A Dose Escalation Study to Investigate the Safety, Pharmacokinetics (PK), Pharmacodynamics (PD) and Clinical Activity of GSK525762 in Subjects With Relapsed, Refractory Hematologic Malignancies

This study is currently recruiting participants. (see Contacts and Locations)
Verified March 2016 by GlaxoSmithKline
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline
ClinicalTrials.gov Identifier:
NCT01943851
First received: September 12, 2013
Last updated: April 28, 2016
Last verified: March 2016

September 12, 2013
April 28, 2016
May 2014
July 2017   (final data collection date for primary outcome measure)
  • 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 [ Time Frame: DLTs up to first 3 weeks and follow-up for up to 24 months after last dose ] [ Designated as safety issue: No ]
    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.
  • Part 1: Safety and tolerability as assessed by changes in safety assessments (e.g., laboratory parameters, vital signs, and cardiac parameters). [ Time Frame: DLTs up to first 3 weeks and follow-up for up to 24 months after last dose ] [ Designated as safety issue: No ]
    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.
  • Part 2: Objective response rate per response criteria for AML [ Time Frame: Up to 24 months after last dose ] [ Designated as safety issue: No ]
    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), or a morphologic leukemia-free state.
  • Part 2: Objective response rate per response criteria for MM [ Time Frame: Up to 24 months after last dose ] [ Designated as safety issue: No ]
    Response rate for MM is defined as the percentage of subjects that have achieved a CR, very good partial response (VGPR), or PR.
  • Part 2: Objective response rate per response criteria for NHL [ Time Frame: Up to 24 months after last dose ] [ Designated as safety issue: No ]
    Response rate for NHL is defined as the percentage of subjects that have achieved a CR, or PR.
  • 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 [ Time Frame: DLTs up to first 3 weeks and follow-up for up to 24 months after last dose ] [ Designated as safety issue: No ]
    A dose-limiting toxicity (DLT) is defined as a clinically significant AE or abnormal laboratory value assessed as unrelated to disease progression, intercurrent illness, or concomitant medications and occurring during the first 3 weeks after administration of the first dose that meets protocol defined criteria for DLT.
  • Part 1: Safety and tolerability as assessed by changes in safety assessments (e.g., laboratory parameters, vital signs, and cardiac parameters). [ Time Frame: DLTs up to first 3 weeks and follow-up for up to 24 months after last dose ] [ Designated as safety issue: No ]
    Safety and tolerability assessment includes: routine physical examinations, vital sign measurements, echocardiograms, and monitoring of AEs, cardiac safety monitoring consisting of at least 48 hours of telemetry following the first dose, 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
  • Part 2: Objective response rate per response criteria. [ Time Frame: Up to 24 months after last dose ] [ Designated as safety issue: No ]
    Response rate is defined as the percentage of subjects who achieved Complete Response (CR), CRp (as per CR but platelet count <100 x 10^9/L), Partial Response (PR) and a morphologic leukemia-free state among subjects who received at least one dose of treatment in the target population.
Complete list of historical versions of study NCT01943851 on ClinicalTrials.gov Archive Site
  • Part 1: GSK525762 PK parameters following single- (Day 1) and repeat-dose (Day 15) administration of GSK525762 following OD and/or BID dosing schedules [ Time Frame: 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 ] [ Designated as safety issue: No ]
    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
  • 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 [ Time Frame: During weeks 1, 2, 3, 4, 5, 7, and 10 and then every three weeks up to 24 month after last dose. ] [ Designated as safety issue: No ]
    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.
  • Part 1: Dose related change in molecular markers in tumor tissue and/or peripheral blood samples. [ Time Frame: Up to 24 months after last dose ] [ Designated as safety issue: No ]
    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)
  • Part 1: Overall response rate (RR) for AML, MM, and NHL [ Time Frame: Up to 24 months after last dose ] [ Designated as safety issue: No ]
    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.
  • Part 2: Population PK parameters for GSK525762 [ Time Frame: 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 ] [ Designated as safety issue: No ]
    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).
  • Part 2: PK/PD relationship between GSK525762 exposure markers and safety and efficacy parameters [ Time Frame: Up to 24 months after last dose ] [ Designated as safety issue: No ]
    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).
  • Part 2: Safety and tolerability as assessed by adverse events (AEs), serious adverse events (SAEs), dose reductions or delays, withdrawals due to toxicities [ Time Frame: Up to 24 months after last dose ] [ Designated as safety issue: No ]
  • Part 2: Safety and tolerability as assessed by changes in safety assessments (e.g., laboratory parameters, vital signs, and cardiac parameters) [ Time Frame: Up to 24 months after last dose ] [ Designated as safety issue: No ]
    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.
  • Part 2: Dose related change in molecular markers in tumor tissue and/or peripheral blood samples [ Time Frame: Up to 24 to months after last dose ] [ Designated as safety issue: No ]
    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).
  • Overall survival (OS) [ Time Frame: Up to 24 months after last dose ] [ Designated as safety issue: No ]
    Overall survival (OS) is the time from the treatment start date until death from any cause
  • Part 1: GSK525762 PK parameters following single- (Day 1) and repeat-dose (Day 15) administration of GSK525762 [ Time Frame: 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 ] [ Designated as safety issue: No ]
    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
  • Part 1: Changes in cardiac QT duration corrected for heart rate by Fridericia's formula (QTcF) and other safety parameters [ Time Frame: During weeks 1, 2, 3, 4, 5, 7, and 10 and then every three weeks up to 24 month after last dose. ] [ Designated as safety issue: No ]
    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.
  • Part 1: Dose related change in molecular markers in tumor tissue and/or peripheral blood samples. [ Time Frame: Up to 24 months after last dose ] [ Designated as safety issue: No ]
    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)
  • Part 2: PK/PD relationship between GSK525762 exposure markers and safety and efficacy parameters. [ Time Frame: Up to 24 months after last dose ] [ Designated as safety issue: No ]
    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).
  • Part 2: Safety and tolerability assessment of GSK525762 at RP2D. [ Time Frame: Up to 24 months after last dose ] [ Designated as safety issue: No ]
    Safety and tolerability assessment at RP2D includes: routine physical examinations, vital sign measurements, echocardiograms, and monitoring of AEs, cardiac safety monitoring consisting of at least 48 hours of telemetry following the first dose, 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.
  • Part 2: Dose related change in molecular markers in tumor tissue and/or peripheral blood samples. [ Time Frame: Up to 24 to months after last dose ] [ Designated as safety issue: No ]
    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)
Not Provided
Not Provided
 
A Dose Escalation Study to Investigate the Safety, Pharmacokinetics (PK), Pharmacodynamics (PD) and Clinical Activity of GSK525762 in Subjects With Relapsed, Refractory Hematologic Malignancies
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
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 (OD) orally and twice daily (BID) 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 relapsed refractory hematological malignancies will be enrolled in the OD 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. 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.
Not Provided
Interventional
Phase 1
Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Cancer
Drug: GSK525762
GSK525762 1 mg, 10 mg and 30 mg will be supplied as white to off-white, round, biconvex tablets with no markings. GSK525762 will be administered with 240 milliliter (mL) water.
  • Experimental: Part 1: GSK525762 OD Cohort
    Subject will be administered a 5 milligram (mg) starting dose of GSK525762, oral tablets, OD. 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 OD dosing. Dose escalation will continue until an MTD is determined or until a dose of 200 mg per day is reached.
    Intervention: Drug: GSK525762
  • 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.
    Intervention: Drug: GSK525762
  • 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.
    Intervention: Drug: GSK525762
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
180
July 2019
July 2017   (final data collection date for primary outcome measure)

Inclusion criteria

  • Written informed consent provided.
  • Males and females 18 years old or older.
  • In Part 1, subjects must have relapsed and/or refractory hematologic malignancies (leukemias, myeloproliferative neoplasms, lymphomas, and myelomas) for which no standard therapies are available or anticipated to result in remission. In Part 2, subjects must have AML, MM, or NHL. Subjects with AML (Part 1 and Part 2), 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.

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 while on study medication must continue to use condoms for 7 days after stopping study medication.
  • Adequate organ system function.
  • Ability to comply with dietary and tobacco/alcohol abstinence requirements.

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 (or 5 half-lives of the drug, whichever is longer) 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.
Both
18 Years and older
No
Contact: US GSK Clinical Trials Call Center 877-379-3718 GSKClinicalSupportHD@gsk.com
United States,   Australia,   United Kingdom
 
NCT01943851
116183
No
Not Provided
Not Provided
GlaxoSmithKline
GlaxoSmithKline
Not Provided
Study Director: GSK Clinical Trials GlaxoSmithKline
GlaxoSmithKline
March 2016

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP