Acute Myeloid Leukemia, Myelodysplastic Syndromes
Conditions
Keywords
BGB324, bemcentinib
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.
Interventions
Sponsors
BerGenBio ASA
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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) Values | Baseline 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
| Measure | Time frame | Description |
|---|---|---|
| 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) | 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 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) | 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 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 and Part B: Pharmacokinetics (PK) Parameter: Area Under The Curve (0-tau) at Steady State (AUCss) for Bemcentinib | Predose, 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 Bemcentinib | Pre-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 Bemcentinib | Pre-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. |
| 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: 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) | 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 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) | 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. |
Countries
Germany, Italy, Norway, United States
Participant flow
Pre-assignment details
A total of 122 participants were enrolled to the study and received study treatment.
Participants by arm
| Arm | Count |
|---|---|
| Part A: Bemcentinib 400/100 mg Participants with relapsed or refractory AML who received daily loading dose of bemcentinib 400 mg on Days 1, 2 and 3 of Cycle 1 followed by a maximum daily maintenance dose of 100 mg thereafter. Each cycle was of 21 days. Maximum exposure was of 568 days. | 6 |
| Part A: Bemcentinib 600/200 mg Participants with relapsed or refractory AML initially received loading dose of bemcentinib 600 mg on Days 1 and 2. However, following the report of DLTs, subjects received daily loading dose of bemcentinib 400 mg on Days 1, 2 and 3 of Cycle 1 followed by a maximum daily maintenance dose of 200 mg thereafter. Each cycle was of 21 days. Maximum exposure was of 126 days. Hence, some participants received 600 mg and some received 400 mg of bemcentinib as loading dose. | 14 |
| Part A: Bemcentinib 900/300 mg Participants with relapsed or refractory AML initially received loading dose of bemcentinib 900 mg on Days 1 and 2. However, following the report of DLTs, participants received daily loading dose of bemcentinib 400 mg on Days 1, 2 and 3 of Cycle 1 followed by a maximum daily maintenance dose of 200 mg thereafter. Each cycle was of 21 days. Maximum exposure was of 122 days. Hence, some participants received 900 mg and some received 400 mg of bemcentinib as loading dose. | 5 |
| Part A: Bemcentinib 200/100 mg Participants with relapsed or refractory AML received daily loading dose of bemcentinib 200 mg on Days 1, 2 and 3 of Cycle 1 followed by a maximum daily maintenance dose of 100 mg thereafter. Each cycle was of 21 days. Maximum exposure was of 68 days. | 4 |
| Part A: Bemcentinib 400/200 mg Participants with relapsed or refractory AML who received daily loading dose of bemcentinib 400 mg on Days 1, 2 and 3 of Cycle 1 followed by a maximum daily maintenance dose of 200 mg thereafter. Each cycle was of 21 days. Maximum exposure was of 717 days. | 7 |
| Part B1: Bemcentinib 400/200 mg, AML 400/200 mg Single Agent Participants with AML who are unsuitable for intensive chemotherapy, as a result of advanced age and/or existing co-morbidities and should have relapsed following at least one line of therapy or be refractory to such prior therapy received daily loading dose of bemcentinib 400 mg on Days 1, 2 and 3 of Cycle 1 followed by a maximum daily maintenance dose of 200 mg thereafter. Each cycle was of 21 days. Maximum exposure was of 602 days. | 14 |
| Part B2: Bemcentinib 400/200 mg + Cytarabine, AML Participants with AML who are unsuitable for intensive chemotherapy, due to advanced age and/or existing co-morbidities, received daily loading dose of bemcentinib 400 mg on Days 1, 2 and 3 of Cycle 1 followed by a maximum daily maintenance dose of 200 mg thereafter. Each cycle was of 21 days. Maximum exposure to treatment was of 1424 days. In combination to this, participants received cytarabine subcutaneously according to standard practice (20 mg/m2 twice daily for 10 days followed by a rest period of \<1 month according to persisting myelosuppression). | 16 |
| Part B3: BGB324 400/200 mg + Decitabine, AML Participants with AML who are unsuitable for intensive chemotherapy, due to advanced age and/or existing co-morbidities, received daily loading dose of bemcentinib 400 mg on Days 1, 2 and 3 of Cycle 1 followed by a maximum daily maintenance dose of 200 mg thereafter. Each cycle was of 21 days. Maximum exposure to treatment was of 393 days. In combination to this, participants received decitabine (up to a maximum dose of 20 mg/m2 body surface area by intravenous infusion over one hour, repeated daily for five consecutive days \[i.e., a total of five doses per treatment cycle\]). | 18 |
| Part B4: BGB324 400/200 mg, MDS Participants with previously treated MDS (with the exception of deletion 5q MDS) including intermediate (int-2) or high-risk MDS and who received prior treatment for the same. Prior treatment included participants who received hypomethylating agents, decitabine or other approved treatments for MDS. Participants received daily loading dose of bemcentinib 400 mg on Days 1, 2 and 3 of Cycle 1 followed by a maximum daily maintenance dose of 200 mg thereafter. Each cycle was of 21 days. Maximum exposure to treatment was of 449 days. | 18 |
| Part B5: BGB324 400/200 mg + Cytarabine, AML Participants with relapsed or refractory AML who are unsuitable for intensive chemotherapy, due to advanced age and/or existing co-morbidities who must have received at least one prior treatment for AML, received daily loading dose of bemcentinib 400 mg on Days 1, 2 and 3 of Cycle 1 followed by a maximum daily maintenance dose of 200 mg thereafter. Each cycle was of 21 days. Maximum exposure to treatment was of 462 days. In combination to this, participants received low dose cytarabine subcutaneously according to standard practice (dose of 20 mg subcutaneously twice daily for 10 days every 28 days). | 20 |
| Total | 122 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 | FG009 |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Part A | Adverse Event | 2 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Part A | Death | 1 | 5 | 0 | 0 | 3 | 0 | 0 | 0 | 0 | 0 |
| Part A | Disease Progression | 2 | 8 | 2 | 3 | 4 | 0 | 0 | 0 | 0 | 0 |
| Part A | Initiation of Alternative Cancer Therapy | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 |
| Part A | Investigator Decision | 0 | 1 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Part A | Other | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Part A | Withdrawal by Subject | 0 | 0 | 2 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Part B | Adverse Event | 0 | 0 | 0 | 0 | 0 | 2 | 2 | 7 | 2 | 2 |
| Part B | Death | 0 | 0 | 0 | 0 | 0 | 3 | 1 | 2 | 2 | 2 |
| Part B | Death due to Disease Progression | 0 | 0 | 0 | 0 | 0 | 2 | 2 | 1 | 1 | 1 |
| Part B | Disease Progression | 0 | 0 | 0 | 0 | 0 | 6 | 9 | 7 | 9 | 11 |
| Part B | Initiation of Alternative Cancer Therapy | 0 | 0 | 0 | 0 | 0 | 1 | 1 | 1 | 2 | 3 |
| Part B | Investigator Decision | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 2 | 1 |
Baseline characteristics
| Characteristic | Part A: Bemcentinib 400/100 mg | Part A: Bemcentinib 600/200 mg | Part A: Bemcentinib 900/300 mg | Part A: Bemcentinib 200/100 mg | Part A: Bemcentinib 400/200 mg | Part B1: Bemcentinib 400/200 mg, AML 400/200 mg Single Agent | Part B2: Bemcentinib 400/200 mg + Cytarabine, AML | Part B3: BGB324 400/200 mg + Decitabine, AML | Part B4: BGB324 400/200 mg, MDS | Part B5: BGB324 400/200 mg + Cytarabine, AML | Total |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Customized <75 years | 3 Participants | 8 Participants | 3 Participants | 2 Participants | 2 Participants | 6 Participants | 5 Participants | 3 Participants | 9 Participants | 7 Participants | 48 Participants |
| Age, Customized >= 75 years | 3 Participants | 6 Participants | 2 Participants | 2 Participants | 5 Participants | 8 Participants | 11 Participants | 15 Participants | 9 Participants | 13 Participants | 74 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 6 Participants | 14 Participants | 5 Participants | 4 Participants | 7 Participants | 14 Participants | 15 Participants | 18 Participants | 17 Participants | 20 Participants | 120 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 5 Participants | 14 Participants | 5 Participants | 4 Participants | 7 Participants | 14 Participants | 16 Participants | 17 Participants | 17 Participants | 20 Participants | 119 Participants |
| Sex: Female, Male Female | 3 Participants | 3 Participants | 4 Participants | 0 Participants | 4 Participants | 4 Participants | 4 Participants | 6 Participants | 8 Participants | 8 Participants | 44 Participants |
| Sex: Female, Male Male | 3 Participants | 11 Participants | 1 Participants | 4 Participants | 3 Participants | 10 Participants | 12 Participants | 12 Participants | 10 Participants | 12 Participants | 78 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 4 / 6 | 5 / 14 | 1 / 5 | 2 / 4 | 6 / 7 | 10 / 14 | 12 / 16 | 12 / 18 | 13 / 18 | 14 / 20 |
| other Total, other adverse events | 5 / 6 | 14 / 14 | 5 / 5 | 4 / 4 | 7 / 7 | 14 / 14 | 16 / 16 | 17 / 18 | 18 / 18 | 20 / 20 |
| serious Total, serious adverse events | 4 / 6 | 11 / 14 | 4 / 5 | 4 / 4 | 7 / 7 | 8 / 14 | 12 / 16 | 14 / 18 | 13 / 18 | 16 / 20 |
Outcome results
Primary
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.
Time frame: Cycle 1 (21 days)
Population: The safety analysis population in Part A included all enrolled participants who received at least one dose of bemcentinib in Part A.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Part A: Bemcentinib | Part A: Maximum Tolerated Dose (MTD) of Bemcentinib (BGB324) | Loading dose for 3 days | 600 mg |
| Part A: Bemcentinib | Part A: Maximum Tolerated Dose (MTD) of Bemcentinib (BGB324) | Maintenance dose | 200 mg |
Primary
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.
Time frame: Baseline to end of the study (Part B: Maximum exposure duration was 1424 days)
Population: The safety analysis population in Part B included all enrolled participants who received at least one dose of bemcentinib in Part B.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part A: Bemcentinib | Part B: Number of Participants With Notable Trends in Physical Examination, Vital Signs, Clinical Laboratory Test and Electrocardiogram (ECG) Values | 0 Participants |
| Part B2: Bemcentinib 400/200 mg + Cytarabine, AML | Part B: Number of Participants With Notable Trends in Physical Examination, Vital Signs, Clinical Laboratory Test and Electrocardiogram (ECG) Values | 0 Participants |
| Part B3: Bemcentinib 400/200 mg + Decitabine, AML | Part B: Number of Participants With Notable Trends in Physical Examination, Vital Signs, Clinical Laboratory Test and Electrocardiogram (ECG) Values | 0 Participants |
| Part B4: Bemcentinib 400/200 mg, MDS | Part B: Number of Participants With Notable Trends in Physical Examination, Vital Signs, Clinical Laboratory Test and Electrocardiogram (ECG) Values | 0 Participants |
| Part B5: Bemcentinib 400/200 mg + Cytarabine, AML | Part B: Number of Participants With Notable Trends in Physical Examination, Vital Signs, Clinical Laboratory Test and Electrocardiogram (ECG) Values | 0 Participants |
Primary
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.
Time frame: Up to 28 days after last dose (up to 1452 days; maximum treatment exposure duration 1424 days)
Population: The safety analysis population in Part B included all enrolled participants who received at least one dose of bemcentinib in Part B.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part A: Bemcentinib | Part B: Number of Participants With Treatment-emergent Adverse Events (TEAEs) | 14 Participants |
| Part B2: Bemcentinib 400/200 mg + Cytarabine, AML | Part B: Number of Participants With Treatment-emergent Adverse Events (TEAEs) | 16 Participants |
| Part B3: Bemcentinib 400/200 mg + Decitabine, AML | Part B: Number of Participants With Treatment-emergent Adverse Events (TEAEs) | 18 Participants |
| Part B4: Bemcentinib 400/200 mg, MDS | Part B: Number of Participants With Treatment-emergent Adverse Events (TEAEs) | 18 Participants |
| Part B5: Bemcentinib 400/200 mg + Cytarabine, AML | Part B: Number of Participants With Treatment-emergent Adverse Events (TEAEs) | 20 Participants |
Secondary
Part A and B: Disease Control Rate (DCR) as Per International Working Group Response Criteria
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.
Time frame: 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)
Population: Efficacy population analyzed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part A: Bemcentinib | Part A and B: Disease Control Rate (DCR) as Per International Working Group Response Criteria | 33.3 Percentage of participants |
| Part B2: Bemcentinib 400/200 mg + Cytarabine, AML | Part A and B: Disease Control Rate (DCR) as Per International Working Group Response Criteria | 20.0 Percentage of participants |
| Part B3: Bemcentinib 400/200 mg + Decitabine, AML | Part A and B: Disease Control Rate (DCR) as Per International Working Group Response Criteria | 25.0 Percentage of participants |
| Part B4: Bemcentinib 400/200 mg, MDS | Part A and B: Disease Control Rate (DCR) as Per International Working Group Response Criteria | 25.0 Percentage of participants |
| Part B5: Bemcentinib 400/200 mg + Cytarabine, AML | Part A and B: Disease Control Rate (DCR) as Per International Working Group Response Criteria | 33.3 Percentage of participants |
| Part B1: Bemcentinib 400/200 mg, AML | Part A and B: Disease Control Rate (DCR) as Per International Working Group Response Criteria | 45.5 Percentage of participants |
| Part B2: Bemcentinib 400/200 mg + Cytarabine, AML | Part A and B: Disease Control Rate (DCR) as Per International Working Group Response Criteria | 50.0 Percentage of participants |
| Part B3: Bemcentinib 400/200 mg + Decitabine, AML | Part A and B: Disease Control Rate (DCR) as Per International Working Group Response Criteria | 30.8 Percentage of participants |
| Part B4: Bemcentinib 400/200 mg, MDs | Part A and B: Disease Control Rate (DCR) as Per International Working Group Response Criteria | 56.3 Percentage of participants |
| Part B5: Bemcentinib 400/200 mg + Cytarabine, AML | Part A and B: Disease Control Rate (DCR) as Per International Working Group Response Criteria | 16.7 Percentage of participants |
Secondary
Part A and B: Percentage of Participants With Objective Response (OR) as Per International Working Group Response Criteria
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.
Time frame: 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)
Population: Efficacy population included all participants from safety analysis population that met key eligibility criteria, have assessable disease at baseline and had at least 1 post-baseline response assessment; had received \>1 dose of bemcentinib (and combination agent in Part B2, B3 and B5).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part A: Bemcentinib | Part A and B: Percentage of Participants With Objective Response (OR) as Per International Working Group Response Criteria | 33.3 Percentage of participants |
| Part B2: Bemcentinib 400/200 mg + Cytarabine, AML | Part A and B: Percentage of Participants With Objective Response (OR) as Per International Working Group Response Criteria | 20.0 Percentage of participants |
| Part B3: Bemcentinib 400/200 mg + Decitabine, AML | Part A and B: Percentage of Participants With Objective Response (OR) as Per International Working Group Response Criteria | 0 Percentage of participants |
| Part B4: Bemcentinib 400/200 mg, MDS | Part A and B: Percentage of Participants With Objective Response (OR) as Per International Working Group Response Criteria | 0 Percentage of participants |
| Part B5: Bemcentinib 400/200 mg + Cytarabine, AML | Part A and B: Percentage of Participants With Objective Response (OR) as Per International Working Group Response Criteria | 33.3 Percentage of participants |
| Part B1: Bemcentinib 400/200 mg, AML | Part A and B: Percentage of Participants With Objective Response (OR) as Per International Working Group Response Criteria | 18.2 Percentage of participants |
| Part B2: Bemcentinib 400/200 mg + Cytarabine, AML | Part A and B: Percentage of Participants With Objective Response (OR) as Per International Working Group Response Criteria | 35.7 Percentage of participants |
| Part B3: Bemcentinib 400/200 mg + Decitabine, AML | Part A and B: Percentage of Participants With Objective Response (OR) as Per International Working Group Response Criteria | 0 Percentage of participants |
| Part B4: Bemcentinib 400/200 mg, MDs | Part A and B: Percentage of Participants With Objective Response (OR) as Per International Working Group Response Criteria | 18.8 Percentage of participants |
| Part B5: Bemcentinib 400/200 mg + Cytarabine, AML | Part A and B: Percentage of Participants With Objective Response (OR) as Per International Working Group Response Criteria | 16.7 Percentage of participants |
Secondary
Part A and B: Percentage of Participants With Stable Disease (SD) as Per International Working Group Response Criteria
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.
Time frame: 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)
Population: Efficacy population analyzed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part A: Bemcentinib | Part A and B: Percentage of Participants With Stable Disease (SD) as Per International Working Group Response Criteria | 0 Percentage of participants |
| Part B2: Bemcentinib 400/200 mg + Cytarabine, AML | Part A and B: Percentage of Participants With Stable Disease (SD) as Per International Working Group Response Criteria | 0 Percentage of participants |
| Part B3: Bemcentinib 400/200 mg + Decitabine, AML | Part A and B: Percentage of Participants With Stable Disease (SD) as Per International Working Group Response Criteria | 25.0 Percentage of participants |
| Part B4: Bemcentinib 400/200 mg, MDS | Part A and B: Percentage of Participants With Stable Disease (SD) as Per International Working Group Response Criteria | 25.0 Percentage of participants |
| Part B5: Bemcentinib 400/200 mg + Cytarabine, AML | Part A and B: Percentage of Participants With Stable Disease (SD) as Per International Working Group Response Criteria | 0 Percentage of participants |
| Part B1: Bemcentinib 400/200 mg, AML | Part A and B: Percentage of Participants With Stable Disease (SD) as Per International Working Group Response Criteria | 27.3 Percentage of participants |
| Part B2: Bemcentinib 400/200 mg + Cytarabine, AML | Part A and B: Percentage of Participants With Stable Disease (SD) as Per International Working Group Response Criteria | 14.3 Percentage of participants |
| Part B3: Bemcentinib 400/200 mg + Decitabine, AML | Part A and B: Percentage of Participants With Stable Disease (SD) as Per International Working Group Response Criteria | 30.8 Percentage of participants |
| Part B4: Bemcentinib 400/200 mg, MDs | Part A and B: Percentage of Participants With Stable Disease (SD) as Per International Working Group Response Criteria | 37.5 Percentage of participants |
| Part B5: Bemcentinib 400/200 mg + Cytarabine, AML | Part A and B: Percentage of Participants With Stable Disease (SD) as Per International Working Group Response Criteria | 0 Percentage of participants |
Secondary
Part A and B: Pharmacokinetics Parameter: Maximum Observed Plasma Concentration (Cmax) for Bemcentinib
Observed maximum predicted PK concentration (Cmax) during 24 hours at steady state (Cmax, ss).
Time frame: Pre-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
Population: PK analysis population=participants who had 1 dose of bemcentinib \& evaluable PK data available. Part A arms combined based on maintenance dose. Part B was not combined as combinations were different or were for different indications; time to attaining steady state affected by magnitude of loading dose, exposure at steady state would only be determined by level of daily maintenance dose. As pre-specified in analysis plan, data for arms that received same maintenance dose were reported combined.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part A: Bemcentinib | Part A and B: Pharmacokinetics Parameter: Maximum Observed Plasma Concentration (Cmax) for Bemcentinib | 140 nanogram per milliliter (ng/mL) | Standard Deviation 110 |
| Part B2: Bemcentinib 400/200 mg + Cytarabine, AML | Part A and B: Pharmacokinetics Parameter: Maximum Observed Plasma Concentration (Cmax) for Bemcentinib | 162 nanogram per milliliter (ng/mL) | Standard Deviation 121 |
| Part B3: Bemcentinib 400/200 mg + Decitabine, AML | Part A and B: Pharmacokinetics Parameter: Maximum Observed Plasma Concentration (Cmax) for Bemcentinib | 398 nanogram per milliliter (ng/mL) | Standard Deviation 200 |
| Part B4: Bemcentinib 400/200 mg, MDS | Part A and B: Pharmacokinetics Parameter: Maximum Observed Plasma Concentration (Cmax) for Bemcentinib | 210 nanogram per milliliter (ng/mL) | Standard Deviation 108 |
| Part B5: Bemcentinib 400/200 mg + Cytarabine, AML | Part A and B: Pharmacokinetics Parameter: Maximum Observed Plasma Concentration (Cmax) for Bemcentinib | 198 nanogram per milliliter (ng/mL) | Standard Deviation 137 |
| Part B1: Bemcentinib 400/200 mg, AML | Part A and B: Pharmacokinetics Parameter: Maximum Observed Plasma Concentration (Cmax) for Bemcentinib | 228 nanogram per milliliter (ng/mL) | Standard Deviation 101 |
| Part B2: Bemcentinib 400/200 mg + Cytarabine, AML | Part A and B: Pharmacokinetics Parameter: Maximum Observed Plasma Concentration (Cmax) for Bemcentinib | 150 nanogram per milliliter (ng/mL) | Standard Deviation 84.7 |
| Part B3: Bemcentinib 400/200 mg + Decitabine, AML | Part A and B: Pharmacokinetics Parameter: Maximum Observed Plasma Concentration (Cmax) for Bemcentinib | 219 nanogram per milliliter (ng/mL) | Standard Deviation 123 |
Secondary
Part A and B: Pharmacokinetics Parameter: t1/2 for Bemcentinib
Median half-life (t1/2) at steady state.
Time frame: Pre-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
Population: PK analysis population=participants who had 1 dose of bemcentinib \& evaluable PK data available. Part A arms combined based on maintenance dose. Part B was not combined as combinations were different or were for different indications; time to attaining steady state affected by magnitude of loading dose, exposure at steady state would only be determined by level of daily maintenance dose. As pre-specified in analysis plan, data for arms that received same maintenance dose were reported combined.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part A: Bemcentinib | Part A and B: Pharmacokinetics Parameter: t1/2 for Bemcentinib | 159 hours |
| Part B2: Bemcentinib 400/200 mg + Cytarabine, AML | Part A and B: Pharmacokinetics Parameter: t1/2 for Bemcentinib | 124 hours |
| Part B3: Bemcentinib 400/200 mg + Decitabine, AML | Part A and B: Pharmacokinetics Parameter: t1/2 for Bemcentinib | 156 hours |
| Part B4: Bemcentinib 400/200 mg, MDS | Part A and B: Pharmacokinetics Parameter: t1/2 for Bemcentinib | 157 hours |
| Part B5: Bemcentinib 400/200 mg + Cytarabine, AML | Part A and B: Pharmacokinetics Parameter: t1/2 for Bemcentinib | 126 hours |
| Part B1: Bemcentinib 400/200 mg, AML | Part A and B: Pharmacokinetics Parameter: t1/2 for Bemcentinib | 155 hours |
| Part B2: Bemcentinib 400/200 mg + Cytarabine, AML | Part A and B: Pharmacokinetics Parameter: t1/2 for Bemcentinib | 116 hours |
| Part B3: Bemcentinib 400/200 mg + Decitabine, AML | Part A and B: Pharmacokinetics Parameter: t1/2 for Bemcentinib | 112 hours |
Secondary
Part A and Part B: Pharmacokinetics (PK) Parameter: Area Under The Curve (0-tau) at Steady State (AUCss) for Bemcentinib
Predicted AUCss = area under the curve PK -time profile during 24 hours at steady state.
Time frame: Predose, 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)
Population: PK analysis population=participants who had 1 dose of bemcentinib \& evaluable PK data available. Part A arms combined based on maintenance dose. Part B was not combined as combinations were different or were for different indications; time to attaining steady state affected by magnitude of loading dose, exposure at steady state would only be determined by level of daily maintenance dose. As pre-specified in analysis plan, data for arms that received same maintenance dose were reported combined.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part A: Bemcentinib | Part A and Part B: Pharmacokinetics (PK) Parameter: Area Under The Curve (0-tau) at Steady State (AUCss) for Bemcentinib | 3310 nanogram*hour per milliliter (ng*h/mL) | Standard Deviation 2630 |
| Part B2: Bemcentinib 400/200 mg + Cytarabine, AML | Part A and Part B: Pharmacokinetics (PK) Parameter: Area Under The Curve (0-tau) at Steady State (AUCss) for Bemcentinib | 3810 nanogram*hour per milliliter (ng*h/mL) | Standard Deviation 2860 |
| Part B3: Bemcentinib 400/200 mg + Decitabine, AML | Part A and Part B: Pharmacokinetics (PK) Parameter: Area Under The Curve (0-tau) at Steady State (AUCss) for Bemcentinib | 9390 nanogram*hour per milliliter (ng*h/mL) | Standard Deviation 4720 |
| Part B4: Bemcentinib 400/200 mg, MDS | Part A and Part B: Pharmacokinetics (PK) Parameter: Area Under The Curve (0-tau) at Steady State (AUCss) for Bemcentinib | 4910 nanogram*hour per milliliter (ng*h/mL) | Standard Deviation 2560 |
| Part B5: Bemcentinib 400/200 mg + Cytarabine, AML | Part A and Part B: Pharmacokinetics (PK) Parameter: Area Under The Curve (0-tau) at Steady State (AUCss) for Bemcentinib | 4650 nanogram*hour per milliliter (ng*h/mL) | Standard Deviation 3260 |
| Part B1: Bemcentinib 400/200 mg, AML | Part A and Part B: Pharmacokinetics (PK) Parameter: Area Under The Curve (0-tau) at Steady State (AUCss) for Bemcentinib | 5320 nanogram*hour per milliliter (ng*h/mL) | Standard Deviation 2380 |
| Part B2: Bemcentinib 400/200 mg + Cytarabine, AML | Part A and Part B: Pharmacokinetics (PK) Parameter: Area Under The Curve (0-tau) at Steady State (AUCss) for Bemcentinib | 3510 nanogram*hour per milliliter (ng*h/mL) | Standard Deviation 2010 |
| Part B3: Bemcentinib 400/200 mg + Decitabine, AML | Part A and Part B: Pharmacokinetics (PK) Parameter: Area Under The Curve (0-tau) at Steady State (AUCss) for Bemcentinib | 5090 nanogram*hour per milliliter (ng*h/mL) | Standard Deviation 2910 |
Secondary
Part A: 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 as per investigator observation. Notable trends meant observations that were outside normal range as specified by sponsor.
Time frame: Baseline to end of the study (Part A: Maximum exposure duration was 717 days)
Population: The safety analysis population in Part A included all enrolled participants who received at least one dose of bemcentinib in Part A.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part A: Bemcentinib | Part A: Number of Participants With Notable Trends in Physical Examination, Vital Signs, Clinical Laboratory Test and Electrocardiogram (ECG) Values | 0 Participants |
| Part B2: Bemcentinib 400/200 mg + Cytarabine, AML | Part A: Number of Participants With Notable Trends in Physical Examination, Vital Signs, Clinical Laboratory Test and Electrocardiogram (ECG) Values | 0 Participants |
| Part B3: Bemcentinib 400/200 mg + Decitabine, AML | Part A: Number of Participants With Notable Trends in Physical Examination, Vital Signs, Clinical Laboratory Test and Electrocardiogram (ECG) Values | 0 Participants |
| Part B4: Bemcentinib 400/200 mg, MDS | Part A: Number of Participants With Notable Trends in Physical Examination, Vital Signs, Clinical Laboratory Test and Electrocardiogram (ECG) Values | 0 Participants |
| Part B5: Bemcentinib 400/200 mg + Cytarabine, AML | Part A: Number of Participants With Notable Trends in Physical Examination, Vital Signs, Clinical Laboratory Test and Electrocardiogram (ECG) Values | 0 Participants |
Secondary
Part A: 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.
Time frame: Up to 28 days after last dose (up to 745 days, maximum exposure duration 717 days)
Population: The safety analysis population in Part A included all enrolled participants who received at least one dose of bemcentinib in Part A.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part A: Bemcentinib | Part A: Number of Participants With Treatment-emergent Adverse Events (TEAEs) | 5 Participants |
| Part B2: Bemcentinib 400/200 mg + Cytarabine, AML | Part A: Number of Participants With Treatment-emergent Adverse Events (TEAEs) | 14 Participants |
| Part B3: Bemcentinib 400/200 mg + Decitabine, AML | Part A: Number of Participants With Treatment-emergent Adverse Events (TEAEs) | 5 Participants |
| Part B4: Bemcentinib 400/200 mg, MDS | Part A: Number of Participants With Treatment-emergent Adverse Events (TEAEs) | 4 Participants |
| Part B5: Bemcentinib 400/200 mg + Cytarabine, AML | Part A: Number of Participants With Treatment-emergent Adverse Events (TEAEs) | 7 Participants |
Secondary
Part B: Event Free Survival (EFS)
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.
Time frame: Day 1 of dosing up to end of the study (Part B: maximum exposure duration 1424 days)
Population: Efficacy population analyzed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part A: Bemcentinib | Part B: Event Free Survival (EFS) | 2.69 Months |
| Part B2: Bemcentinib 400/200 mg + Cytarabine, AML | Part B: Event Free Survival (EFS) | 3.75 Months |
| Part B3: Bemcentinib 400/200 mg + Decitabine, AML | Part B: Event Free Survival (EFS) | 4.13 Months |
| Part B4: Bemcentinib 400/200 mg, MDS | Part B: Event Free Survival (EFS) | 4.18 Months |
| Part B5: Bemcentinib 400/200 mg + Cytarabine, AML | Part B: Event Free Survival (EFS) | 2.33 Months |
Secondary
Part B: Overall Survival (OS)
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.
Time frame: Day 1 of dosing up to end of the study (Part B: maximum exposure duration 1424 days)
Population: Efficacy population analyzed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part A: Bemcentinib | Part B: Overall Survival (OS) | 18.0 Months |
| Part B2: Bemcentinib 400/200 mg + Cytarabine, AML | Part B: Overall Survival (OS) | 11.1 Months |
| Part B3: Bemcentinib 400/200 mg + Decitabine, AML | Part B: Overall Survival (OS) | 6.4 Months |
| Part B4: Bemcentinib 400/200 mg, MDS | Part B: Overall Survival (OS) | 9.2 Months |
| Part B5: Bemcentinib 400/200 mg + Cytarabine, AML | Part B: Overall Survival (OS) | 8.0 Months |
Secondary
Part B: Relapse Free Survival (RFS)
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).
Time frame: Day 1 of dosing up to end of the study (Part B: maximum exposure duration 1424 days)
Population: Efficacy population analyzed. Overall Number of Participants Analyzed: Participants evaluable for this outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part A: Bemcentinib | Part B: Relapse Free Survival (RFS) | 6.61 Months |
| Part B2: Bemcentinib 400/200 mg + Cytarabine, AML | Part B: Relapse Free Survival (RFS) | 17.25 Months |
| Part B4: Bemcentinib 400/200 mg, MDS | Part B: Relapse Free Survival (RFS) | 3.08 Months |
| Part B5: Bemcentinib 400/200 mg + Cytarabine, AML | Part B: Relapse Free Survival (RFS) | 3.05 Months |