Last updated: 07/17/2024 16:59:12
A Phase I Dose Escalation Study of GSK2879552 in Subjects with Acute Myeloid Leukemia (AML)
EudraCT ID
Not applicable
EU CT Number
Not applicable
Trial status
Other
Other
Trial overview
Official title: 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
Trial description: This study is a phase I, open-label study to determine recommended phase 2 dose (RP2D) and regimen for the orally administered lysine specific demethylase 1 (LSD1) inhibitor GSK2879552, alone or in combination with All-Trans Retinoic Acid (ATRA). The recommended dose and regimen will be selected based on the safety, pharmacokinetic (PK), and pharmacodynamic (PD) profiles observed after the treatment of subjects with relapsed/refractory AML. The study consists of two parts. Part 1 will identify the maximum tolerated dose (MTD) and/or RP2D using a dose-escalation procedure. Dose escalations will be guided by the Neuenschwander-continual reassessment method (N-CRM). PK/PD expansion cohorts will also be included in Part 1 to characterize the range of biologically effective doses by assessing PD markers and obtain additional PK data. Part 2 will explore further the safety, tolerability, and clinical activity of GSK2879552, alone or in combination with ATRA, at the RP2D in subjects with AML.
Primary purpose:
Treatment
Trial design:
Single Group Assignment
Masking:
None (Open Label)
Allocation:
Non-randomized
Primary outcomes:
NUMBER OF SUBJECTS WITH ADVERSE EVENTS (AES) AND SERIOUS ADVERSE EVENTS (SAES): PART 1
Timeframe: Up to 3 years
NUMBER OF SUBJECTS WITH DOSE LIMITING TOXICITIES (DLT) AS A MEASURE OF SAFETY: PART 1
Timeframe: Start of treatment to 4 weeks
NUMBER OF SUBJECTS WITH DOSE REDUCTIONS OR DELAYS AS A MEASURE OF SAFETY: PART 1
Timeframe: Up to 3 years
NUMBER OF SUBJECTS WITH ABNORMAL CLINICAL CHEMISTRY LABORATORY TESTS: PART 1
Timeframe: Up to 3 years
NUMBER OF SUBJECTS WITH ABNORMAL HEMATOLOGY LABORATORY TESTS: PART 1
Timeframe: Up to 3 years
NUMBER OF SUBJECTS WITH ABNORMAL SYSTOLIC BLOOD PRESSURE (SBP) AND DIASTOLIC BLOOD PRESSURE (DBP) AS A MEASURE OF SAFETY: PART 1
Timeframe: Up to 3 years
NUMBER OF SUBJECTS WITH ABNORMAL PULSE RATE: PART 1
Timeframe: Up to 3 years
NUMBER OF SUBJECTS WITH ABNORMAL RESPIRATORY RATE: PART 1
Timeframe: Up to 3 years
NUMBER OF SUBJECTS WITH ABNORMAL BODY TEMPERATURE: PART 1
Timeframe: Up to 3 years
NUMBER OF SUBJECTS WITH ABNORMALITY IN ELECTROCARDIOGRAM (ECG) : PART 1
Timeframe: Up to 3 years
NUMBER OF SUBJECTS WITH ABNORMAL PHYSICAL EXAMINATION FINDING: PART 1
Timeframe: Up to 3 years
OBJECTIVE RESPONSE RATE (ORR): PART 2
Timeframe: Up to 3 years
Secondary outcomes:
AREA UNDER THE PLASMA CONCENTRATION TIME CURVE FOLLOWING SINGLE DOSE ADMINISTRATION OF GSK2879552 ALONE OR IN COMBINATION WITH ATRA: PART 1
Timeframe: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 hours post dose on Day 1
AREA UNDER THE PLASMA CONCENTRATION TIME CURVE FOLLOWING REPEAT DOSE ADMINISTRATION OF GSK2879552 ALONE OR IN COMBINATION WITH ATRA: PART 1
Timeframe: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 hours post dose on Day 15
MAXIMUM OBSERVED PLASMA CONCENTRATION (CMAX) FOLLOWING SINGLE DOSE ADMINISTRATION OF GSK2879552 ALONE OR IN COMBINATION WITH ATRA: PART 1
Timeframe: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 hours post dose on Day 1
MAXIMUM OBSERVED PLASMA CONCENTRATION (CMAX) FOLLOWING REPEAT DOSE ADMINISTRATION OF GSK2879552 ALONE OR IN COMBINATION WITH ATRA: PART 1
Timeframe: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 hours post dose on Day 15
TIME TO CMAX (TMAX) FOLLOWING SINGLE DOSE ADMINISTRATION OF GSK2879552 ALONE OR IN COMBINATION WITH ATRA: PART 1
Timeframe: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 hours post dose on Day 1
TIME TO CMAX (TMAX) FOLLOWING REPEAT DOSE ADMINISTRATION OF GSK2879552 ALONE OR IN COMBINATION WITH ATRA: PART 1
Timeframe: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 hours post dose on Day 15
APPARENT TERMINAL PHASE HALF-LIFE (T½) FOLLOWING SINGLE DOSE ADMINISTRATION OF GSK2879552 ALONE OR IN COMBINATION WITH ATRA: PART 1
Timeframe: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 hours post dose on Day 1
APPARENT TERMINAL PHASE HALF-LIFE (T½) FOLLOWING REPEAT DOSE ADMINISTRATION OF GSK2879552 ALONE OR IN COMBINATION WITH ATRA: PART 1
Timeframe: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 hours post dose on Day 15
OBSERVED ACCUMULATION RATIO (RO) FOLLOWING SINGLE DOSE ADMINISTRATION OF GSK2879552 ALONE OR IN COMBINATION WITH ATRA: PART 1
Timeframe: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 hours post dose on Day 1
OBSERVED ACCUMULATION RATIO (RO) FOLLOWING REPEAT DOSE ADMINISTRATION OF GSK2879552 ALONE OR IN COMBINATION WITH ATRA: PART 1
Timeframe: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 hours post dose on Day 15
TIME INVARIANCE FOR GSK2879552 FOLLOWING SINGLE DOSE ADMINISTRATION OF GSK2879552 ALONE OR IN COMBINATION WITH ATRA: PART 1
Timeframe: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 hours post dose on Day 1
TIME INVARIANCE FOR GSK2879552 FOLLOWING REPEAT DOSE ADMINISTRATION OF GSK2879552 ALONE OR IN COMBINATION WITH ATRA: PART 1
Timeframe: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 hours post dose on Day 15
ORR: PART 1
Timeframe: Up to 3 years
CHANGE FROM BASELINE IN CD86: PART 1
Timeframe: Baseline and up to 3 years
CHANGE FROM BASELINE IN CD11B: PART 1
Timeframe: Baseline and up to 3 years
AREA UNDER THE PLASMA CONCENTRATION TIME CURVE FOLLOWING SINGLE DOSE ADMINISTRATION OF ATRA: PART 1
Timeframe: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 hours post-dose on Day 1
AREA UNDER THE PLASMA CONCENTRATION TIME CURVE FOLLOWING REPEAT DOSE ADMINISTRATION OF ATRA: PART 1
Timeframe: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24 hours post-dose on Day 15
MAXIMUM OBSERVED PLASMA CONCENTRATION (CMAX) FOLLOWING SINGLE DOSE ADMINISTRATION OF ATRA: PART 1
Timeframe: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 hours post-dose on Day 1
MAXIMUM OBSERVED PLASMA CONCENTRATION (CMAX) FOLLOWING REPEAT DOSE ADMINISTRATION OF ATRA: PART 1
Timeframe: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24 hours post-dose on Day 15
TIME TO CMAX (TMAX) FOLLOWING SINGLE DOSE ADMINISTRATION OF ATRA: PART 1
Timeframe: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 hours post-dose on Day 1
TIME TO CMAX (TMAX) FOLLOWING REPEAT DOSE ADMINISTRATION OF ATRA: PART 1
Timeframe: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24 hours post-dose on Day 15
APPARENT TERMINAL PHASE HALF-LIFE (T½) FOLLOWING SINGLE DOSE ADMINISTRATION OF ATRA: PART 1
Timeframe: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 hours post-dose on Day 1
APPARENT TERMINAL PHASE HALF-LIFE (T½) FOLLOWING REPEAT DOSE ADMINISTRATION OF ATRA: PART 1
Timeframe: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24 hours post-dose on Day 15
NUMBER OF SUBJECTS WITH ADVERSE EVENTS (AES) AND SERIOUS ADVERSE EVENTS (SAES): PART 2
Timeframe: Up to 3 years
NUMBER OF SUBJECTS WITH DOSE LIMITING TOXICITIES (DLT) AS A MEASURE OF SAFETY: PART 2
Timeframe: Up to 4 Weeks
NUMBER OF SUBJECTS WITH DOSE REDUCTIONS OR DELAYS AS A MEASURE OF SAFETY: PART 2
Timeframe: Up to 3 years
NUMBER OF SUBJECTS WITH ABNORMAL CLINICAL CHEMISTRY LABORATORY TESTS: PART 2
Timeframe: Up to 3 years
NUMBER OF SUBJECTS WITH ABNORMAL HEMATOLOGY LABORATORY TESTS: PART 2
Timeframe: Up to 3 years
NUMBER OF SUBJECTS WITH ABNORMAL SYSTOLIC BLOOD PRESSURE (SBP) AND DIASTOLIC BLOOD PRESSURE (DBP) AS A MEASURE OF SAFETY: PART 2
Timeframe: Up to 3 years
NUMBER OF SUBJECTS WITH ABNORMAL PULSE RATE: PART 2
Timeframe: Up to 3 years
NUMBER OF SUBJECTS WITH ABNORMAL RESPIRATORY RATE: PART 2
Timeframe: Up to 3 years
NUMBER OF SUBJECTS WITH ABNORMAL BODY TEMPERATURE: PART 2
Timeframe: Up to 3 years
NUMBER OF SUBJECTS WITH ABNORMALITY IN ELECTROCARDIOGRAM (ECG) : PART 2
Timeframe: Up to 3 years
NUMBER OF SUBJECTS WITH ABNORMAL PHYSICAL EXAMINATION FINDING: PART 2
Timeframe: Up to 3 years
APPARENT CLEARANCE FOLLOWING ADMINISTRATION OF GSK2879552 ALONE OR IN COMBINATION WITH ATRA: PART 2
Timeframe: Day 1 (pre-dose, 0.5 and 3 hours post dose), Days 4, 8, 15 (pre-dose), and every 4 week up to week 48
VOLUME OF DISTRIBUTION FOLLOWING ADMINISTRATION OF GSK2879552 ALONE OR IN COMBINATION WITH ATRA: PART 2
Timeframe: Day 1 (pre-dose, 0.5 and 3 hours post dose), Days 4, 8, 15 (pre-dose), and every 4 week up to week 48
NUMBER OF SUBJECTS WITH ABNORMAL COVARIATES: PART 2
Timeframe: Up to 3 years
CHANGE FROM BASELINE IN CD86: PART 2
Timeframe: Baseline and up to 3 years
CHANGE FROM BASELINE IN CD11B: PART 2
Timeframe: Baseline and up to 3 years
DURATION OF RESPONSE (DOR): PART 2
Timeframe: Up to 3 years
BEST OVERALL RESPONSE: PART 2
Timeframe: Up to 3 years
Interventions:
Enrollment:
41
Primary completion date:
2017-08-12
Observational study model:
Not applicable
Time perspective:
Not applicable
Clinical publications:
Not applicable
Medical condition
Leukaemia, Myelocytic, Acute
Product
GSK2879552
Collaborators
Not applicable
Study date(s)
August 2014 to December 2017
Type
Interventional
Phase
1
Participation criteria
Sex
Female & Male
Age
18+ years
Accepts healthy volunteers
No
- Subjects >=18 years of age and provided signed written informed consent.
- Subjects must have relapsed/refractory AML by world health organization (WHO) classification for which no standard therapies are available or anticipated to result in a durable remission. French- American- British system (FAB) subtype M3 will be excluded.
- 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 may be enrolled.
- History of or concurrent malignancy of solid tumours, except: 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 GlaxoSmithKline (GSK) Medical Monitor if unsure whether second malignancies meet requirements specified above.
Inclusion and exclusion criteria
Inclusion criteria:
- Subjects >=18 years of age and provided signed written informed consent.
- Subjects must have relapsed/refractory AML by world health organization (WHO) classification for which no standard therapies are available or anticipated to result in a durable remission. French- American- British system (FAB) subtype M3 will be excluded.
- Subjects >= 60 years of age with AML who are not candidates for or have refused standard chemotherapy.
- 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.
- Subjects with a history of allogeneic stem cell transplant are eligible for study participation provided the following eligibility criteria are met: transplant was >60 days prior to study enrolment; subject has not taken immunosuppressive medications for at least 1 month; no signs or symptoms of graft versus host disease other than Grade 1 skin involvement; no active infection.
- Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.
- Subjects must be stable and, in the opinion of the investigator, be expected to complete 4 week treatment period.
- 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.
- 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).
- Adequate baseline organ function.
- 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.
- 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.
Exclusion criteria:
- 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 may be enrolled.
- History of or concurrent malignancy of solid tumours, except: 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 GlaxoSmithKline (GSK) Medical Monitor if unsure whether second malignancies meet requirements specified above.
- Currently receiving cancer therapy. Hydroxyurea will be allowed.
- Received major surgery, radiotherapy, or immunotherapy within 4 weeks of GSK2879552 administration.
- Prior treatment with temozolomide, dacarbazine or procarbazine
- Prior treatment with poly ADP ribose polymerase (PARP) inhibitors (eg., olaparib, ABT-888)
- Baseline Montreal Cognitive Assessment (MOCA) score of 22 or lower
- Evidence of severe or uncontrolled systemic diseases. Any serious and/or unstable pre-existing medical, 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
- Current active liver or biliary disease.
- Patients at risk of non-AML related major bleeding (e.g. recent gastrointestinal [GI] hemorrhage or neurosurgery).
- 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.
- Cardiac abnormalities
- 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.
- Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to GSK2879552 or LSD1 inhibitors that contraindicates their participation.
- Lactating female.
- 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.
- 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.
- Previous treatment with GSK2879552 For ATRA Combination arm ONLY
- Known hypersensitivity to ATRA, parabens (preservatives in the gelatin capsule) or other retinoids.
- ATRA capsule contains sorbitol. Subjects with rare hereditary problems of fructose intolerance are excluded.
- History of seizure within 12 months or brain tumor (primary)
- History of taking mega-dose vitamin A (>25,000 USP U/day) within 3 months from the dosing start.
Trial location(s)
Location
GSK Investigational Site
New York, New York, United States, 10065
Status
Study Complete
Study documents
Clinical study report
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
Results posted on ClinicalTrials.gov
Recruitment status
Other
Actual primary completion date
2017-08-12
Actual study completion date
2017-08-12
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
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