Last updated: 09/06/2024 11:11:04
A dose escalation study to investigate the safety, pharmacokinetics (PK), pharmacodynamics (PD) and clinical activity of GSK525762 in subjects with relapsed, refractory hematologic malignancies
Clinicaltrials.gov ID
EudraCT ID
EU CT Number
Not applicable
Trial status
Completed
Completed
Trial overview
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
Trial 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.
Primary purpose:
Treatment
Trial design:
Single Group Assignment
Masking:
None (Open Label)
Allocation:
Non-randomized
Primary outcomes:
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
Timeframe: DLTs up to first 3 weeks and follow-up for up to 24 months after last dose
Part 1: Safety and tolerability as assessed by changes in safety assessments (e.g., laboratory parameters, vital signs, and cardiac parameters).
Timeframe: DLTs up to first 3 weeks and follow-up for up to 24 months after last dose
Part 2: Objective response rate per response criteria for AML
Timeframe: Up to 24 months after last dose
Part 2: Objective response rate per response criteria for MM
Timeframe: Up to 24 months after last dose
Part 2: Objective response rate per response criteria for NHL
Timeframe: Up to 24 months after last dose
Secondary outcomes:
Part 1: GSK525762 PK parameters following single- and repeat-dose administration of gsk525762 following QD and/or bid dosing schedules
Timeframe: 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
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
Timeframe: During weeks 1, 2, 3, 4, 5, 7, and 10 and then every three weeks up to 24 month after last dose.
Part 1: Dose/exposure marker related change in molecular markers in tumor tissue and/or peripheral blood samples.
Timeframe: Up to 24 months after last dose
Part 1: Overall response rate (ORR) for AML, MM, and NHL as a function of dose and exposure markers
Timeframe: Up to 24 months after last dose
PART 1: safety, tolerability AND AEs, SAEs, DLTs
Timeframe: DLTs up to first 3 weeks and follow-up for up to 24 months after last dose
Part 1: ORR as an efficacy measure
Timeframe: Up to 24 months after last dose
Part 2: Population PK parameters for GSK525762
Timeframe: 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
Part 2: PK/PD relationship between GSK525762 exposure markers and safety and efficacy parameters
Timeframe: Up to 24 months after last dose
Part 2: safety and tolerability as assessed by adverse events (AES), serious adverse events (SAES), dose reductions or delays, withdrawals due to toxicities
Timeframe: Up to 24 months after last dose
Part 2: Safety and tolerability as assessed by changes in safety assessments (e.g., laboratory parameters, vital signs, and cardiac parameters)
Timeframe: Up to 24 months after last dose
Part 2: dose /exposure markers related change in molecular markers in tumor tissue and/or peripheral blood samples
Timeframe: Up to 24 to months after last dose
Part 2: Time to progression (TTP) for subjects with MM
Timeframe: Up to 24 months after last dose
Part 2: Duration of response (DOR) for subjects with MM and NHL
Timeframe: Up to 24 months after last dose
Part 2: Progression free survival (PFS) for subjects with MM and NHL
Timeframe: Up to 24 months after last dose
Efficacy as assessed by dose reductions or delays, withdrawals due to toxicities
Timeframe: Up to 24 months after last dose
Overall survival (OS) for subjects AML, MM and NHL.
Timeframe: Up to 24 months after last dose
Interventions:
Drug: GSK525762
Enrollment:
111
Observational study model:
Not applicable
Primary completion date:
2020-30-04
Time perspective:
Not applicable
Clinical publications:
Bell C; Fennell K; Chan YC; Rambow F; Yeung M; Vassiliadis D; Lara L; Yeh P; Martelotto L; Rogiers A; Kremer B; Barbash O; Mohammad H; Johanson T; Burr M; Dhar A; Karpinich N; Tian L; Tyler D; MacPherson L; Shi J; Pinnawala N; Fong CY; Papenfuss A; Grimmond S; Dawson SJ; Allan R; Kruger R; Vakoc C; Goode D; Naik S; Gilan O; Lam E; Marine JC; Prinjha R; and Dawson M.Enhancer remodeling overcomes therapeutic resistance driven by epigenetic evolution in cancer.Nature.2019;
Medical condition
Neoplasms
Product
molibresib
Collaborators
Not applicable
Study date(s)
May 2014 to April 2020
Type
Interventional
Phase
2
Participation criteria
Sex
Female & Male
Age
18+ years
Accepts healthy volunteers
No
- Inclusion criteria
- Written informed consent provided.
Inclusion and exclusion criteria
Inclusion criteria:
- Inclusion criteria
- Written informed consent provided.
- Males and females 18 years old or older.
- 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.
- 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.
In Part 1 and, Part 2, subjects must have AML, MM, or NHL. Subjects with AML, are eligible if they
Subjects with a prior history of stem cell transplant (autologous and/or allogeneic) are allowed if
Trial location(s)
Location
GSK Investigational Site
Aurora, Colorado, United States, 80045
Status
Study Complete
Location
GSK Investigational Site
East Melbourne, Victoria, Australia, 3002
Status
Study Complete
Location
GSK Investigational Site
Little Rock, Arkansas, United States, 72205
Status
Study Complete
Location
GSK Investigational Site
New York, New York, United States, 10065
Status
Study Complete
Location
GSK Investigational Site
Philadelphia, Pennsylvania, United States, 19104
Status
Study Complete
Study documents
Study report synopsis
Available language(s): English
Protocol
Available language(s): English
Statistical analysis plan
Available language(s): English
If you wish to request for full study report, please contact - [email protected]
Results overview
Refer to study documents
Recruitment status
Completed
Actual primary completion date
2020-30-04
Actual study completion date
2020-30-04
Plain language summaries
Plain language summaries of clinical trial results for Phase 2-4 clinical trials that were initiated on or after January 2022 will be posted by GSK within one year following study completion.
Additional information about the trial
Additional information
Not applicable
Participate in clinical trial
Access to clinical trial data by researchers
Visit website