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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 November 2014 by GlaxoSmithKline
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline
ClinicalTrials.gov Identifier:
NCT01587703
First received: April 3, 2012
Last updated: November 13, 2014
Last verified: November 2014
  Purpose

This study is divided into three parts; Part 1A (Adult Participants) and 1B (Adolescents and Pediatric Participants)of the study are dose escalation phases to select the recommended dose for Part 2 based on the safety, pharmacokinetic, and pharmacodynamic profiles observed after oral administration of GSK525762. Part 2 of the study will explore the safety, tolerability, pharmacokinetics, pharmacodynamics, and clinical activity of the recommended dose from Part 1 in two cohorts comprised of NMC patients. Approximately 70-90 subjects will be enrolled in the whole study


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:
  • Dose limiting toxicities within first 6 weeks [ Time Frame: 7 Weeks ] [ Designated as safety issue: No ]
    MTD

  • Overall response rate (RR) by RECIST 1.1 [ Time Frame: 7 Weeks ] [ Designated as safety issue: No ]
    To evaluate the clinical activity of GSK525762 in subjects with NUT Midline Carcinoma (NMC) ) and other cancers.

  • AEs, SAEs, dose reductions or delays, withdrawals due to toxicities and changes in safety assessments (e.g., laboratory parameters, vital signs, ECG, cardiotoxicity, gastrointestinal, etc) [ Time Frame: Changes pre-dose to 7 weeks ] [ Designated as safety issue: No ]
    Safety and Tolerability


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)


Estimated Enrollment: 90
Study Start Date: March 2012
Estimated Study Completion Date: December 2014
Estimated Primary Completion Date: December 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Single and Repeat Dose finding cohort
All subjects will follow a "1-3-5-7" dosing model of GSK525762.
Drug: GSK525762
Begin at Dose Level 1 and increase 2 fold
Experimental: Expansion Cohort
Up to 40 additional subjects with NMC may be enrolled in an expansion cohort. 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 1A and 1B for the respective age groups.
Drug: GSK525762
Begin at Dose Level 1 and increase 2 fold

  Eligibility

Ages Eligible for Study:   12 Years to 65 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Part 1A: Male or female 16 years or older, at the time of signing the informed consent.
  • Part 1B: Male or female 12 years to < 15 years, at the time of signing the informed consent.
  • Part 2: Male or female 16 years or older, at the time of signing the informed consent. After completion of Part 1B, male or female 12 years to < 15 years, 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 subject is less than 18 years old, an Assent form and Consent form (replacing "you will" with "your child will" will be required).
  • Diagnosis of one of the following: 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, MM (subjects with history of allotransplant are excluded) and any other solid tumor (e.g., NSCLC) which has been confirmed by clinical testing to be MYCN amplified (amplified is 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.; Pediatric solid tumors in Part 1B must have progressed after receiving at least one prior standard/approved chemotherapy, or where there is no approved therapy, or where standard therapy is refused, may be enrolled.
  • Subjects with solid tumors must demonstrate measurable disease, per RECIST v1.1.
  • All prior treatment- related toxicities must be CTCAE (Version 4.0) less than and equal to Grade 1 (except alopecia) at the time of treatment allocation [NCI-CTCAE, 2009], and stable for 4 weeks or longer at the time of screening evaluation.
  • 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 - greater than and equal to 1.5 X 109/L; Hematologic system: Hemoglobin, Lab values - greater than and equal to 9.5 g/dL (patients that required transfusion or growth factor need to demonstrate stable haemoglobin for 7 days of 9.5 g/dL); Hematologic system: Platelets, Lab values - greater than and equal to 100 X 109/L ); Hematologic system: PT/INR and PTT, Lab values - less than and equal to 1.5 X ULN. Renal system: Creatinine, lab values - less than and equal to 1.5 X ULN; or Renal system: Calculated creatinine clearance [calculated by Cockcroft Gault formula1], lab values - greater than and equal to 50 mL/min; or Renal system: 24-hour urine creatinine clearance, lab values - 24-hour urine creatinine clearance; or Metabolic system: Fasting Serum Glucose, lab values - less than 126 mg/dL. Cardiac system: Ejection fraction, lab values - greater than and equal to LLN by ECHO (minimum of 50%); Cardiac system: Troponin (I or T), lab values - less than and equal to ULN; Cardiac system: Potassium, lab values - greater than and equal to LLN and less than and equal to ULN; Cardiac system: Magnesium, lab values - greater than and equal to LLN. Thyroid system: TSH, lab values greater than and equal to LLN and less than and equal to ULN
  • 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 MlU/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 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 less than and equal to 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 half-life 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.

Exclusion Criteria:

  • Primary malignancy of the central nervous system or malignancies related to HIV 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, major surgery, anti-neoplastic antibody or targeted therapy or immunotherapy within 14 days (or 42 days for prior nitrosoureas or mitomycin C) prior to the first dose of the investigational product. NOTE: Limited palliative radiation is permitted if completed at least 2 weeks prior to first dose of investigational product. Chemotherapy regimens given continuously or on an intermittent basis with limited potential for delayed toxicity are permitted if dosing of that chemotherapy is terminated at least 14 days or five half lives(whichever is longer) prior to the first dose of the investigational products and any therapy related toxicities have resolved to Grade 1 or less.
  • 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 CNS disease (verified with consecutive imaging studies) for >1months months, 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. If patient 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 taken EIAC 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 greater than and equal to 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 EKG findings: Baseline QTcF interval greater than and equal to 450 msec; Any clinically significant ECG assessments should be reviewed 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.
  • Pulmonary hemoptysis greater than 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 (positive guaiac fecal occult blood test) excludes the subject.
  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: November 13, 2014
Health Authority: United States: Food and Drug Administration

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

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

ClinicalTrials.gov processed this record on November 25, 2014