A Phase Ib/II Multicenter Open-label Study of Bemcentinib (BGB324) in Patients With AML or MDS

Exclusion Criteria

• •1. Participants who have a matched donor and are candidates for allogeneic bone marrow transplantation.
• •2. Pregnant or lactating
• •3. History of the following cardiac conditions:
• •* Congestive cardiac failure of \>Class II severity according to the New York Heart Association (defined as symptomatic at less than ordinary levels of activity)
• •* Ischemic cardiac event including myocardial infarction within 3 months prior to first dose. Participants with prior history or ECG evidence of old myocardial infarction should be discussed with the Sponsor to confirm eligibility.
• •* Uncontrolled cardiac disease, including unstable angina, uncontrolled hypertension (i.e. sustained systolic BP \>160 mmHg or diastolic BP \>90 mmHg), or need to change medication within 6 weeks of provision of consent due to lack of BP control
• •* History or presence of sustained bradycardia (\<=55 beats per minute), left bundle branch block, cardiac pacemaker or ventricular arrhythmia.
• •Note: Participants with supraventricular arrhythmia should be discussed with the Sponsor to confirm eligibility.
• •* Family history of long QTc syndrome; personal history of long QTc syndrome or previous drug-induced QTc prolongation of at least Grade 3 (QTc \>500 ms).
• •* Presence of any factors that increase the risk for QTc prolongation, e.g. resistant or inadequately treated heart failure, presence of hypokalemia or hypomagnesemia not corrected by, or not responding to, replacement therapy or inadequately treated hypothyroidism as defined by the thyroid-stimulating hormone not within the expected range of the institution.
• •4. Abnormal left ventricular ejection fraction (less than the lower limit of normal for a participants of that age at the treating institution or \<45%, whichever is lower).
• •5. Current treatment with any agent known to cause QT prolongation and have a risk for Torsades de Pointes which cannot be discontinued at least 5 half-lives or 2 weeks prior to the first dose of study treatment. Please see Appendix 3 for list of relevant medications.
• •6. Screening 12-lead ECG with a measurable QTcF \>450 ms.
• •7. Ongoing infection requiring systemic treatment. participants who are on prophylactic antimicrobials or who have been afebrile for 48 hours following the initiation of antimicrobials are eligible.
• •8. Inadequate liver function as demonstrated by serum bilirubin \>=1.5 times the upper limits of normal range (ULN) or alanine aminotransferase (ALT) or aspartate aminotransferase (AST) \>=2.5 times the ULN (or \>=5 times the ULN for AST or ALT in the presence of liver involvement by leukemia).
• •9. Inability to tolerate oral medication.
• •10. Existing gastrointestinal disease affecting drug absorption such as celiac disease or Crohn's disease.
• •11. Known lactose intolerance.
• •12. Requires vitamin K antagonists. Note: participants receiving low doses prescribed to maintain the patency of venous access devices may be included.
• •13. Treatment with any of the following H2 receptor antagonists, proton pump inhibitors or antacids within 3 days of administration of bemcentinib.
• •14. Treatment with any medication which is predominantly metabolized by CYP3A4 and has a narrow therapeutic index.
• •15. Previous bowel resection that would interfere with drug absorption.
• •16. Evidence of ongoing gastrointestinal graft versus host disease.
• •17. Hematopoietic stem cell transplantation within 6 months.
• •18. Impaired renal function as demonstrated by a creatinine clearance of \<30 mL/min determined by Cockcroft-Gault formula.
• •19. Radiotherapy or chemotherapy within the 14 days prior to the first dose of bemcentinib being administered (other than hydroxyurea).
• •20. Receiving an investigational anti-cancer treatment concurrently or within 14 days or five half-lives (whichever is shorter) of either the parent drug or any known active metabolite prior to the start of bemcentinib.
• •21. Unresolved CTCAE \>Grade 2 toxicity (other than stable toxicity) from previous anti-cancer therapy excluding alopecia.
• •22. Any evidence of severe or uncontrolled systemic conditions (e.g., severe hepatic impairment) or current unstable or uncompensated respiratory or cardiac conditions which makes it undesirable for the participants to participate in the study or which could jeopardize compliance with the protocol.
• •23. Active, uncontrolled central nervous system (CNS) disease including CNS leukemia.
• •24. Active infection with human immunodeficiency virus (HIV), hepatitis B or C viruses - screening for viral infections is not required for entry to this study.
• •25. Major surgery within 28 days prior to the start of bemcentinib - excluding skin biopsies and procedures for insertion of central venous access devices.
• •26. Hypersensitivity to cytarabine, decitabine or any of its excipients.
• •27. Prior exposure to Astellas ASP2215 (FLT3/AXL Inhibitor - Gilteritinib).