A Phase Ib/II multicentre open label study of bemcentinib (BGB324) as a single agent in participants with Acute Myeloid Leukemia (AML) or Myelodysplastic syndrome (MDS) or in a combination with cytarabine or decitabine in AML participants.

Bemcentinib is a potent selective small molecule inhibitor of AXL a surface membrane protein kinase receptor which is overexpressed in up to half of AML cases.

This study is a dose-escalation of bemcentinib (BGB324), a selective AXL kinase inhibitor, in participants with AML and MDS, followed by a cohort expansion study of bemcentinib either as a single agent in participants with AML or MDS, or in combination with cytarabine (cytosine arabinoside, Ara-C) or decitabine in participants with AML.

The study will run in Germany, Norway, Italy and the US and may enrol up to approximately 90 participants with AML or MDS.

The study consisted of a dose-escalation phase to determine the MTD (maximum tolerated dose) and/or recommended dose for Phase II (RP2D) of bemcentinib in participants with relapsed or refractory AML or MDS (Part A) followed by a cohort expansion phase in five disease-specific cohorts (Part B).

Bemcentinib was administered orally according to a daily schedule, with the first three doses of Cycle 1 serving as a 'loading' dose. Each 21-day (three week) period will constitute 1 cycle of treatment.

Inclusion Criteria:

1. Provision of signed written informed consent.

2. Histological, molecular or cytological confirmation of:

   1. Part A: Participants must have received previous treatment with cytotoxic chemotherapy (with or without hematopoietic stem cell transplantation) or a gene expression modulator, such as a demethylating agent. Participants suitable for intensive chemotherapy should be in second or subsequent relapse or be refractory to at least two induction regimens. If eligible they should have undergone hematopoietic stem cell transplantation. Participants receiving an allograft in first remission would be eligible at the time of relapse. Participants who are unsuitable for intensive chemotherapy as a result of advanced age or co-morbidities should have relapsed following at least one line of therapy or be refractory.

   2. Part B1: Participants with AML who are unsuitable for intensive chemotherapy as a result of advanced age or co-morbidities. Participants should have relapsed following at least one line of therapy or be refractory to such prior therapy. Participants should not have received standard dose intensive chemotherapy.

   3. Part B2: Participants with AML who are unsuitable for intensive chemotherapy as a result of advancing age or co-morbidities and who are suitable to receive treatment with cytarabine.

   4. Part B3: Participants with AML who are unsuitable for intensive chemotherapy as a result if advancing age or co-morbidities and who are suitable to receive treatment with decitabine.

   5. Part B4: Participants with MDS (with the exception of deletion 5q MDS) including intermediate and high-risk participants who must have received prior treatment for their disease. Prior treatment may include those participants who have received hypomethylating agents, decitabine or other approved treatments for MDS.

   6. Part B5: Participants with relapsed or refractory AML who are unsuitable for intensive chemotherapy as a result of advanced age or co-morbidities meeting the following criteria:

      • Must have received at least one prior treatment for AML Are suitable to receive treatment with "low-dose" cytarabine (LDAC). LDAC is defined as 20 mg cytarabine administered subcutaneously twice daily for 10 days every 28 days. The number of participants with refractory AML, defined as no hematological response to last AML treatment and/or participants who have received 2 or more prior treatments for AML, will be restricted to 1/3 of the sample size (i.e. no more than 6 evaluable participants).

3. Eastern Cooperative Oncology Group (ECOG) performance status 0, 1 or 2.

4. Age 18 years or older.

5. Female participants of childbearing potential must have a negative serum pregnancy test within 3 days prior to taking their first dose of bemcentinib. Male participants and female participants of reproductive potential must practice highly effective methods of contraception (such as hormonal implants, combined oral contraceptives, injectable contraceptives, intrauterine device with hormone spirals, total sexual abstinence, vasectomy) throughout the study and for >=3 months after the last dose of bemcentinib.

Female participants are considered NOT of childbearing potential if they have a history of surgical sterility or evidence of post-menopausal status defined as any of the following:

1. Natural menopause with last menses >1 year ago.
2. Radiation induced oophorectomy with last menses >1 year ago.
3. Chemotherapy induced menopause with last menses >1 year ago.

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).

Individual participant data that underlie the results reported in the article, after deidentification [text, tables, figures and appendices].

Beginning 3 months and ending 5 years following article publication

Proposal should be directed to HYPERLINK "mailto:clinical@bergenbio.com" clinical@bergenbio.com. To gain access, data requestors will need to sign a data access agreement.