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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/show/NCT01587703




Registration number
NCT01587703
Ethics application status
Date submitted
3/04/2012
Date registered
30/04/2012
Date last updated
10/01/2019

Titles & IDs
Public title
A Study to Investigate the Safety, Pharmacokinetics, Pharmacodynamics, and Clinical Activity of GSK525762 in Subjects With NUT Midline Carcinoma (NMC) and Other Cancers
Scientific 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
Secondary ID [1] 0 0
2014-004982-25
Secondary ID [2] 0 0
115521
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Carcinoma, Midline 0 0
Condition category
Condition code
Cancer 0 0 0 0
Non melanoma skin cancer
Cancer 0 0 0 0
Kidney

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - GSK525762

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.

Experimental: Expansion Cohort - Up to 150 additional subjects with NMC and other solid tumors may be enrolled in expansion cohorts. The recommended Phase 2 (Part 2) dose (RP2D) of GSK525762 will be determined based on the MTD or biologically active dose (example: clinical response), the safety profile and available pharmacodynamic data generated from all subjects in Parts 1

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


Treatment: Drugs: GSK525762
Begin at Dose Level 1 and increase up to 2 fold

Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Overall response rate (RR) by response evaluation criteria in solid tumors (RECIST) 1.1. - To evaluate the clinical activity of GSK525762 in subjects with NUT Midline Carcinoma (NMC) ) and other solid tumors.
Timepoint [1] 0 0
5 weeks
Primary outcome [2] 0 0
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). - To determine Safety, Tolerability and Maximum Tolerated Dose (MTD).
Timepoint [2] 0 0
From start of study treatment until MTD is achieved (Assessed up to 5 weeks).
Primary outcome [3] 0 0
Composite of pharmacokinetic (PK) parameters following single oral administration of GSK525762 as amorphous free-base or besylate tablet. - PK Parameters includes maximum observed plasma concentration (Cmax), time to Cmax (tmax), area under the plasma concentration-time curve (AUC[0-t]), AUC(0-infinity) and apparent terminal phase half-life (t½).
Timepoint [3] 0 0
PK samples will be collected up to 9 weeks.
Secondary outcome [1] 0 0
Cmax (maximum observed concentrations) (0, 2, 4, 8, 12, 24, 48 hours post dose), 7 timepoints up to 9 weeks. - PK parameter values for GSK525762 following single and repeat-dose oral administration. (0, 2, 4, 8, 12, 24, 48 hours post dose) 7 timepoints up to 9 weeks.
Timepoint [1] 0 0
Week 1, Week 2, Week3, Week 9
Secondary outcome [2] 0 0
AUC (area under concentration-time curve) (0-48 hours post dose); AUC (0-infinity for single dose); AUC (0-tau at steady state). - 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).
Timepoint [2] 0 0
7 Weeks
Secondary outcome [3] 0 0
Changes in cardiac safety including QT interval corrected by Fridericia formula (QTcF) following single and repeat-dose oral administration of GSK525762.
Timepoint [3] 0 0
From start of study treatment until 2 years after their last treatment or upon death, whichever is first.
Secondary outcome [4] 0 0
Progression free survival (PFS), time to response, duration of response, overall survival (OS).
Timepoint [4] 0 0
From start of study treatment until 2 years after their last treatment or upon death, whichever is first.
Secondary outcome [5] 0 0
Antitumor response assessed by various imaging modalities.
Timepoint [5] 0 0
From start of study treatment until 2 years after their last treatment or upon death, whichever is first.

Eligibility
Key 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.
Minimum age
16 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key 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.

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Phase 1
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Active, not recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 0 0
GSK Investigational Site - Clayton
Recruitment postcode(s) [1] 0 0
3168 - Clayton
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
Maryland
Country [2] 0 0
United States of America
State/province [2] 0 0
Massachusetts
Country [3] 0 0
United States of America
State/province [3] 0 0
Pennsylvania
Country [4] 0 0
United States of America
State/province [4] 0 0
Tennessee
Country [5] 0 0
United States of America
State/province [5] 0 0
Texas
Country [6] 0 0
Canada
State/province [6] 0 0
Alberta
Country [7] 0 0
France
State/province [7] 0 0
Bordeaux Cedex
Country [8] 0 0
France
State/province [8] 0 0
Lyon Cedex 08
Country [9] 0 0
France
State/province [9] 0 0
Paris Cedex 5
Country [10] 0 0
Korea, Republic of
State/province [10] 0 0
Seoul
Country [11] 0 0
Netherlands
State/province [11] 0 0
Amsterdam
Country [12] 0 0
Spain
State/province [12] 0 0
Barcelona
Country [13] 0 0
Spain
State/province [13] 0 0
Madrid
Country [14] 0 0
Spain
State/province [14] 0 0
Málaga
Country [15] 0 0
United Kingdom
State/province [15] 0 0
Surrey
Country [16] 0 0
United Kingdom
State/province [16] 0 0
Newcastle upon Tyne

Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
Name
GlaxoSmithKline
Address
Country

Ethics approval
Ethics application status

Summary
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 two doses of GSK525762 administered as besylate tablet.
Trial website
https://clinicaltrials.gov/show/NCT01587703
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
GSK Clinical Trials
Address 0 0
GlaxoSmithKline
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries

Summary results
Other publications