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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/show/NCT01943851


Additional trial details provided through ANZCTR are available at the end of this record.


Registration number
NCT01943851
Ethics application status
Date submitted
12/09/2013
Date registered
17/09/2013
Date last updated
14/05/2020

Titles & IDs
Public title
A Dose Escalation Study to Investigate the Safety, Pharmacokinetics (PK), Pharmacodynamics (PD) and Clinical Activity of GSK525762 in Subjects With Relapsed, Refractory Hematologic Malignancies
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 Relapsed, Refractory Hematologic Malignancies
Secondary ID [1] 0 0
2013-000445-39
Secondary ID [2] 0 0
116183
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Neoplasms 0 0
Condition category
Condition code
Cancer 0 0 0 0
Leukaemia - Acute leukaemia
Cancer 0 0 0 0
Leukaemia - Chronic leukaemia

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

Experimental: Part 1: GSK525762 QD Cohort - Subject will be administered a 5 milligram (mg) starting dose of GSK525762, oral tablets, QD. Dose escalations will be performed in Part 1 and dose adjustments are allowed to address tolerability and safety issues. Thereafter, subjects will be enrolled in a standard 3+3 design. Separate dose escalation cohorts will be opened for subjects with AML, NHL, and MM for QD dosing. Dose escalation will continue until an MTD is determined or until a dose of 200 mg per day is reached.

Experimental: Part 1: GSK525762 BID Cohort - Subject will be administered a starting dose of GSK525762, oral tablets, 20 mg BID (12 hours apart, total daily dose of 40 mg). Dose escalations will be performed in Part 1 and dose adjustments are allowed to address tolerability and safety issues. Thereafter, subjects will be enrolled in a standard 3+3 design. Separate dose escalation cohorts will be opened for subjects with AML, NHL, and MM, for BID dosing. Dose escalation will continue until an MTD is determined or until a dose of 200 mg per day is reached.

Experimental: Part 2: GSK525762 dose expansion cohort - After the MTD has been determined in Part1, Part 2 dose expansion cohorts will be opened for AML, NHL and MM.


Treatment: Drugs: GSK525762
GSK525762 1 mg, 10 mg and 30 mg will be supplied as white to off-white, amorphous free base and white to slightly colored crystalline besylate tablets, round, biconvex tablets with no markings. GSK525762 will be administered with 240 milliliter (mL) water.

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

Outcomes
Primary outcome [1] 0 0
Part 1: Safety and tolerability as assessed by adverse events (AEs), serious adverse events (SAEs), dose limiting toxicity (DLT), dose reductions or delays, withdrawals due to toxicities - An event will be considered a DLT if it occurs within the first 3 weeks of treatment and meets one of the protocol defined criteria for DLT, unless it can be clearly established that the event is unrelated to treatment.
Timepoint [1] 0 0
DLTs up to first 3 weeks and follow-up for up to 24 months after last dose
Primary outcome [2] 0 0
Part 1: Safety and tolerability as assessed by changes in safety assessments (e.g., laboratory parameters, vital signs, and cardiac parameters). - Safety and tolerability assessment includes: routine physical examinations, vital sign measurements, echocardiograms, and monitoring of AEs, cardiac safety monitoring consisting of 24 hours of Holter monitoring and triplicate 12-lead ECGs. Laboratory testing includes: hematology, clinical chemistry, pancreatic, coagulation, and liver chemistry panels, testing for troponin, B-type Natriuretic Peptide (BNP), c-peptide, 1,5-Anhydroglucitol (1, 5 AG), Hemoglobin A1c (HbA1c), and thyroid monitoring.
Timepoint [2] 0 0
DLTs up to first 3 weeks and follow-up for up to 24 months after last dose
Primary outcome [3] 0 0
Part 2: Objective response rate per response criteria for AML - Response rate for AML is defined as the percentage of subjects achieving Complete Response (CR), Partial Response (PR), CRp (as per CR but platelet count <100 x 10^9/L) and CRi [as per CR but platelet count <100 x 10^9/L or neutrophil count <1 x 10^9/L], or Partial Response [PR]
Timepoint [3] 0 0
Up to 24 months after last dose
Primary outcome [4] 0 0
Part 2: Objective response rate per response criteria for MM - Response rate for MM is defined as the percentage of subjects that have achieved a stringent CR [sCR], CR, very good partial response (VGPR), or PR
Timepoint [4] 0 0
Up to 24 months after last dose
Primary outcome [5] 0 0
Part 2: Objective response rate per response criteria for NHL - Response rate for NHL is defined as the percentage of subjects that have achieved a CR, or PR.
Timepoint [5] 0 0
Up to 24 months after last dose
Secondary outcome [1] 0 0
Part 1: GSK525762 PK parameters following single- and repeat-dose administration of gsk525762 following QD and/or bid dosing schedules - PK parameters include: Area under concentration-time curve(AUC), Minimum observed concentration (Cmin), Pre-dose (trough) concentration at the end of a dosing interval (Ctau), Maximum observed concentration (Cmax), Time of maximum concentration (tmax), Apparent terminal half-life (t1/2) (or t1/2, eff), time invariance and accumulation ratio
Timepoint [1] 0 0
Week 1 (Days 1, 2,5), Week 2 (Day 4,6,7), Week 3, week 7 and for subjects on study longer than 12 weeks, collect a pre-dose PK sample every 6 weeks
Secondary outcome [2] 0 0
Part 1: Changes in cardiac QT duration corrected for heart rate by Fridericia's formula (QTcF) and other safety parameters in relation to GSK525762 exposure markers - Changes in cardiac QTcF dose and other safety assessment in relation to GSK525762 exposure markers including dose concentration, Cmax, AUC, following single and repeat-dose oral administration of GSK525762 will be measured.
Timepoint [2] 0 0
During weeks 1, 2, 3, 4, 5, 7, and 10 and then every three weeks up to 24 month after last dose.
Secondary outcome [3] 0 0
Part 1: Dose/exposure marker related change in molecular markers in tumor tissue and/or peripheral blood samples. - Tumor tissue and/or peripheral blood samples will be collected for the assessment of dose related change in molecular markers (e.g., gene transcription and/or expression of proteins regulated by Bromodomain [BRD] proteins)
Timepoint [3] 0 0
Up to 24 months after last dose
Secondary outcome [4] 0 0
Part 1: Overall response rate (ORR) for AML, MM, and NHL as a function of dose and exposure markers - AML: The percentage of subjects who achieved CR, CRp, CRi, and PR. A waterfall plot of percent change from baseline in bone marrow blasts and peripheral blasts will be provided. MM: The percentage of subjects who achieved CR, VGPR, or PR. NHL: The percentage of subjects who achieved CR or PR.
Timepoint [4] 0 0
Up to 24 months after last dose
Secondary outcome [5] 0 0
PART 1: safety, tolerability AND AEs, SAEs, DLTs - An event will be considered a DLT if it occurs within the first 3 weeks of treatment and meets one of the protocol defined criteria for DLT, unless it can be clearly established that the event is unrelated to treatment.
Timepoint [5] 0 0
DLTs up to first 3 weeks and follow-up for up to 24 months after last dose
Secondary outcome [6] 0 0
Part 1: ORR as an efficacy measure - AML: The percentage of subjects who achieved CR, CRp, CRi, and PR. A waterfall plot of percent change from baseline in bone marrow blasts and peripheral blasts will be provided. MM: The percentage of subjects who achieved sCR, CR, VGPR, or PR. NHL: The percentage of subjects who achieved CR or PR.
Timepoint [6] 0 0
Up to 24 months after last dose
Secondary outcome [7] 0 0
Part 2: Population PK parameters for GSK525762 - Apparent clearance following oral administration (CL/F) and volume of distribution (V/F), and relevant covariates which may influence exposure (e.g., age, weight, or disease associated covariates).
Timepoint [7] 0 0
Week 1 (Days 1, & 3), Week 4, Week 7 and for subjects on study longer than 10 weeks, collect a pre-dose PK sample every 6 weeks
Secondary outcome [8] 0 0
Part 2: PK/PD relationship between GSK525762 exposure markers and safety and efficacy parameters - The relationship between QTcF and concentration of GSK525762 include: Cmax, average observed concentration (Cav), and instantaneous time-matched concentration. Safety (biomarkers of interest; changes in troponin levels) and efficacy (overall tumor burden) parameters and will be measured against summary exposure measures (e.g., Cmax, pre-dose (trough) concentration at the end of a dosing interval (Ctau), and Cav).
Timepoint [8] 0 0
Up to 24 months after last dose
Secondary outcome [9] 0 0
Part 2: safety and tolerability as assessed by adverse events (AES), serious adverse events (SAES), dose reductions or delays, withdrawals due to toxicities
Timepoint [9] 0 0
Up to 24 months after last dose
Secondary outcome [10] 0 0
Part 2: Safety and tolerability as assessed by changes in safety assessments (e.g., laboratory parameters, vital signs, and cardiac parameters) - Safety and tolerability assessment at RP2D includes: routine physical examinations, vital sign measurements, echocardiograms, and monitoring of AEs, cardiac safety monitoring, 24 hours of Holter monitoring and triplicate 12-lead ECGs. Laboratory testing at RP2D includes: hematology, clinical chemistry, pancreatic, coagulation, and liver chemistry panels, testing for troponin, B-type Natriuretic Peptide (BNP), c-peptide, 1,5-Anhydroglucitol (1, 5 AG), Hemoglobin A1c (HbA1c), and thyroid monitoring
Timepoint [10] 0 0
Up to 24 months after last dose
Secondary outcome [11] 0 0
Part 2: dose /exposure markers related change in molecular markers in tumor tissue and/or peripheral blood samples - Tumor tissue and/or peripheral blood samples will be collected for the assessment of dose related change in molecular markers (e.g., gene transcription and/or expression of proteins regulated by BRD proteins).
Timepoint [11] 0 0
Up to 24 to months after last dose
Secondary outcome [12] 0 0
Part 2: Time to progression (TTP) for subjects with MM - TTP is calculated from the start of treatment defined, until the first documented disease progression or death due to any cause.
Timepoint [12] 0 0
Up to 24 months after last dose
Secondary outcome [13] 0 0
Part 2: Duration of response (DOR) for subjects with MM and NHL - DOR is defined for the subject or subjects with a CR or PR for NHL, and sCR, CR, VGPR, or PR for MM as the time from the first documented evidence response until the first documented disease progression or death due to any cause.
Timepoint [13] 0 0
Up to 24 months after last dose
Secondary outcome [14] 0 0
Part 2: Progression free survival (PFS) for subjects with MM and NHL - PFS is defined as the time elapsed between treatment initiation and tumor progression or death from any cause.
Timepoint [14] 0 0
Up to 24 months after last dose
Secondary outcome [15] 0 0
Efficacy as assessed by dose reductions or delays, withdrawals due to toxicities
Timepoint [15] 0 0
Up to 24 months after last dose
Secondary outcome [16] 0 0
Overall survival (OS) for subjects AML, MM and NHL. - Overall survival (OS) is the time from the treatment start date until death from any cause
Timepoint [16] 0 0
Up to 24 months after last dose

Eligibility
Key inclusion criteria
Inclusion criteria

- Written informed consent provided.

- Males and females 18 years old or older.

- In Part 1 and, Part 2, subjects must have AML, MM, or NHL. Subjects with AML, are
eligible if they • have relapsed and/or refractory disease, OR are>=65 years of age
and not candidates for or have refused standard chemotherapy. Subjects with multiple
myeloma are eligible if they have progressed despite therapy with an alkylating agent,
proteasome inhibitor, and immunomodulatory agent, either as individual regimens or in
combination. Subjects with NHL are eligible if they have received at least two prior
lines of systemic therapy, including at least one line of immunochemotherapy with an
anti-CD20 antibody (if their tumor expresses CD20).

In Part 2, the NHL cohort will separately enrol subjects with double- and triple hit
lymphoma, so that a minimum of 10 subjects with this subset of disease will be enrolled. To
be eligible for this sub-cohort, tumor sample from the subject must demonstrate
rearrangement and/or overexpression of MYC and either BCL2 and/or BCL6 genes. Evaluation of
double- or triple-hit status may be performed via appropriate local testing, and the
determination of double- or triple-hit diagnosis will be at the discretion of the
investigator and GSK Medical Monitor.

- Subjects with a prior history of stem cell transplant (autologous and/or allogeneic)
are allowed if

- At least 3 months has elapsed from the time of transplant and

- the subject has recovered from transplant-associated toxicities prior to the
first dose of GSK525762, and For subjects with a prior history of allogeneic
transplant,

- the subject has been off systemic immunosuppressive medications (including but
not limited to: cyclosporine, tacrolimus, mycophenolate mofetil, or
corticosteroids) for at least 1 month prior to the first dose of GSK525762.
Topical steroids are permitted

- there are no signs or symptoms of graft versus host disease, other than Grade 1
skin involvement.

- Eastern Cooperative Oncology Group (ECOG) performance status of <=1.

- Subject must be stable enough to be expected to complete dosing through the DLT
observation period as assessed by the investigator.

- 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) > 40
milli-International units per milliliter and estradiol < 40 picograms per milliliter
(< 140 picomole per liter) 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 defined in protocol if they wish to continue their HRT during
the study. Otherwise, they must discontinue HRT to allow confirmation of
post-menopausal status prior to study enrolment. For most forms of HRT, at least two
to four 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 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 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 16 weeks
after the last dose of study medication. In addition, male subjects whose partners are
or become pregnant must continue to use condoms for 7 days after stopping study
medications.

- Adequate organ system function.

- Ability to comply with dietary and tobacco/alcohol abstinence requirements.
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Exclusion Criteria

- Haematological malignancy associated with human immunodeficiency virus (HIV) infection
or solid organ transplant or history of known Hepatitis B Antigen or positive
Hepatitis C antibody (confirmed by Recombinant ImmunoBlot Assay [RIBA], if available
or alternately confirmed by Hepatitis C Virus [HCV] Ribonucleic acid [RNA]).

- History or concurrent malignancy of solid tumours, except for below. Exception:
Subjects who have been disease-free for 5 years, or subjects with a history of
completely resected non-melanoma skin cancer or successfully treated in situ carcinoma
are eligible. Subjects with second malignancies that are indolent or definitively
treated may be enrolled even if less than 5 years have elapsed since treatment.
Consult the GSK Medical Monitor if unsure whether second malignancies meet
requirements specified above.

- Currently receiving cancer therapy (chemotherapy, radiation therapy, immuno- therapy,
biologic therapy, hormonal therapy, surgery, and/or tumour embolization).The following
are allowed: Hydroxyurea for proliferative disease, Corticosteroids, Use of
hematopoetic growth factors is permitted at the discretion of the investigator
according to published guidelines (e.g., National Comprehensive Cancer Network (NCCN),
American Society of Clinical Oncology (ASCO), American Society of Hematology (ASH),
etc.). The following are NOT allowed: Investigational anti cancer drug within 2 weeks
prior to the first dose of GSK525762; Major surgery, radiotherapy, or immunotherapy
within 4 weeks of GSK525762 Chemotherapy regimens with delayed toxicity within the
last 4 weeks. Chemotherapy regimens given continuously or on a weekly basis with
limited potential for delayed toxicity within the last 2 weeks.

Nitrosourea or mitomycin C within the last 6 weeks

- Evidence of severe of uncontrolled infection.

- 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, as appropriate.

- Current use of a prohibited medication or requires any of these medications during
treatment with the investigational drugs. This includes excluding current medications
known or suspected to be associated QT prolongation. In addition, any subject who is
expected to 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 Central nervous system (CNS) disease, Subjects with a history
of CNS disease (leukemia, lymphoma or myeloma) are permitted to enrol if they have
previously received appropriate therapy and CNS remission has been documented. Subject
with primary CNS lymphoma (defined as isolated CNS lymphoma without systemic
involvement) are excluded from study.

- Cardiac abnormalities as evidenced by any of the following: History or current
clinically significant uncontrolled arrhythmias or hypertension; 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 or assessments including: Baseline QTcF interval
>=450 milliseconds; 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.

- Evidence of hemoptysis within the last 7 days.

- History of major gastrointestinal bleeding within the last 3 months or any evidence of
active gastrointestinal bleeding excludes the subject.

- Presence of gastrointestinal disease that would significantly affect compound
absorption.

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 2
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Completed
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 - East Melbourne
Recruitment postcode(s) [1] 0 0
3002 - East Melbourne
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
Arkansas
Country [2] 0 0
United States of America
State/province [2] 0 0
Colorado
Country [3] 0 0
United States of America
State/province [3] 0 0
New York
Country [4] 0 0
United States of America
State/province [4] 0 0
Pennsylvania
Country [5] 0 0
United States of America
State/province [5] 0 0
Texas
Country [6] 0 0
Korea, Republic of
State/province [6] 0 0
Seoul
Country [7] 0 0
Spain
State/province [7] 0 0
Barcelona
Country [8] 0 0
Spain
State/province [8] 0 0
Madrid
Country [9] 0 0
Spain
State/province [9] 0 0
Málaga
Country [10] 0 0
Spain
State/province [10] 0 0
Salamanca
Country [11] 0 0
United Kingdom
State/province [11] 0 0
Cambridge
Country [12] 0 0
United Kingdom
State/province [12] 0 0
London

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

Ethics approval
Ethics application status

Summary
Brief summary
This is an open-label repeat dose, multicenter, 2-part study to determine the maximum
tolerated dose (MTD) and the recommended Phase 2 dose (RP2D) for GSK525762 given once-daily
(QD) orally. Part 1 of the study is a dose escalation phase to select the recommended Part 2
dose (RP2D) based on the safety, PK, and PD profiles observed after oral administration of
GSK525762. Eligible subjects with select relapsed refractory hematological malignancies
(acute myeloid leukemia [AML], non-Hodgkin's Lymphoma [NHL]and multiple myeloma [MM]), will
be enrolled in the QD and/or BID dosing cohorts until a MTD is established. Subjects may
continue treatment in the study until disease progression, unacceptable toxicity, or
withdrawal of consent. . Upon determination of the MTD, twice daily (BID) dosing cohorts may
be opened to collect additional safety data and evaluate the preliminary efficacy of
GSK525762 administered BID. Part 2 will explore clinical activity at the MTD or RP2D;
separate expansion cohorts will be planned for acute myeloid leukemia (AML), non-Hodgkin's
Lymphoma (NHL, including an exploratory sub-cohort of subjects with myc and B-Cell Leukemia
(BCL)2 and/or BCL6 rearrangements/overexpression [double- and triple-hit lymphoma]), and
multiple myeloma (MM). This is the first study of this agent to be conducted in subjects with
these relapsed and/or refractory hematological malignancies for which no standard therapies
are anticipated to result in a durable remission.
Trial website
https://clinicaltrials.gov/show/NCT01943851
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

Additional trial details provided through ANZCTR
Accrual to date
Recruiting in Australia
Recruitment state(s)
VIC
Funding & Sponsors
Primary sponsor
Commercial sector/Industry
Primary sponsor name
GlaxoSmithKline
Primary sponsor address
Primary sponsor country
Ethics approval
Ethics application status
Approved
 
Public notes

Contacts
Principal investigator
Title 53 0
Prof
Name 53 0
Mark Dawson
Address 53 0
Peter MacCallum Cancer Center, Melbourne VIC 3000
Country 53 0
Australia
Phone 53 0
Fax 53 0
Email 53 0
Contact person for public queries
Title 54 0
Name 54 0
Address 54 0
Country 54 0
Phone 54 0
Fax 54 0
Email 54 0
GSKClinicalSupportHD@gsk.com
Contact person for scientific queries
Title 55 0
Name 55 0
Address 55 0
Country 55 0
Phone 55 0
Fax 55 0
Email 55 0
GSKClinicalSupportHD@gsk.com