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

NCT01943851

Description:

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.

Related Conditions:
  • Acute Myeloid Leukemia
  • Hematopoietic and Lymphoid Malignancy
  • Multiple Myeloma
  • Non-Hodgkin Lymphoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief 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
  • 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 Relapsed, Refractory Hematologic Malignancies

Clinical Trial IDs

  • ORG STUDY ID: 116183
  • NCT ID: NCT01943851

Conditions

  • Cancer

Interventions

DrugSynonymsArms
GSK525762Part 1: GSK525762 QD Cohort

Purpose

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 Arms

NameTypeDescriptionInterventions
Part 1: GSK525762 QD CohortExperimentalSubject 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.
  • GSK525762
Part 1: GSK525762 BID CohortExperimentalSubject 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.
  • GSK525762
Part 2: GSK525762 dose expansion cohortExperimentalAfter the MTD has been determined in Part1, Part 2 dose expansion cohorts will be opened for AML, NHL and MM.
  • GSK525762

Eligibility 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.

        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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

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
Safety Issue:
Description: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.

Secondary Outcome Measures

Measure:Part 1: GSK525762 PK parameters following single- and repeat-dose administration of gsk525762 following QD 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
Safety Issue:
Description: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
Measure: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.
Safety Issue:
Description: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.
Measure:Part 1: Dose/exposure marker related change in molecular markers in tumor tissue and/or peripheral blood samples.
Time Frame:Up to 24 months after last dose
Safety Issue:
Description: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)
Measure:Part 1: Overall response rate (ORR) for AML, MM, and NHL as a function of dose and exposure markers
Time Frame:Up to 24 months after last dose
Safety Issue:
Description: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.
Measure:PART 1: safety, tolerability AND AEs, SAEs, DLTs
Time Frame:DLTs up to first 3 weeks and follow-up for up to 24 months after last dose
Safety Issue:
Description: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.
Measure:Part 1: ORR as an efficacy measure
Time Frame:Up to 24 months after last dose
Safety Issue:
Description: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.
Measure: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
Safety Issue:
Description: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).
Measure:Part 2: PK/PD relationship between GSK525762 exposure markers and safety and efficacy parameters
Time Frame:Up to 24 months after last dose
Safety Issue:
Description: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).
Measure: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
Safety Issue:
Description:
Measure: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
Safety Issue:
Description: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
Measure:Part 2: dose /exposure markers related change in molecular markers in tumor tissue and/or peripheral blood samples
Time Frame:Up to 24 to months after last dose
Safety Issue:
Description: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).
Measure:Part 2: Time to progression (TTP) for subjects with MM
Time Frame:Up to 24 months after last dose
Safety Issue:
Description:TTP is calculated from the start of treatment defined, until the first documented disease progression or death due to any cause.
Measure:Part 2: Duration of response (DOR) for subjects with MM and NHL
Time Frame:Up to 24 months after last dose
Safety Issue:
Description: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.
Measure:Part 2: Progression free survival (PFS) for subjects with MM and NHL
Time Frame:Up to 24 months after last dose
Safety Issue:
Description:PFS is defined as the time elapsed between treatment initiation and tumor progression or death from any cause.
Measure:Efficacy as assessed by dose reductions or delays, withdrawals due to toxicities
Time Frame:Up to 24 months after last dose
Safety Issue:
Description:
Measure:Overall survival (OS) for subjects AML, MM and NHL.
Time Frame:Up to 24 months after last dose
Safety Issue:
Description:Overall survival (OS) is the time from the treatment start date until death from any cause

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:GlaxoSmithKline

Trial Keywords

  • leukemia
  • Acute myeloid leukemia
  • BET inhibitor
  • lymphoma
  • Myelodysplastic syndromes
  • Oncology
  • multiple myeloma
  • GSK525762

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