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

NCT02488408 | Completed Phase 1 Results DMC FDA Drug

• 1 other identifier: BGBC003
• Study Type: interventional
• Target: 122
• Locations: 4 countries
• Sites: 12

Brief Summary

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.

Conditions

Acute Myeloid Leukemia; Myelodysplastic Syndromes

Keywords

BGB324; bemcentinib

Outcome Measures

Primary Outcomes (3)

• Part A: Maximum Tolerated Dose (MTD) of Bemcentinib (BGB324)

  If 1 participant in a cohort experienced a dose limiting toxicity (DLT) during Cycle 1, the cohort was expanded to 6 participants. If 2 of 3 or 2 of 6 participants in a cohort experience DLT no further dose escalation took place and the dose below was nominated as the MTD. DLT was assessed during the first 3 weeks of treatment (Cycle 1) with bemcentinib. DLT was defined as according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) \[NCI CTCAE\] version 4, considered unrelated to leukemia progression or intercurrent illness.

  Cycle 1 (21 days)

• Part B: Number of Participants With Treatment-emergent Adverse Events (TEAEs)

  An AE was any untoward medical occurrence in a participant or clinical study participant administered a pharmaceutical product and which did not necessarily had a causal relationship with the product. A TEAE was defined as an AE that started or worsened after the first dose of the study intervention until 28 days after the last dose.

  Up to 28 days after last dose (up to 1452 days; maximum treatment exposure duration 1424 days)

• Part B: Number of Participants With Notable Trends in Physical Examination, Vital Signs, Clinical Laboratory Test and Electrocardiogram (ECG) Values

  Number of participants with notable trends in physical examinations (including weight), vital signs (blood pressure \[BP\], heart rate \[HR\]), clinical laboratory test (including clinical chemistry, hematology and urinalysis), and ECG values over the time were reported in this outcome measure. Notable trends were defined as observations which were outside the normal range for these mentioned parameters as specified by the sponsor.

  Baseline to end of the study (Part B: Maximum exposure duration was 1424 days)

Secondary Outcomes (11)

• Part A: Number of Participants With Treatment-emergent Adverse Events (TEAEs)

  Up to 28 days after last dose (up to 745 days, maximum exposure duration 717 days)

• Part A: Number of Participants With Notable Trends in Physical Examination, Vital Signs, Clinical Laboratory Test and Electrocardiogram (ECG) Values

  Baseline to end of the study (Part A: Maximum exposure duration was 717 days)

• Part A and B: Percentage of Participants With Objective Response (OR) as Per International Working Group Response Criteria

  Day 1 of dosing up to end of the study (for Part A: maximum exposure duration 717 days, and for Part B: maximum exposure duration 1424 days)

• Part A and B: Percentage of Participants With Stable Disease (SD) as Per International Working Group Response Criteria

  Day 1 of dosing up to end of the study (for Part A: maximum exposure duration 717 days, and for Part B: maximum exposure duration 1424 days)

• Part A and B: Disease Control Rate (DCR) as Per International Working Group Response Criteria

  Day 1 of dosing up to end of the study (for Part A: maximum exposure duration 717 days, and for Part B: maximum exposure duration 1424 days)

Study Arms (6)

Part A

EXPERIMENTAL

Bemcentinib will be administered as monotherapy in participants with relapsed or refractory AML following previous treatment with cytotoxic chemotherapy (with or without hematopoietic stem cell transplantation) or a gene expression modulator, such as a demethylating agent.

Drug: Bemcentinib

Part B1

EXPERIMENTAL

Single agent bemcentinib will be administered to participants with AML who are unsuitable for intensive chemotherapy as a result of advanced age and/or existing co-morbidities.

Drug: Bemcentinib

Part B2

EXPERIMENTAL

Bemcentinib will be administered in combination with low dose cytarabine in participants with AML who are unsuitable for intensive chemotherapy as a result of advanced age or existing co-morbidities.

Drug: Bemcentinib; Drug: Cytarabine

Part B3

EXPERIMENTAL

Bemcentinib will be administered in combination with decitabine in participants with AML who are unsuitable for intensive chemotherapy as a result of advanced age or existing co-morbidities.

Drug: Bemcentinib; Drug: Decitabine

Part B4

EXPERIMENTAL

Bemcentinib will be administered as a monotherapy to participants with previously treated MDS (including high risk and intermediate with the exception of deletion 5q MDS).

Drug: Bemcentinib

Part B5

EXPERIMENTAL

Bemcentinib will be administered in combination with low dose cytarabine in participants with relapsed or refractory who have received at least one prior treatment for. Participants must be unsuitable for intensive chemotherapy as a results of advanced age or existing co-morbidities.

Drug: Bemcentinib; Drug: Cytarabine

Interventions

Bemcentinib DRUG

Also known as: BGB324

Part A; Part B1; Part B2; Part B3; Part B4; Part B5

Cytarabine DRUG

Also known as: Ara-C

Part B2; Part B5

Decitabine DRUG

Also known as: Dacogen

Part B3

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Provision of signed written informed consent.
• Histological, molecular or cytological confirmation of:
• 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.
• 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.
• 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.
• 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.
• 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.
• 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).
• Eastern Cooperative Oncology Group (ECOG) performance status 0, 1 or 2.
• Age 18 years or older.
• 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:
• Natural menopause with last menses \>1 year ago.
• Radiation induced oophorectomy with last menses \>1 year ago.

You may not qualify if:

• Participants who have a matched donor and are candidates for allogeneic bone marrow transplantation.
• Pregnant or lactating
• 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.
• 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).
• 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.
• Screening 12-lead ECG with a measurable QTcF \>450 ms.
• 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.
• 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).

Sponsors & Collaborators

• BerGenBio ASA: lead

Study Sites (12)

University of Iowa Hospitals and Clinics

Iowa City, Iowa, 52242, United States

Location

The University of Texas M.D. Anderson Cancer Center

Houston, Texas, 77030, United States

Location

Medizinische Hochschule Hannover,Hämatologie, Hämostaseologie, Onkologie und Stammzelltransplantation,

Hanover, Carl-Neuberg-Str, 30625, Germany

Location

University Medical Center Hamburg

Hamburg, Hamburg-Eppendorf, 20246, Germany

Location

Frankfurt Medizinische Klinik II, Hämatologie/Onkologie, Haus 33, 2. OG

Frankfurt, Theodor-Stern-Kai, 60590, Germany

Location

Studienzentrale der Hämatologie/Onkologie III, Medizinische Klinik

Mannheim, Germany

Location

Universitätsklinikum Ulm

Ulm, 89081, Germany

Location

Azienda Ospedaliera S Croce E Carle, Via Michele Coppino

Cuneo, 12100, Italy

Location

Ospedale Policlinico San Martino

Genoa, 16132, Italy

Location

Ospedale Lecce - 'V Fazzi' U. O. Ematologia - P. O. Vito Fazz Piazza Muratore, IV piano Polo Oncologico

Lecce, 73100, Italy

Location

Azienda Ospedaliero-Universitaria di Parma

Parma, 43126, Italy

Location

University of Bergen Department of Clinical Science, Translational Hemato-Oncology group, Faculty of Medicine and Dentistry, Haukelands University Hospital

Bergen, Jonas Lies Vei, 5021, Norway

Location

Related Publications (16)

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• Schmidt T, Ben-Batalla I, Schultze A, Loges S. Macrophage-tumor crosstalk: role of TAMR tyrosine kinase receptors and of their ligands. Cell Mol Life Sci. 2012 May;69(9):1391-414. doi: 10.1007/s00018-011-0863-7. Epub 2011 Nov 11.

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• Gjerdrum C, Tiron C, Hoiby T, Stefansson I, Haugen H, Sandal T, Collett K, Li S, McCormack E, Gjertsen BT, Micklem DR, Akslen LA, Glackin C, Lorens JB. Axl is an essential epithelial-to-mesenchymal transition-induced regulator of breast cancer metastasis and patient survival. Proc Natl Acad Sci U S A. 2010 Jan 19;107(3):1124-9. doi: 10.1073/pnas.0909333107. Epub 2009 Dec 28.

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  PMID: 40122885 DERIVED

Related Links

• Please see BerGenBio's website for more information.

MeSH Terms

Conditions

Leukemia, Myeloid, Acute; Myelodysplastic Syndromes

Interventions

bemcentinib; Cytarabine; Decitabine

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Bone Marrow Diseases

Intervention Hierarchy (Ancestors)

Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Arabinonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Azacitidine; Aza Compounds; Organic Chemicals; Ribonucleosides

Results Point of Contact

• Title: BerGenBio Clinical Team
• Organization: BerGenBio ASA

trialsites@bergenbio.com

+47 559 61 159

Study Officials

• Sonja Loges, MD

  Universitätsmedizin Mannheim, Universitätsklinikum Mannheim GmbH

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 23, 2015
• First Posted: July 2, 2015
• Study Start: October 22, 2014
• Primary Completion: June 8, 2022
• Study Completion: June 8, 2022
• Last Updated: December 19, 2024
• Results First Posted: December 19, 2024

Record last verified: 2024-11

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP
• Time Frame: Beginning 3 months and ending 5 years following article publication
• 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.

Locations

IT (4); US (2); NO (1); DE (5)