Progression Free Survival-Besylate Sub-study
timeFrame: Median of 1.87 months of drug exposure
measure: Time to Response-Part 1 QD
timeFrame: Median of 1.38 months of drug exposure
measure: Time to Response-Part 1 BID
timeFrame: Median of 1.41 months of drug exposure
measure: Time to Response-Part 2
timeFrame: Median of 1.41 months of drug exposure
measure: Time to Response-Besylate Sub-study
timeFrame: Median of 1.87 months of drug exposure
measure: Duration of Response-Part 1 QD
timeFrame: Median of 1.38 months of drug exposure
measure: Duration of Response-Part 1 BID
timeFrame: Median of 1.41 months of drug exposure
measure: Duration of Response-Part 2
timeFrame: Median of 1.41 months of drug exposure
measure: Duration of Response-Besylate Sub-study
timeFrame: Median of 1.87 months of drug exposure
measure: Overall Survival-Part 1 QD
timeFrame: Median of 1.38 months of drug exposure
measure: Overall Survival-Part 1 BID
timeFrame: Median of 1.41 months of drug exposure
measure: Overall Survival-Part 2
timeFrame: Median of 1.41 months of drug exposure
measure: Overall Survival-Besylate Sub-study
timeFrame: Median of 1.87 months of drug exposure
measure: AUC (0 to t), AUC (0 to 24) and AUC (0 to Inf) of GSK525762-Part 1 QD
timeFrame: 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
measure: Maximum Observed Concentration for GSK525762-Part 1 QD
timeFrame: 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
measure: Lambda z for GSK525762-Part 1 QD
timeFrame: 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
measure: Tmax for GSK525762-Part 1 QD
timeFrame: 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
measure: Apparent Clearance of GSK525762-Part 1 QD
timeFrame: 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
measure: Volume of Distribution of GSK525762-Part 1 QD
timeFrame: 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
measure: AUC (0 to Inf), AUC (0 to 24) and AUC (0 to t) of GSK525762-Part 1 BID
timeFrame: 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
measure: Maximum Observed Concentration of GSK525762-Part 1 BID
timeFrame: 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
measure: Lambda z for GSK525762-Part 1 BID
timeFrame: 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
measure: Tmax for GSK525762-Part 1 BID
timeFrame: 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
measure: Apparent Clearance of GSK525762-Part 1 BID
timeFrame: 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
measure: Volume of Distribution of GSK525762-Part 1 BID
timeFrame: 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
Other outcomes:
Locations:
city: Baltimore
country: United States
facility: GSK Investigational Site
state: Maryland
city: Boston
country: United States
facility: GSK Investigational Site
state: Massachusetts
city: Philadelphia
country: United States
facility: GSK Investigational Site
state: Pennsylvania
city: Nashville
country: United States
facility: GSK Investigational Site
state: Tennessee
city: Houston
country: United States
facility: GSK Investigational Site
state: Texas
city: Clayton
country: Australia
facility: GSK Investigational Site
state: Victoria
city: Bordeaux Cedex
country: France
facility: GSK Investigational Site
city: Lyon Cedex 08
country: France
facility: GSK Investigational Site
city: Paris Cedex 5
country: France
facility: GSK Investigational Site
city: Seoul
country: Korea, Republic of
facility: GSK Investigational Site
city: Seoul
country: Korea, Republic of
facility: GSK Investigational Site
city: Amsterdam
country: Netherlands
facility: GSK Investigational Site
city: Barcelona
country: Spain
facility: GSK Investigational Site
city: Madrid
country: Spain
facility: GSK Investigational Site
city: Málaga
country: Spain
facility: GSK Investigational Site
city: Sutton
country: United Kingdom
facility: GSK Investigational Site
state: Surrey
city: Newcastle upon Tyne
country: United Kingdom
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.