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

This study is currently recruiting participants. (see Contacts and Locations)
Verified June 2015 by GlaxoSmithKline
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline
ClinicalTrials.gov Identifier:
NCT01587703
First received: April 3, 2012
Last updated: June 11, 2015
Last verified: June 2015
  Purpose

This study is divided into two parts; Part 1of 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 two doses of GSK525762 administered as besylate tablet.


Condition Intervention Phase
Carcinoma, Midline
Drug: GSK525762
Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Pharmacokinetics/Dynamics Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
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

Resource links provided by NLM:


Further study details as provided by GlaxoSmithKline:

Primary Outcome Measures:
  • Overall response rate (RR) by response evaluation criteria in solid tumors (RECIST) 1.1. [ Time Frame: 5 weeks ] [ Designated as safety issue: No ]
    To evaluate the clinical activity of GSK525762 in subjects with NUT Midline Carcinoma (NMC) ) and other solid tumors.

  • Adverse event (AEs), serious adverse event s(SAEs), dose reductions or delays, withdrawals due to toxicities and changes in safety assessments (e.g., laboratory parameters, vital signs, electrocardiograms, cardiotoxicity, gastrointestinal, etc). [ Time Frame: From start of study treatment until MTD is achieved (Assessed up to 5 weeks). ] [ Designated as safety issue: No ]
    To determine Safety, Tolerability and Maximum Tolerated Dose (MTD).

  • Composite of pharmacokinetic (PK) parameters following single oral administration of GSK525762 as amorphous free-base or besylate tablet. [ Time Frame: PK samples will be collected up to 9 weeks. ] [ Designated as safety issue: No ]
    PK Parameters includes maximum observed plasma concentration (Cmax), time to Cmax (tmax), area under the plasma concentration-time curve (AUC(0-t) and AUC(0-infinity) and apparent terminal phase half-life (t½).


Secondary Outcome Measures:
  • Cmax (maximum observed concentrations) (0, 0.25, 0.5, 1, 2, 4, 8,16, 24, 33,48 hours post dose), 11 timepoints up to 9 weeks. [ Time Frame: Week 1, Week 2, Week3, Week 9 ] [ Designated as safety issue: No ]
    PK parameter values for GSK525762 following single and repeat-dose oral administration. (0, 0.25, 0.5, 1, 2, 4, 8, 16, 24, 33, 48 hours post dose11 timepoints up to 9 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 ] [ Designated as safety issue: No ]
    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).

  • Changes in cardiac safety including QT interval corrected by Fridericia formula (QTcF) following single and repeat-dose oral administration of GSK525762. [ Time Frame: From start of study treatment until 2 years after their last treatment or upon death, whichever is first. ] [ Designated as safety issue: No ]
  • Progression free survival (PFS), time to response, duration of response, overall survival (OS). [ Time Frame: From start of study treatment until 2 years after their last treatment or upon death, whichever is first. ] [ Designated as safety issue: No ]
  • Antitumor response assessed by various imaging modalities. [ Time Frame: From start of study treatment until 2 years after their last treatment or upon death, whichever is first. ] [ Designated as safety issue: No ]

Estimated Enrollment: 90
Study Start Date: March 2012
Estimated Study Completion Date: March 2018
Estimated Primary Completion Date: March 2018 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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.
Drug: GSK525762
Begin at Dose Level 1 and increase 2 fold
Experimental: Expansion Cohort
Up to 150 additional subjects with NMCand 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
Begin at Dose Level 1 and increase 2 fold
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
Drug: GSK525762
Begin at Dose Level 1 and increase 2 fold

  Eligibility

Ages Eligible for Study:   16 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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 at least 4 weeks 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.
  • 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

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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01587703

Contacts
Contact: US GSK Clinical Trials Call Center 877-379-3718 GSKClinicalSupportHD@gsk.com

Locations
United States, Maryland
GSK Investigational Site Recruiting
Baltimore, Maryland, United States, 21231
Contact: US GSK Clinical Trials Call Center    877-379-3718    GSKClinicalSupportHD@gsk.com   
Contact: EU GSK Clinical Trials Call Center    +44 (0) 20 8990 4466    GSKClinicalSupportHD@gsk.com   
United States, Massachusetts
GSK Investigational Site Recruiting
Boston, Massachusetts, United States, 02215
Contact: US GSK Clinical Trials Call Center    877-379-3718    GSKClinicalSupportHD@gsk.com   
Contact: EU GSK Clinical Trials Call Center    +44 (0) 20 8990 4466    GSKClinicalSupportHD@gsk.com   
United States, Pennsylvania
GSK Investigational Site Recruiting
Philadelphia, Pennsylvania, United States, 19104
Contact: US GSK Clinical Trials Call Center    877-379-3718    GSKClinicalSupportHD@gsk.com   
Contact: EU GSK Clinical Trials Call Center    +44 (0) 20 8990 4466    GSKClinicalSupportHD@gsk.com   
United States, Texas
GSK Investigational Site Recruiting
Houston, Texas, United States, 77030
Contact: US GSK Clinical Trials Call Center    877-379-3718    GSKClinicalSupportHD@gsk.com   
Contact: EU GSK Clinical Trials Call Center    +44 (0) 20 8990 4466    GSKClinicalSupportHD@gsk.com   
Sponsors and Collaborators
GlaxoSmithKline
Investigators
Study Director: GSK Clinical Trials GlaxoSmithKline
  More Information

No publications provided by GlaxoSmithKline

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT01587703     History of Changes
Other Study ID Numbers: 115521
Study First Received: April 3, 2012
Last Updated: June 11, 2015
Health Authority: United States: Food and Drug Administration

Keywords provided by GlaxoSmithKline:
BRD4
BET inhibitor
Small Cell Lung Cancer
MYCN-amplified Solid Tumor
BRD3
NMC
NUT Midline Carcinoma
bromodomains
Colorectal C ancer
Multiple Myeloma
GSK525762
Neuroblastoma
Oncology

Additional relevant MeSH terms:
Carcinoma
Neoplasms
Neoplasms by Histologic Type
Neoplasms, Glandular and Epithelial

ClinicalTrials.gov processed this record on August 27, 2015