A phase I/II, open-label, 2 arm study to investigate the safety, clinical activity, pharmacokinetics and pharmacodynamics of GSK2879552 administered alone or in combination with azacitidine, in adult subjects with very high risk myelodysplastic syndromes (MDS) previously treated with hypomethylating agents (HMA)
- Conditions
- Myelodysplastic syndromeMedDRA version: 20.0Level: HLTClassification code 10028536Term: Myelodysplastic syndromesSystem Organ Class: 100000004851Therapeutic area: Diseases [C] - Cancer [C04]
- Registration Number
- EUCTR2016-002294-35-ES
- Lead Sponsor
- GlaxoSmithKline Research & Development Ltd
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- ot Recruiting
- Sex
- All
- Target Recruitment
- 78
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 =<1.3 X ULN
Hematologic: PLT>10,000 (transfusions permitted to bring platelet count to >10,000)
Hepatic:Total bilirubin=< 1.5 X ULNa; ALT=< 2.5 x ULN
RenalCreatinine=1.5 X ULN
Calculated creatinine clearance by Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation (Appendix 3) or measured from 24hr urine = 50 mL/min
Cardiac: Ejection Fraction= LLN by Echocardiogram (ECHO) or MUGA
a.Isolated bilirubin >1.5 X ULN is acceptable if bilirubin is fractionated and direct bilirubin <35% or subject has a diagnosis of Gilbert’s syndrome
10.Women of childbearing potential must have a negative serum pregnancy test within 7 days of first dose of study treatment and agree to use effective contraception, during the study and for 7 days following the last dose of study treatment.
11.Men with a female partner of childbearing potential must have either had a prior vasectomy or agree to use effective contraception, , from the administration of the first dose of study treatment until 3 months after the last dose of study treatment to allow for clearance of any altered sperm.
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 6
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 18
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
Study & Design
- Study Type
- Interventional clinical trial of medicinal product
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method
- Secondary Outcome Measures
Name Time Method