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Trial record 1 of 1 for:    BGBC003
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A Phase Ib/II Multicenter Open-label Study of Bemcentinib (BGB324) in Patients With AML or MDS

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02488408
Recruitment Status : Active, not recruiting
First Posted : July 2, 2015
Last Update Posted : March 2, 2022
Sponsor:
Information provided by (Responsible Party):
BerGenBio ASA

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.


Condition or disease Intervention/treatment Phase
Acute Myeloid Leukemia Myelodysplastic Syndromes Drug: Bemcentinib Drug: Cytarabine Drug: Decitabine Phase 1 Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 121 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : September 2014
Estimated Primary Completion Date : April 2022
Estimated Study Completion Date : April 2022


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 Name: 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: Bemcentinib
Other Name: BGB324

Drug: Cytarabine
Other Name: Ara-C

Drug: Decitabine
Other Name: Dacogen




Primary Outcome Measures :
  1. Part A- Maximum tolerated dose (MTD) of bemcentinib (BGB324) [ Time Frame: 15 Months ]
    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

  2. Part B: Number of Participants with Treatment-emergent Adverse Events (TEAE) [ Time Frame: 10 months ]
    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.

  3. Part B: Number of Participants with Physical Examination, Vital Signs, Clinically Significant Clinical Laboratory Test and Electrocardiogram (ECG) Abnormalities [ Time Frame: 10 months ]
    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.


Secondary Outcome Measures :
  1. Part A: Number of Participants with Treatment-emergent Adverse Events [ Time Frame: 15 months ]
    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.

  2. Part A: Number of Participants with Physical Examination, Vital Signs, Clinical Laboratory Test and Echocardiogram Abnormalities [ Time Frame: 15 months ]
    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.

  3. Part A and B: Objective Response Rate (ORR) [ Time Frame: 15 months ]
    Percentage of participants with objective response according to the revised recommendations of the International Working Group (IWG) will be reported.

  4. Part A and B: Percentage of Participants with Stable Disease (SD) [ Time Frame: 15 months ]
    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.

  5. Part A and B: Percentage of Participants with Objective Response and Stable Disease as Estimate of Clinical Benefit [ Time Frame: 15 months ]
  6. Part A and B: Relapse Free Survival [ Time Frame: 15 months ]
  7. Part A and B: Event Free Survival [ Time Frame: 15 months ]
  8. Part A and B: Overall Survival [ Time Frame: 15 months ]
  9. Part A: Pharmacokinetics (PK) Parameter: Area Under The Curve Within A Dosing Interval (AUC0-tau) for Bemcentinib [ Time Frame: 15 months ]
    AUC0-tau defined as the area under the curve within a dosing interval, calculated by the linear up-log down trapezoidal method.

  10. Part A: Pharmacokinetics Parameter: Maximum Observed Plasma Concentration (Cmax) for Bemcentinib [ Time Frame: 15 months ]
    Cmax defined as the observed maximum plasma concentration after single dose administration.

  11. Part A: Pharmacokinetics Parameter: Time to Reach Maximum Plasma Concentration (Tmax) for Bemcentinib [ Time Frame: 15 months ]
    Tmax defined as the time to reach Cmax.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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).

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02488408


Locations
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United States, Iowa
University of Iowa Hospitals and Clinics
Iowa City, Iowa, United States, 52242
United States, Texas
The University of Texas M.D. Anderson Cancer Center
Houston, Texas, United States, 77030
Germany
Johann-Wolfgang-Goethe Universität
Frankfurt, Germany, 60596
University Medical Center Hamburg
Hamburg, Germany, 20246
Medizinische Hochschule Hannover
Hannover, Germany, 30625
Universitätsmedizin Mannheim, Universitätsklinikum Mannheim GmbH
Mannheim, Germany
Universitätsklinikum Ulm
Ulm, Germany, 89081
Italy
Azienda Ospedaliera S.
Cuneo, Italy, 12100
University of Genoa
Genoa, Italy, 6 16132
U.O. Ematologia - P.O. Vito Fazzi
Lecce, Italy, 73100
Azienda Ospedaliero-Universitaria di Parma
Parma, Italy, 14 43126
Norway
Haukelands University Hospital
Bergen, Norway, 5021
Sponsors and Collaborators
BerGenBio ASA
Investigators
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Principal Investigator: Sonja Loges, MD, PhD Universitätsmedizin Mannheim, Universitätsklinikum Mannheim GmbH
Additional Information:
Publications:
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Responsible Party: BerGenBio ASA
ClinicalTrials.gov Identifier: NCT02488408    
Other Study ID Numbers: BGBC003
First Posted: July 2, 2015    Key Record Dates
Last Update Posted: March 2, 2022
Last Verified: March 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Individual participant data that underlie the results reported in the article, after deidentification [text, tables, figures and appendices].
Supporting Materials: Study Protocol
Statistical Analysis Plan (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.

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by BerGenBio ASA:
BGB324
bemcentinib
Additional relevant MeSH terms:
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Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Preleukemia
Myelodysplastic Syndromes
Neoplasms by Histologic Type
Neoplasms
Bone Marrow Diseases
Hematologic Diseases
Precancerous Conditions
Cytarabine
Decitabine
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Antiviral Agents
Anti-Infective Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Enzyme Inhibitors