Myelodysplastic syndrome MedDRA version: 20.0 Level: HLT Classification code 10028536 Term: Myelodysplastic syndromes System Organ Class: 100000004851
Conditions
Interventions
Product Name: GSK2879552
Product Code: GSK2879552
Pharmaceutical Form: Capsule
INN or Proposed INN: Not available
Current Sponsor code: GSK2879552
Concentration unit: mg milligram(s)
Concentration typ
Sponsors
GlaxoSmithKline Research & Development Ltd
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: Subjects elegible for enrolment in the study must meet all the following criteria: 1.Subjects must have IPSS-R high or very high risk myelodysplastic syndromes (MDS) by WHO classification 2.Subjects must have failed hypomethylating treatment where “failure” is defined as: a)Progression (according to 2006 IWG criteria) at any time after initiation of the hypomethylating treatment OR b)Failure to achieve complete or partial response or hematological improvement (HI) (according to 2006 IWG) after at least 4 cycles treatment OR c)Relapse after initial complete or partial response or HI (according to 2006 IWG criteria). 4. Subjects are not a candidate, or have failed allogeneic stem cell transplantation. Subjects who underwent allo-transplant in the past are eligible under following conditions: a)transplant was >2 year prior to enrolment, and b)no evidence of active GVHD 5. Eastern Cooperative Oncology Group (ECOG) performance status of 0-2. 6. Subjects have a life expectancy of at least 12 weeks, in the opinion of 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. All prior treatment-related toxicities must be National Cancer Institute- Common Toxicity Criteria for Adverse Events (NCI-CTCAE), version 4.0 =Grade 1 at the time of enrolment (except for alopecia) 9.Adequate baseline organ function defined by: System Laboratory Values Coagulation:INR and aPTT =10,000 (transfusions permitted to bring platelet count to >10,000) Hepatic:Total bilirubin =1.5 X ULN is acceptable if bilirubin is fractionated and direct bilirubin =65 years) yes F.1.3.1 Number of subjects for this age range 18
Exclusion criteria
Exclusion criteria: Subjects meeting any of the following criteria must not be enrolled in the study: 1.AML according to WHO criteria (i.e. bone marrow blasts >20%) 2.Active hepatitis B or hepatitis C treatment 3.Baseline (pre-dose Day 1) Montreal Cognitive Assessment (MOCA) score of 22 or lower 4.History of or concurrent malignancy of solid tumours, except for below: Exception: Subjects who have been disease-free for 2 years, or subjects with a history of completely resected non-melanoma skin cancer or successfully treated in situ carcinoma are eligible. Consult GSK Medical Monitor if unsure whether second malignancies meet requirements specified above 5.Prior treatment with temozolomide, dacarbazine or procarbazine 6.Prior treatment with poly ADP ribose polymerase (PARP) inhibitors (e.g., olaparib, ABT-888) 7.Currently receiving other anti-cancer therapy (chemotherapy, radiation therapy, immuno- therapy, biologic therapy, hormonal therapy, surgery, and/or tumour embolization) 8.Received major surgery, radiotherapy, or immunotherapy within 4 weeks of GSK2879552 administration 9.Evidence of severe or uncontrolled systemic diseases (e.g., severe/chronic infection, unstable or uncompensated respiratory, renal, or cardiac disease). 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 10.Current active liver or biliary disease (with the exception of Gilbert's syndrome or asymptomatic gallstones or otherwise stable chronic liver disease per investigator’s assessment) 11.Patients with any major bleeding within the past 4 weeks. (e.g. recent GI hemorrhage or neurosurgery). 12.Administration of an investigational drug within 14 days or 5 half-lives, whichever is shorter, preceding the first dose of study treatment(s) in this study. 13.Cardiac abnormalities as evidenced by any of the following: -Clinically significant uncontrolled arrhythmias or uncontrolled hypertension. -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 -Baseline QTc interval using Fridericia’s formula >450 msec or >480 msec in or >480 msec in subjects with Bundle Branch Block. QTc value based on single or average of triplicate ECGs obtained over a brief recording period 14. Current use of a prohibited medication including anticoagulants or platelet inhibitors or expected to require any of these medications during treatment with the investigational drug 15. Consumption of Seville oranges, grapefruit, grapefruit hybrids, grapefruit juice, pommelos, or exotic citrus fruits, from 1 day prior to the first dose of study treatment(s) until the last dose of study drug 16. Lactating female 17. Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to GSK2879552 or LSD1 inhibitors that contraindicates their participation 18. Known hypersensitivity to azacitidine or mannitol
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Part I. To determine the recommended phase 2 dose (RP2D) of GSK2879552 administered alone and in combination with azacitidine in adult subjects with HR MDS previously treated with HMA. Part II. To evaluate clinical activity after treatment with GSK2879552, alone or in combination with azacitidine, in adult subjects with HR MDS previously treated with HMA.;Secondary Objective: PartI. 1. To evaluate clinical activity after treatment with GSK2879552, alone or in combination with azacitidine, in adult subjects with HR MDS previously treated with HMA. 2. To measure the exposure to GSK2879552 alone and to GSK2879552 and azacitidine in combination, in patients with HR MDS previously treated with HMA. 3. To evaluate duration of response, duration of clinical benefit, progression-free survival and overall survival. 4. To evaluate frequency and time to progression to AML (per 2006 IWG criteria). 5. To evaluate platelet and RBC transfusion dependence Part II. 1. To further evaluate the safety and tolerability of GSK2879552 administered alone or in combination with azacitidine. 2. To characterize the population PK of GSK2879552, alone or in combination with azacitidine in patients with HR MDS previously treated with HMA. 3. To evaluate duration of response, duration of clinical benefit, progression-free survival, and overall survival. Please see protocol;Primary end point(s): Part 1: AEs, SAEs, dose limiting toxicities, dose reductions or delays, withdrawals due to toxicities and changes in safety parameters (e.g., laboratory values, vital signs, electrocardiograms [ECGs], physical examinations). Part 2: Clinical benefit rate (CBR) defined as % of subjects achieving CR, mCR, PR, cytogenetic response, HI or SD. Objective response rate (ORR) defined as % of subjects achieving CR, mCR, PR, cytogenetic response, or HI [as per 2006 IWG criteria]).;Timepoint(s) of evaluation of this end point: AEs/SAEs are evaluated throughout the trial at each visit. The rest of sa | — |
Secondary
| Measure | Time frame |
|---|---|
| Timepoint(s) of evaluation of this end point: These parameters are evaluated at planned visit per Time and Event table in the protocol.;Secondary end point(s): Part1. Clinical benefit rate (CBR) defined as % of subjects achieving CR, mCR, PR, cytogenetic response, hematologic improvement (HI) or SD. Objective response rate (ORR) defined as % of subjects achieving CR, mCR, PR, cytogenetic response, or HI [as per 2006 IWG criteria]). 2. GSK2879552 and azacitidine concentrations pre-dose and post-dose. 3. Duration of response (DOR) defined as the time from first documented response to disease progression. Progression-free survival (PFS) defined as the time from first dosing day to disease progression or death from any cause. Overall survival (OS) defined as the time from first dosing day until death from any cause. 4. Proportion of subjects with disease progression to AML. Time to AML progression. 5. Number of documented platelet and RBC transfusions per month prior to study entry and on study. PartII. 1. Changes in safety parameters: e.g. AEs and SAEs, changes in laboratory values, vital signs, electrocardiograms [ECGs], and physical examinations. 2. Population PK parameters for GSK2879552 such as clearance (CL/F). 3. Duration of response (DOR) defined as the time from first documented response to disease progression. Progression free survival (PFS) defined as the time from first dosing day to disease progression or death from any cause. Overall survival (OS) defined as the time from first dosing day until death from any cause. Proportion of subjects with disease progression to AML. Time to AML progression. 5. Number of documented platelet and RBC transfusions per month within 3 months prior to study entry and while on study | — |
Countries
Canada, Spain, United States
Contacts
Public ContactClinical Trials HelpDesk
GlaxoSmithKline Research & Development Ltd
Outcome results
None listed