Patients with relapsed and/or refractory haematological malignancies (lymphoma, leukemia, or multiple myeloma) MedDRA version: 18.0 Level: LLT Classification code 10066481 Term: Hematological malignancy System Organ Class: 100000004864
Conditions
Interventions
Product Name: GSK525762
Product Code: GSK525762
Pharmaceutical Form: Tablet
INN or Proposed INN: GSK525762
CAS Number: 1260907-17-2
Current Sponsor code: GSK525762
Concentration unit: mg milligram(s)
Sponsors
GlaxoSmithKline Research and Development Limited
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Written informed consent provided. 2. Males and females 18 years old or older. 3. 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 Acute Myeloid Leukemia (AML), Multiple Myeloma (MM), or non-Hodgkin’s Lymphoma (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. 4. Subjects with a prior history of stem cell transplant are allowed if - At least 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 5. Eastern Cooperative Oncology Group (ECOG) performance status of =1. 6. Subject must be stable enough to be expected to complete dosing through the DLT observation period as assessed by the investigator. 7. 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. 8. 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 MlU/mL and estradiol < 40 pg/mL (< 140 pmol/L) 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 (described in section 9.1), for an appropriate period of time (as
Exclusion criteria
Exclusion criteria: 1. 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). 2. 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. 3. Currently receiving cancer therapy (chemotherapy, radiation therapy, immunotherapy, biologic therapy, hormonal therapy, surgery, and/or tumour embolization). Note: the following are allowed: Hydroxyurea for proliferative disease Corticosteroids Use of hematopoetic growthfactors 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.). Note: 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 4. Evidence of severe of uncontrolled infection. 5. 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. 6. 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 (see Section 8.3). In addition, any subject who is expected to require a QT prolonging medication while on trial should not be enrolled. 7. 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. 8. Symptomatic or untreated 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. 9. Cardiac abnormalities as evidenced by any of the following: -History or current clinically sig
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: PART 1 To determine the safety, tolerability and maximum tolerated dose (MTD), following once daily (QD) and/or twice daily (BID) dosing schedules, establishing the recommended Phase 2 dose (RP2D) of GSK525762 in adult subjects with acute leukemia (AML), multiple myeloma (MM), or non-Hodgkin’s lymphoma (NHL). PART 2 To evaluate clinical efficacy after treatment with GSK525762 in acute myeloid leukemia (AML). To evaluate clinical efficacy after treatment with GSK525762 in multiple myeloma (MM) To evaluate clinical efficacy after treatment with GSK525762 in non- Hodgkin’s Lymphoma (NHL);Secondary Objective: PART 1 - To characterize the Pharmacokinetic (PK) of GSK525762 after single- and repeat-dose administration following QD and/or BID dosing schedules. -To evaluate the relationship between GSK525762 exposure and cardiac and other safety parameters following QD and/or BID dosing schedules. -To evaluate the relationship between GSK525762 exposure and pharmacodynamic (PD) response following QD and/or BID dosing schedules. -To evaluate the relationship between GSK525762 dose and exposure with clinical activity of GSK525762. PART 2 -To characterize the PK of GSK525762 in 3 disease specific cohorts of subjects with AML, MM, or NHL after repeat-dose administration. -To evaluate the exposure response (i.e., PK/PD) relationship between GSK525762 and safety/efficacy parameters in 3 disease-specific cohorts of subjects with AML, MM, or NHL.. Please see also protocol page 45;Primary end point(s): PART 1 Adverse Events (AEs), Serious Adverse Events (SAEs), Dose Limiting Toxicity (DLT), dose reductions or delays, withdrawals due to toxicities and changes in safety assessments (e.g., laboratory parameters, vital signs, and cardiac parameters). PART 2 For AML: Objective response rate (% of subjects achieving Complete Response (CR), Partial Response (PR), CRp (as per CR but platelet count <100 x 10^9/L) or morphologic leukemia-free state) per response criter | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): PART 1 GSK525762 PK parameters following single and repeat-dose administration of GSK525762, including Area under concentration-time curve (AUC), Minimum observed concentration (Cmin), Pre-dose (trough) concentration at the end of a dosing interval (CT), Maximum observed concentration (Cmax), Time of maximum concentration (tmax), Apparent terminal half-life (t1/2) (or t1/2, eff), time invariance and accumulation ratio. Changes in cardiac QT duration corrected for heart rate by Fridericia’s formula (QTcF) and other safety parameters in relation to GSK525762 exposure markers (dose, concentration, Cmax, AUC, following single and repeat-dose oral administration of GSK525762 Dose related change in molecular markers (e.g., gene transcription and/or expression of proteins regulated by Bromodomain [BRD] proteins) in tumor tissue and/or peripheral blood samples. Assess overall response rate (RR) according to disease specific assessments for leukemia, multiple myeloma, and non-Hodgkin’s lymphoma. PART 2 Population PK parameters for GSK525762 such as 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). PK/PD relationship between GSK525762 exposure markers and safety and efficacy parameters. AEs, SAEs, dose reductions or delays, withdrawals due to toxicities and changes in safety assessments (e.g., laboratory parameters, vital signs, and cardiac parameters) at RP2D. Dose related change in molecular markers (e.g., gene transcription and/or expression of proteins regulated by BRD proteins) in tumor tissue and/or peripheral blood samples. Overall survival (OS, the time from the treatment start date until death from any cause). ;Timepoint(s) of evaluation of this end point: PART 1 Subjects will be evaluated for secondary endpoints such as pharmacokinetics for the first 3 weeks, at Week 7 and eve | — |
Countries
Spain, United Kingdom, United States
Contacts
Public ContactClinical Trials Helpdesk
GlaxoSmithKline Research and Development Ltd
Outcome results
None listed