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

A Phase Ib/II Multicenter Open-label Study of BGB324 as a Single Agent and in Combination With Cytarabine or Decitabine in Patients With Acute Myeloid Leukemia or as a Single Agent in Patients With Myelodysplastic Syndrome

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Acute Myeloid Leukemia; Myelodysplastic Syndromes
• Intervention / Treatment: Drug: Cytarabine; Drug: Bemcentinib; Drug: Decitabine

Detailed Description

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 consists 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 up to four disease-specific cohorts (Part B).

Bemcentinib will be 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.

• Study Type: Interventional
• Enrollment (Actual): 121
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Germany
  • Frankfurt, Germany, 60596
    • Johann-Wolfgang-Goethe Universität
  • Hamburg, Germany, 20246
    • University Medical Center Hamburg
  • Hannover, Germany, 30625
    • Medizinische Hochschule Hannover
  • Mannheim, Germany
    • Universitätsmedizin Mannheim, Universitätsklinikum Mannheim GmbH
  • Ulm, Germany, 89081
    • Universitatsklinikum Ulm
• Italy
  • Cuneo, Italy, 12100
    • Azienda Ospedaliera S.
  • Genoa, Italy, 6 16132
    • University of Genoa
  • Lecce, Italy, 73100
    • U.O. Ematologia - P.O. Vito Fazzi
  • Parma, Italy, 14 43126
    • Azienda Ospedaliero-Universitaria di Parma
• Norway
  • Bergen, Norway, 5021
    • Haukelands University Hospital
• United States
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa Hospitals and Clinics
  • Texas
    • Houston, Texas, United States, 77030
      • The University of Texas M.D. Anderson Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Part A; To identify the maximum tolerated dose (MTD) of bemcentinib (BGB324) in participants with relapsed or refractory AML following treatment with cytotoxic chemotherapy or a targeted or biologic agent, or in participants with high risk MDS (Norway only).- This Arm of the study has completed recruitment	Drug: Bemcentinib; Other Names: BGB324
Experimental: Part B; To identify the safety and tolerability of bemcentinib: as a single agent in participants with AML who are unsuitable for intensive chemotherapy; in a combination with cytarabine in participants with AML who are unsuitable for intensive chemotherapy; in a combination with decitabine in participants with AML who are unsuitable for intensive chemotherapy; as a single agent in participants with previously treated MDS	Drug: Cytarabine; Other Names: Ara-C; Drug: Bemcentinib; Other Names: BGB324; Drug: Decitabine; Other Names: Dacogen

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Part A- Maximum tolerated dose (MTD) of bemcentinib (BGB324)	Dose escalation will occur continue until dose limiting toxicity occurs at which point a MTD will be determined and Dose confirmation for Phase II will be made. Dose Limiting Toxicity (DLT) will be assessed during the first 3 weeks of treatment (Cycle 1) with BGB324, according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events [NCI CTCAE] version 4, considered unrelated to leukemia progression or intercurrent illness	15 Months
Part B: Number of Participants with Treatment-emergent Adverse Events (TEAE)	An adverse event (AE) is any unfavorable or unintended sign, symptom or disease temporally associated with the use of the investigational medicinal product (IMP) whether or not considered related to the study IMP.	10 months
Part B: Number of Participants with Physical Examination, Vital Signs, Clinically Significant Clinical Laboratory Test and Electrocardiogram (ECG) Abnormalities	Number of participants with physical examinations (including weight), vital signs (blood pressure [BP], heart rate [HR]), clinical laboratory test (including clinical chemistry, hematology and urinalysis), and ECG abnormalities will be reported.	10 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Part A: Number of Participants with Treatment-emergent Adverse Events	An AE is any unfavorable or unintended sign, symptom or disease temporally associated with the use of the IMP whether or not considered related to the study IMP.	15 months
Part A: Number of Participants with Physical Examination, Vital Signs, Clinical Laboratory Test and Echocardiogram Abnormalities	Number of participants with physical examinations (including weight), vital signs (BP, HR), clinical laboratory test (including clinical chemistry, hematology and urinalysis), and echocardiogram abnormalities will be reported.	15 months
Part A and B: Objective Response Rate (ORR)	Percentage of participants with objective response according to the revised recommendations of the International Working Group (IWG) will be reported.	15 months
Part A and B: Percentage of Participants with Stable Disease (SD)	SD defined as having unchanged disease for at least 3 treatment cycles and as failure to achieve at least Partial Remission (PR), but not evidence of Progressive Disease (PD) for at least 3 treatment cycles.	15 months
Part A and B: Percentage of Participants with Objective Response and Stable Disease as Estimate of Clinical Benefit		15 months
Part A and B: Relapse Free Survival		15 months
Part A and B: Event Free Survival		15 months
Part A and B: Overall Survival		15 months
Part A: Pharmacokinetics (PK) Parameter: Area Under The Curve Within A Dosing Interval (AUC0-tau) for Bemcentinib	AUC0-tau defined as the area under the curve within a dosing interval, calculated by the linear up-log down trapezoidal method.	15 months
Part A: Pharmacokinetics Parameter: Maximum Observed Plasma Concentration (Cmax) for Bemcentinib	Cmax defined as the observed maximum plasma concentration after single dose administration.	15 months
Part A: Pharmacokinetics Parameter: Time to Reach Maximum Plasma Concentration (Tmax) for Bemcentinib	Tmax defined as the time to reach Cmax.	15 months

Collaborators and Investigators

• Sponsor: BerGenBio ASA
• Investigators: Principal Investigator: Sonja Loges, MD, PhD, Universitätsmedizin Mannheim, Universitätsklinikum Mannheim GmbH

Publications and helpful links

General Publications

• Janning M, Ben-Batalla I, Loges S. Axl inhibition: a potential road to a novel acute myeloid leukemia therapy? Expert Rev Hematol. 2015 Apr;8(2):135-8. doi: 10.1586/17474086.2015.997704. Epub 2015 Jan 12.
• Ben-Batalla I, Schultze A, Wroblewski M, Erdmann R, Heuser M, Waizenegger JS, Riecken K, Binder M, Schewe D, Sawall S, Witzke V, Cubas-Cordova M, Janning M, Wellbrock J, Fehse B, Hagel C, Krauter J, Ganser A, Lorens JB, Fiedler W, Carmeliet P, Pantel K, Bokemeyer C, Loges S. Axl, a prognostic and therapeutic target in acute myeloid leukemia mediates paracrine crosstalk of leukemia cells with bone marrow stroma. Blood. 2013 Oct 3;122(14):2443-52. doi: 10.1182/blood-2013-03-491431. Epub 2013 Aug 27.

Helpful Links

• Please see BerGenBio's website for more information.

Study record dates

Study Major Dates

• Study Start (Actual): September 1, 2014
• Primary Completion (Anticipated): April 1, 2022
• Study Completion (Anticipated): April 1, 2022

Study Registration Dates

• First Submitted: April 23, 2015
• First Submitted That Met QC Criteria: June 30, 2015
• First Posted (Estimate): July 2, 2015

Study Record Updates

• Last Update Posted (Actual): March 2, 2022
• Last Update Submitted That Met QC Criteria: March 1, 2022
• Last Verified: March 1, 2022

More Information

Terms related to this study

• Keywords: bemcentinib; BGB324
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Bone Marrow Diseases; Hematologic Diseases; Precancerous Conditions; Myelodysplastic Syndromes; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Preleukemia; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Decitabine; Cytarabine
• Other Study ID Numbers: BGBC003

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: Individual participant data that underlie the results reported in the article, after deidentification [text, tables, figures and appendices].
• IPD Sharing Time Frame: Beginning 3 months and ending 5 years following article publication
• IPD Sharing Access Criteria: 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.
• IPD Sharing Supporting Information Type: Study Protocol; Statistical Analysis Plan (SAP)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No