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 not yet open for participant recruitment. (see Contacts and Locations)
Verified May 2014 by GlaxoSmithKline
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline
ClinicalTrials.gov Identifier:
NCT01943851
First received: September 12, 2013
Last updated: May 22, 2014
Last verified: May 2014
  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 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 dosing cohorts until a MTD is established. Subjects may continue treatment in the study until disease progression, unacceptable toxicity, withdrawal of consent, or commercial supply of GSK525762 becomes available to the subject. An expansion cohort (Part 2) is planned in subjects with acute leukemias to further explore clinical activity at the MTD. 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.


Condition Intervention Phase
Cancer
Drug: GSK525762
Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
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

Resource links provided by NLM:


Further study details as provided by GlaxoSmithKline:

Primary Outcome Measures:
  • 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.


Secondary Outcome Measures:
  • 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)


Estimated Enrollment: 70
Study Start Date: May 2014
Estimated Study Completion Date: June 2015
Estimated Primary Completion Date: June 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Part 1
Subject will be administered with a 5 milligram (mg) starting dose of GSK525762, oral tablets, once daily. Dose escalations will be performed in Part 1 and dose adjustments are allowed to address tolerability and safety issues. Dose escalation will continue until an MTD is determined or until a dose of 100 mg per day is reached.
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 2
After the MTD has been determined in Part1, Part 2 dose expansion cohorts will be opened.
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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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 a diagnosis of relapsed and/or refractory Acute Myeloid Leukemia (AML). AML subjects >=65 years of age who are not candidates for or have refused standard chemotherapy.
  • Subjects who have previously received an autologous stem cell transplant are allowed if a minimum of 3 months has elapsed from the time of transplant (T0) and the subject has recovered from transplant-associated toxicities prior to the first dose of GSK525762.
  • 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 4 weeks 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.
  • 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] 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 for leukemia, 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

  • Subjects with prior allogeneic stem cell transplant are excluded.
  • Current use of anticoagulants (e.g., warfarin, heparin) at therapeutic levels within 14 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 leptomeningeal or brain metastases or spinal cord compression, other compressive mass, uncontrolled painful lesion, bone fracture, etc (e.g., change in mental status, focal weakness). Subjects are permitted to enrol if they were previously treated for CNS leukemia or brain metastases and have had stable central nervous system (CNS) disease (verified with consecutive imaging studies) for >2 months, are asymptomatic and off corticosteroids, or are on stable dose of corticosteroids for at least 1 month prior to study Day 1.
  • 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.
  • No evidence of pulmonary 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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01943851

Contacts
Contact: US GSK Clinical Trials Call Center 877-379-3718 GSKClinicalSupportHD@gsk.com

Locations
United States, Texas
GSK Investigational Site Not yet recruiting
Houston, Texas, United States, 77030
Contact: US GSK Clinical Trials Call Center    877-379-3718    GSKClinicalSupportHD@gsk.com   
Contact: EU GSK Clinical Trials Call Center    +44 (0) 20 8990 4466    GSKClinicalSupportHD@gsk.com   
United Kingdom
GSK Investigational Site Not yet recruiting
Cambridge, United Kingdom, CB2 0QQ
Contact: US GSK Clinical Trials Call Center    877-379-3718    GSKClinicalSupportHD@gsk.com   
Contact: EU GSK Clinical Trials Call Center    +44 (0) 20 8990 4466    GSKClinicalSupportHD@gsk.com   
GSK Investigational Site Not yet recruiting
London, United Kingdom, W12 0NN
Contact: US GSK Clinical Trials Call Center    877-379-3718    GSKClinicalSupportHD@gsk.com   
Contact: EU GSK Clinical Trials Call Center    +44 (0) 20 8990 4466    GSKClinicalSupportHD@gsk.com   
Sponsors and Collaborators
GlaxoSmithKline
Investigators
Study Director: GSK Clinical Trials GlaxoSmithKline
  More Information

No publications provided

Responsible Party: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT01943851     History of Changes
Other Study ID Numbers: 116183
Study First Received: September 12, 2013
Last Updated: May 22, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by GlaxoSmithKline:
leukemia
Acute myeloid leukemia
BET inhibitor
lymphoma
Myelodysplastic syndromes
Oncology
multiple myeloma
GSK525762

Additional relevant MeSH terms:
Hematologic Neoplasms
Neoplasms by Site
Neoplasms
Hematologic Diseases

ClinicalTrials.gov processed this record on July 26, 2014