A phase I open-label, dose escalation study to investigate the safety, pharmacokinetics, pharmacodynamics and clinical activity of GSK2879552 given orally in subjects with relapsed/refractory acute myeloid leukemia
The goal of this clinical research study is to find the highest tolerable dose of the study drug, GSK2879552, that can be given alone or in combination with ATRA to patients with AML. Researchers also want to learn if the drug may be able to help to control the disease. This study is made up of 2 parts, each with 2 sub-parts. Part 1 will test different doses and schedules for giving GSK2879552. Part 2 will continue testing the recommended dose from Part 1. In both Parts 1 and 2, there will be a "Mono Arm" (in which only GSK2879552 is given) and a "Combination Arm" (in which GSK2879552 and ATRA are given). This consent form is for Part 1 "combination arm" only.
Disease Group: Malignant neoplasms stated as primary lymphoid haematopoietic
Treatment Agent: GSK2879552
Treatment Location: Both at MDACC & and Other Sites
Part 1: Escalation Cohort Primary: To determine the safety, tolerability, maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) and regimen of GSK2879552, alone or in combination with ATRA, given orally in adult subjects with acute myeloid leukemia (AML). Secondary: To characterize the pharmacokinetic (PK) of GSK2879552, alone or in combination with ATRA, after single- and repeat-dose oral administration. To evaluate clinical response after treatment with GSK2879552, alone or in combination with ATRA,. To evaluate the relationship between GSK2879552 exposure, alone or in combination with ATRA, and safety/efficacy/ pharmacodynamic (PD) parameters. To characterize the PK of ATRA in combination with GSK2879552 after single and repeat-dose oral administration. Exploratory: To explore markers of differentiation in response to GSK2879552, alone or in combination with ATRA. To investigate the mechanism of action and indicators of sensitivity and resistance to GSK2879552 alone or in combination with ATRA. To characterize the metabolite profile of GSK2879552 after oral single and repeat-dosing in some subjects. To determine the amount of GSK2879552 excreted in urine after oral single and repeat-dosing in some subjects treated with GSK2879552. To investigate the relationship between genetic variants in candidate genes, PK and safety profile of GSK2879552, alone or in combination with ATRA. Part 2: Expansion Cohort Primary: To evaluate clinical activity of GSK2879552, alone or in combination with ATRA, at the RP2D given orally in adult subjects with AML. Secondary: To evaluate the safety and tolerability of respective RP2D of GSK2879552, alone or in combination with ATRA. To characterize the population PK of GSK2879552, alone or in combination with ATRA. To evaluate the exposure response (PK/PD) relationship between GSK2879552, alone or in combination with ATRA and safety/efficacy/PD parameters. To evaluate duration of response and best overall response Exploratory: To investigate the mechanism of action and indicators of sensitivity and resistance to GSK2879552, alone or in combination with ATRA. To investigate the relationship between genetic variants in candidate genes, PK and safety profile of GSK2879552, alone or in combination with ATRA.
IRB Review and Approval Date: 02/28/2017
Recruitment Status: Open
Projected Accrual: 140
1) >/= 18 years of age and provided signed written informed consent.
2) Subjects must have relapsed/refractory acute myeloid leukemia by World Health Organization (WHO) classification for which no standard therapies are available or anticipated to result in a durable remission. French-American-British (FAB) subtype M3 will be excluded.
3) Subjects >/= 60 years of age with AML who are not candidates for or have refused standard chemotherapy.
4) 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 and the subject has recovered from transplant-associated toxicities prior to the first dose of GSK2879552.
5) Subjects with a history of allogeneic stem cell transplant are eligible for study participation provided the following eligibility criteria are met: 1) transplant was >60 days prior to study enrollment; 2) subject has not taken immunosuppressive medications (including but not limited to: cyclosporine, tacrolimus, methotrexate, or mycophenolate mofetil) for at least 1 month; 3) no signs or symptoms of graft versus host disease other than Grade 1 skin involvement; 4) no active infection.
6) Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.
7) Subjects must be stable and, in the opinion of the investigator, be expected to complete 4 week treatment period.
8) 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,
9) 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 enrollment (except for alopecia).
10) Adequate baseline organ function defined by: Hematologic: white blood cell count (absolute): </=30,000/uL; coagulation assays (PT/INR and aPTT): </=1.3 x upper limit of normal (ULN); Hepatic: total bilirubin: </=1.5 x ULN; ALT and AST: </=2.5 x ULN; Renal: creatinine: </=1.5 x ULN or calculated creatinine clearance by Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation or measured from 24hr urine: >/=50 mL/min; Cardiac: ejection fraction: >/= lower limit of normal (LLN) by echocardiogram (ECHO) or multigated (radionuclide) angiogram (MUGA); Lipid (ATRA combination only): Triglyceride (fasting) </= 300 mg/dL; Cholesterol (fasting) </= 300 mg/dL
11) 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 (GSK2879552 mono therapy) or 30 days (combination with ATRA) following the last dose of study treatment.
12) 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.
1) Active Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV) or
Hepatitis C Virus (HCV) infections at the time of screening. Subjects
with laboratory evidence of HCV clearance (HCV RNA PCR is negative) may
2) History of 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 GSK Medical Monitor if unsure whether second malignancies meet requirements specified above.
3) Currently receiving cancer therapy (chemotherapy, radiation therapy, immuno- therapy, biologic therapy, hormonal therapy, surgery, and/or tumour embolization) Note: HYDREA (hydroxyurea) will be allowed.
4) Received major surgery, radiotherapy, or immunotherapy within 4 weeks of GSK2879552 administration.
5) Prior treatment with temozolomide, dacarbazine or procarbazine.
6) Prior treatment with poly ADP ribose polymerase (PARP) inhibitors (e.g., olaparib, ABT-888).
7) Baseline Montreal Cognitive Assessment (MOCA) score of 22 or lower.
8) 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.
9) Current active liver or biliary disease (with the exception of Gilbert's syndrome or asymptomatic gallstones, liver metastases or otherwise stable chronic liver disease per investigator’s assessment).
10) Patients at risk of non-AML related major bleeding (e.g. recent GI hemorrhage or neurosurgery).
11) Symptomatic or untreated central nervous system (CNS) leukemia. Subjects are permitted to enroll if previously treated for CNS disease, free of symptoms at the time of screening, and have not required intrathecal chemotherapy at least 1 month prior to study Day 1.
12) Cardiac abnormalities as evidenced by any of the following: 1) Clinically significant uncontrolled arrhythmias or uncontrolled hypertension; 2) History or evidence of current >/=Class II congestive heart failure as defined by New York Heart Association (NYHA, Appendix 2); 3) History of acute coronary syndromes (including unstable angina and myocardial infarction), coronary angioplasty, or stenting within the past 3 months; 4) Baseline QTc interval using Fridericia’s formula >/=450 msec 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.
13) Administration of an investigational drug within 14 days or 5 half-lives, whichever is shorter with a minimum of 14 days preceding the first dose of study treatment(s) in this study.
14) Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to GSK2879552 or LSD1 inhibitors that contraindicates their participation.
15) Lactating female.
16) 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.
17) 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.
18) Previous treatment with GSK2879552
19) For ATRA Combination arm ONLY: Known hypersensitivity to ATRA, parabens (preservatives in the gelatin capsule) or other retinoids.
20) ATRA capsule contains sorbitol. Subjects with rare hereditary problems of fructose intolerance are excluded.
21) History of seizure within 12 months or brain tumor (primary)
22) History of taking mega-dose vitamin A (>25,000 USP U/day) within 3 months from the dosing start.
Information and next steps
Malignant neoplasms stated as primary lymphoid haematopoietic
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