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

Phase 1
Completed
Conditions
Acute Myeloid Leukemia
Myelodysplastic Syndromes
Interventions
Registration Number
NCT02488408
Lead Sponsor
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.

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 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.

Recruitment & Eligibility

Status
COMPLETED
Sex
All
Target Recruitment
122
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 & Design

Study Type
INTERVENTIONAL
Study Design
SEQUENTIAL
Arm && Interventions
GroupInterventionDescription
Part B2CytarabineBemcentinib 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.
Part B3BemcentinibBemcentinib 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.
Part B3DecitabineBemcentinib 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.
Part B4BemcentinibBemcentinib will be administered as a monotherapy to participants with previously treated MDS (including high risk and intermediate with the exception of deletion 5q MDS).
Part B5BemcentinibBemcentinib 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.
Part B5CytarabineBemcentinib 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.
Part B1BemcentinibSingle 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.
Part B2BemcentinibBemcentinib 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.
Part ABemcentinibBemcentinib 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.
Primary Outcome Measures
NameTimeMethod
Part A: Maximum Tolerated Dose (MTD) of Bemcentinib (BGB324)Cycle 1 (21 days)

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.

Part B: Number of Participants With Treatment-emergent Adverse Events (TEAEs)Up to 28 days after last dose (up to 1452 days; maximum treatment exposure duration 1424 days)

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.

Part B: Number of Participants With Notable Trends in Physical Examination, Vital Signs, Clinical Laboratory Test and Electrocardiogram (ECG) ValuesBaseline to end of the study (Part B: Maximum exposure duration was 1424 days)

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.

Secondary Outcome Measures
NameTimeMethod
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)

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.

Part A: Number of Participants With Notable Trends in Physical Examination, Vital Signs, Clinical Laboratory Test and Electrocardiogram (ECG) ValuesBaseline to end of the study (Part A: Maximum exposure duration was 717 days)

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 as per investigator observation. Notable trends meant observations that were outside normal range as specified by sponsor.

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

AML: complete remission (CR): Bone marrow (BM) \<5% \& no myeloblasts with Auer rods; absolute neutrophil count(ANC) \>=1.0\*10\^9/L or \>=1000/μL; platelet count (PC) \>=100\*10\^9/L or \>=100000/μL:CR with incomplete hematologic recovery(CRi): BM \<5% and no myeloblasts with Auer rods; ANC \<1.0\*10\^9/L or \<1000/μL; PC \<100\*10\^9/L or \<100000/μL, CR with partial hematologic recovery (CRh): CR but ANC \> 0.5 × 10\^9/L and PC \> 50 × 10\^9/L; partial remission (PR): all CR hematologic criteria but decrease of myeloblasts to 5% to 25% and of pretreatment myeloblasts % by \>= 50%; MDS: CR: BM \<=5% myeloblasts, normal maturation of all cell lines, no evidence for dysplasia, Hb \>=11 g/dL;PC \>=100\*10\^9/L or 100000/μL; ANC \>=1.5\*10\^9/L or 1500/μL; PB 0%; marrow CR: \<=5% myeloblasts \& decrease by \>=50% over pretreatment value; CRh =CR with ANC \> 0.5\*10\^9/L and PC \> 50\*10\^9/L; PR: decrease of myeloblasts to 5% to 25% \& decrease of pretreatment myeloblast by \>= 50%; all hematologic criteria of CR.

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

AML: SD= unchanged disease for at least 3 treatment cycles; MDS: SD = failure to achieve at least PR but no evidence of PD for at least 3 treatment cycles. AML: Absence of CR, Cri or PR and criteria for PD not met. MDS: PR = all CR criteria met if abnormal before treatment except for, myeloblasts decrease by 50% or more over pretreatment value but still \>5%, or less advanced French-American-British (FAB) or International Prognostic Scoring System (IPPS) category compared to pretreatment value; hematologic improvement; absolute values must last at least 6 weeks. MDS: PD = for participants with \<5% myeloblasts: a 50% or more increase in myeloblasts to more than 5% myeloblasts, for participants with 5% to 10% myeloblasts: a 50% or more increase to more than 10% myeloblasts, for participants with 10% to 20% myeloblasts: a 50% or more increase to more than 20% myeloblasts, for participants with 20% to 30% myeloblasts: a 50% or more increase to more than 30% myeloblasts.

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

AML and MDS: DCR= percentage of participants with OR and SD. AML: OR= CR, CRi, CRp, CRh and PR. MDS: OR= CR, PR, MR, PMR. AML: SD = unchanged disease for at least 3 treatment cycles; MDS: SD = failure to achieve at least PR but not evidence of PD for at least 3 treatment cycles.

Part B: Relapse Free Survival (RFS)Day 1 of dosing up to end of the study (Part B: maximum exposure duration 1424 days)

RFS: defined as the months from the date of response until the date of relapse as confirmed by blast counts assessment (date of the disease progression was used since disease progression is based in blast count assessment).

Part B: Event Free Survival (EFS)Day 1 of dosing up to end of the study (Part B: maximum exposure duration 1424 days)

Event was defined as death or progression. Duration of EFS was calculated as (days)= Date of onset of Event, subject death or censoring - Date of first intake of study treatment (Bemcentinib ) + 1. EFS data reported below is in months.

Part B: Overall Survival (OS)Day 1 of dosing up to end of the study (Part B: maximum exposure duration 1424 days)

OS was defined as the months from the first day of treatment until date of death for any cause. Participants who were alive at the time of the final analysis were censored at the date the participants were known to be alive.

Part A and Part B: Pharmacokinetics (PK) Parameter: Area Under The Curve (0-tau) at Steady State (AUCss) for BemcentinibPredose, 2, 4, 6 hours post dose on Day 1;predose and 6hours post dose on Day2, predose, 2,4,6,8 hours post dose on Day 3 and predose on Day 4 of Cycle 1; Predose collected on Day1 of each cycle up to and including Cycle 15 and at end of the study (EOS)

Predicted AUCss = area under the curve PK -time profile during 24 hours at steady state.

Part A and B: Pharmacokinetics Parameter: Maximum Observed Plasma Concentration (Cmax) for BemcentinibPre-dose 2, 4, 6 on Day 1; predose and 6 hours post dose on Day 2; predose, 2, 4, 6 and 8 hours post dose on Day 3 and predose on Day 4 of Cycle 1; Predose collected on Day 1 of each cycle up to and including Cycle 15 and at EOS

Observed maximum predicted PK concentration (Cmax) during 24 hours at steady state (Cmax, ss).

Part A and B: Pharmacokinetics Parameter: t1/2 for BemcentinibPre-dose 2, 4, 6 on Day 1; predose and 6 hours post dose on Day 2; predose, 2, 4, 6 and 8 hours post dose on Day 3 and predose on Day 4 of Cycle 1; Predose collected on Day 1 of each cycle up to and including Cycle 15 and at EOS

Median half-life (t1/2) at steady state.

Trial Locations

Locations (12)

Universitätsklinikum Ulm

🇩🇪

Ulm, Germany

Azienda Ospedaliero-Universitaria di Parma

🇮🇹

Parma, Italy

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

🇩🇪

Hannover, Carl-Neuberg-Str, Germany

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

🇩🇪

Frankfurt, Theodor-Stern-Kai, Germany

Studienzentrale der Hämatologie/Onkologie III, Medizinische Klinik

🇩🇪

Mannheim, Germany

Azienda Ospedaliera S Croce E Carle, Via Michele Coppino

🇮🇹

Cuneo, Italy

Ospedale Policlinico San Martino

🇮🇹

Genoa, Italy

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

🇮🇹

Lecce, Italy

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

🇳🇴

Bergen, Jonas Lies Vei, Norway

University of Iowa Hospitals and Clinics

🇺🇸

Iowa City, Iowa, United States

The University of Texas M.D. Anderson Cancer Center

🇺🇸

Houston, Texas, United States

University Medical Center Hamburg

🇩🇪

Hamburg, Hamburg-Eppendorf, Germany

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