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
- Part 1A: Male or female 16 years or older, at the time of signing the informed
- Part 1B: Male or female 12 years to < 15 years, at the time of signing the informed
- 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
- 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.
- 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
- 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