A Phase I Dose Escalation Study of GSK2879552 in Subjects With Acute Myeloid Leukemia (AML)
Condition: Leukaemia, Myelocytic, Acute
MeSH terms: Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute
Intervention: GSK2879552; ATRA
Intervention description: GSK2879552 capsules contain 0.25 mg, 0.5 mg, 2 mg or 5 mg of GSK2879552 as parent. The initial dosing regimen will be continuous oral daily dosing.; ATRA (Tretinoin) will be supplied as a 10 mg capsule for oral administration. The initial dosing regimen will be continuous oral twice daily dosing
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 41.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Oncology; LSD1; GSK2879552; Acute myeloid leukemia

Summary:

      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.
    

Eligibility 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.