Acute Leukemia, Myelodysplastic Syndromes
Conditions
Keywords
Leukemia, Leukemia, Myeloid, Leukemia, Myeloid, Acute, MER, MERTK, TYRO3, AXL, AML, Relapsed/ Refractory AML, TAM, MDS, Myelodysplastic Syndrome, Relapsed/ Refractory MDS
Brief summary
\[Updated\]: To assess the safety and tolerability of ONO-7475 monotherapy in patients with relapsed or refractory acute myeloid leukemia or relapsed or refractory myelodysplastic syndromes and to assess: i) safety and tolerability and ii) preliminary efficacy of the combination of ONO-7475 and venetoclax in patients with relapsed or refractory acute myeloid leukemia.
Detailed description
Part A is a dose escalation study of ONO-7475 in patients with acute myeloid leukemia or relapsed or refractory myelodysplastic syndromes. Part D is a dose escalation study of ONO-7475 in combination with venetoclax. ONO-7475 starting dose is selected following safety and tolerability outcome of Part A.
Interventions
DRUGONO-7475 3mg once daily
Part A initial dose level
DRUGONO-7475 6mg once daily
Part A 2nd dose level
DRUGONO-7475 10mg once daily
Part A 3rd dose level
DRUGONO-7475 6mg + Venetoclax (70-400mg)
Part D ONO-7475 + Venetoclax Combination
Sponsors
Ono Pharmaceutical Co. Ltd
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Part A: ONO-7475 open-label, dose escalation in R/R AML or R/R MDS Part D: ONO-7475 plus venetoclax open-label, dose escalation in R/R AML
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Patients aged ≥18 years at time of screening. 2. Written informed consent by the patient (or their legal representative) prior to admission to this study. In addition, any locally required authorization (Health Insurance Portability and Accountability Act in the US), must be obtained from the patient prior to performing any protocol-related procedures, including screening evaluations. 3. Adequate renal and hepatic function defined as: 1. Total bilirubin within 1.5 x upper limit of normal (ULN), except those with Gilberts syndrome for whom this must be ≤3 x ULN 2. AST and ALT ≤2.5 x ULN 3. Calculated creatinine clearance ≥45 mL/min 4. Serum albumin ≥2.5 g/dL For any patient with laboratory values outside the ranges outlined above that are considered due to the patient's underlying disease (AML or MDS), the patient may be enrolled into the study following consultation between the Investigator and the Sponsor's Medical Officer, if the patient is likely to benefit from receiving ONO-7475 (based on the Investigator's assessment). 4. Eastern Cooperative Oncology Group (ECOG) performance status 0-2 as assessed during the screening period and then again anytime during the 2-day period immediately preceding the start of dosing in Parts A and D. 5. Life expectancy of at least 3 months 6. Sexually active female patients of childbearing potential and sexually active male patients must agree to use an effective method of birth control (e.g., barrier methods with spermicides, oral or parenteral contraceptives and/or intrauterine devices) during the entire duration of the study and for 4 months after final administration of study drug. Note that sterility in female patients must be confirmed in the patients' medical records and be defined as any of the following: surgical hysterectomy with bilateral oophorectomy, bilateral tubular ligation, natural menopause with last menses \>1 year ago, radiation-induced oophorectomy with last menses \>1 year ago, chemotherapy-induced menopause with last menses \>1 year ago. 7. Diagnosis of AML or MDS according to WHO criteria 2016 (Part A only). 8. Either criterion is met (Part A only): 1. Patients with R/R AML with at least 5% blasts by BM biopsy or aspirate, or at least 1% blasts in peripheral blood, not likely to benefit from standard salvage chemotherapy 2. Patients with R/R MDS who are either not eligible for (or unlikely to benefit from) other forms of therapy, including HSCT, according to the treating Physician/Investigator . 9. All patients must have received at least one previous line of therapy (Part A only). 10. Diagnosis of AML according to WHO criteria (2016) (Part D only). 11. Patients with R/R AML who have no standard-of-care options known to provide clinical benefit in patients with R/R AML (Part D only) 1. Refractory AML: Patients who have not achieved complete remission after two cycles of induction chemotherapy (i.e., anthracycline containing regimen), four cycles of hypomethylating agents, or two cycles of other AML therapy 2. Relapsed AML: Patients who have ≥5% BM blasts in BM, or reappearance of blasts in the peripheral blood not attributable to another cause (e.g., recovery of normal cells following chemotherapy-induced aplasia) or (re)appearance of extramedullary disease after CR of prior AML therapy. 12. Patients must have measured BM aspirate blast counts at Screening. Where the aspirate is hypo cellular or inaspirable a biopsy would be considered. 13. Patients who were refractory to or relapsed after their 1st line treatment for AML must have received 2 or less additional lines of intensive / aggressive chemotherapy, which also includes a venetoclax-based regimen, as per the latest National Comprehensive Cancer Network (NCCN) Guidelines.
Exclusion criteria
1. Patients with active central nervous system leukemia. 2. QT interval corrected according to Fredericia's formula (QTcF) prolongation defined as a QTcF interval \>470 msec or other significant ECG abnormalities including second degree (type II) or third degree atrioventricular block or bradycardia (ventricular rate \<50 beats/min). 3. Clinically significant liver disease, including active viral or other hepatitis, current alcohol abuse, or severe cirrhosis. 4. Human immunodeficiency virus (HIV), active hepatitis B (HBV) or C (HCV) infection. 5. Retinal disease (e.g., retinitis pigmentosa including Mertk mutations), retinal hemorrhage or any disorder which may inhibit follow up for retinal toxicity. 6. Serious intercurrent medical or psychiatric illness that will prevent participation or compliance with study procedures, including serious active infection (including COVID-19). 7. Acute promyelocytic leukemia (the French-American-British M3 classification). 8. Patients not recovered to Grade 1 or stabilized from the effects (excluding alopecia) of any prior therapy for their malignancies. 9. Concurrent treatment with other investigational drugs. 10. Daily requirement of ≥10 mg/day of prednisone or equivalent dose of other corticosteroids. 11. Prior HSCT within 12 weeks of the first dose of study treatment or ongoing immunosuppressive therapy for graft-versus-host disease. 12. Participation in another clinical trial with any investigational drug within 14 days or with any licensed drug within five half-lives, prior to the first ONO-7475 dosing (for Part A) or prior to the first venetoclax dosing (for Part D). 13. Prior AML or MDS therapy (non-experimental) within 14 days or 5 half-lives, whichever is longer, prior to the first dose of ONO-7475 (for Part A) or prior to the first venetoclax dosing (for Part D) (except those permitted in Section 7.1) and no residual toxicity from the prior therapy hindering of the ONO-7475 dosing (for Part A) or ONO-7475 plus venetoclax dosing (for Part D). 14. Prior radiotherapy within 21 days of screening, with the exception of localized palliative radiotherapy. 15. Patients undergoing current treatments for other cancers. 16. Pregnant or lactating women. 17. Proliferative disease (white blood cell \[WBC\] counts \>30 x 10e9/L) confirmed prior to the first dose of ONO-7475 (for Part A) or WBC \>25 x 10e9/L in Part D. 18. Active malignancy, other than AML (Parts A and D) or MDS (Part A), requiring systemic therapy except for those patients who have been diagnosed with either prostate or breast cancer and who have received a stable dose of hormone therapy for a minimum of 6 months prior to entering this study. 19. Known hypersensitivity to venetoclax (Part D only). 20. Calculated creatinine clearance \<45 mL/min
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Adverse Events (Part A) | From start of study drug up to 30 days after permanent discontinuation of study drug or initiation of new anti-cancer therapy, whichever occurs first (maximum of 32 months). | Incidence of most common (frequency of \>20%) treatment-emergent adverse events (TEAEs) of CTCAE grade 3 or higher by preferred terms coded with MedDRA version 23.1. CTCAE = Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. |
| Incidence of Serious Adverse Events (Part A) | From start of study drug up to 30 days after permanent discontinuation of study drug or initiation of new anti-cancer therapy, whichever occurs first (maximum of 32 months). | Incidence (frequency ≥ 2 participants) of serious treatment-emergent adverse events (all CTCAE grades) by preferred terms coded with MedDRA version 23.1. CTCAE = Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. |
| Clinically Significant Changes in Ophthalmology Examination Parameters (Part A) | From start of study drug up to 30 days after permanent discontinuation of study drug or initiation of new anti-cancer therapy, whichever occurs first (maximum of 32 months). | Incidence (all participants) of ophthalmological treatment-emergent adverse events (all CTCAE grades) by preferred terms coded with MedDRA Version 23.1. CTCAE = Common Terminology Criteria for Adverse Event version 4.03. |
| Clinically Significant Changes in 12-Lead Electrocardiogram Parameters (Part A) | From start of study drug up to 30 days after permanent discontinuation of study drug or initiation of new anti-cancer therapy, whichever occurs first (maximum of 32 months). | Participants with clinically significant changes in 12-lead Electrocardiogram (ECG) parameters. |
| Incidence of Adverse Events (Part D) | From start of study drug up to 30 days after permanent discontinuation of study drug or initiation of new anti-cancer therapy, whichever occurs first (maximum of 21 months). | Incidence of most common (frequency \> 20%) treatment-emergent adverse events (TEAEs) of CTCAE grade 3 or higher by preferred term coded with MedDRA version 23.1. CTCAE = Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. |
| Incidence of Serious Adverse Events (Part D) | From start of study drug up to 30 days after permanent discontinuation of study drug or initiation of new anti-cancer therapy, whichever occurs first (maximum of 21 months). | Incidence (frequency ≥ 2 participants) of serious treatment-emergent adverse events (all CTCAE grades) by preferred terms coded with MedDRA version 23.1. CTCAE = Common Terminology Criteria for Adverse Events (CTXAE) Version 4.03. |
| Complete Response (CR) / Complete Response With Partial Hematologic Recovery (CRh) Rate (Part D) | From baseline up to maximum of 21 months | Summary of complete response (CR) and complete response with partial hematologic recovery (CRh) rate. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Pharmacodynamics (Axl and Mer Inhibition) of ONO-7475 (Part A) | Day 2 and Day 28 | Assessment of the pharmacodynamic activity by measurement of Axl and Mer inhibition using a Plasma Inhibitory Activity (PIA) assay. PIA is a flow cytometry assay measuring auto-phosphorylation in Axl-expressing Ba/F3 and Mer-expressing Ba/F3 cells, respectively the percentage of inhibition. Pre-dose samples were collected for the analysis on day 2 and day 28. |
| Event Free Survival in ONO-7475 Groups (Part A) | From baseline up to maximum of 32 months | Part A analysis of event free survival in ONO-7475 treatment groups |
| Pharmacokinetics (Cmax) of ONO-7475 in Treatment Group ONO-7475 + Venetoclax (Part D) | Day 29 | Part D Pharmacokinetics (Cmax) of ONO-7475 in treatment group ONO-7475 + venetoclax. |
| Pharmacokinetics (Tmax) of ONO-7475 in Treatment Group ONO-7475 + Venetoclax (Part D) | Day 29 | Part D Pharmacokinetics (Tmax) of ONO-7475 in treatment group ONO-7475 + venetoclax. |
| Pharmacokinetics (AUC) of ONO-7475 in Treatment Group ONO-7475 + Venetoclax (Part D) | Day 29 | Part D Pharmacokinetics (AUC) of ONO-7475 in treatment group ONO-7475 + venetoclax. |
| Pharmacokinetics (T1/2) of ONO-7475 in Treatment Group ONO-7475 + Venetoclax (Part D) | Day 29 | Part D Pharmacokinetics (T1/2) of ONO-7475 in treatment group ONO-7475 + venetoclax. |
| Pharmacokinetics (Cmax) of Venetoclax in Treatment Group ONO-7475 + Venetoclax (Part D) | Day 1 and Day 29 | Part D Pharmacokinetics (Cmax) of Venetoclax in treatment group ONO-7475 + Venetoclax. |
| Pharmacokinetics (Tmax) of Venetoclax in Treatment Group ONO-7475 + Venetoclax (Part D) | Day 1 and Day 29 | Part D Pharmacokinetics (Tmax) of Venetoclax in treatment group ONO-7475 + venetoclax. |
| Determination of Maximum Tolerated Dose (MTD) by Assessing Dose Limiting Toxicities (DLT) (Part A) | 28 days | Dose Limiting Toxicities (DLT) Criteria: 1) ONO-7475-related ≥Grade 4 hematologic toxicity, 2) any pre-existing condition that worsens by more than 1 grade or to Grade 4, not caused by AML, 3) any ≥Grade 3 non-hematologic toxicity not caused by AML (exception: alopecia, nausea, vomiting, fatigue, headache, chills, electrolyte disturbances), 4) ≥Grade 2 blurred vision (confirmed by loss of 15 letters or more on Early Treatment Diabetic Retinopathy chart and by ophthalmological and retinal assessments) not caused by AML, 5) ≥Grade 2 clinically significant changes in night blindness not caused by AML, 6) ≥Grade 3 differentiation syndrome, 7) death not caused by AML, and 8) any other event determined by the Safety Review Committee for dosing stop. Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 was applied for toxicity grading. |
| Pharmacokinetics (T1/2) of Venetoclax in Treatment Group ONO-7475 + Venetoclax (Part D) | Day 29 | Part D Pharmacokinetics (T1/2) of Venetoclax in treatment group ONO-7475 + venetoclax. |
| Incidence of Adverse Events in ONO-7475 + Venetoclax Group (Part D) | From start of study drug up to 30 days after permanent discontinuation of study drug or initiation of new anti-cancer therapy, whichever occurs first (maximum of 21 months). | Part D Incidence (frequency \> 20%) and severity (CTCAE grades) of treatment-emergent adverse events in ONO-7475 + Venetoclax Group, in preferred terms coded MedDRA version 23.1. CTCAE = common terminology criteria for adverse events (CTCAE) version 4.03. |
| Incidence of Serious Adverse Events in ONO-7475 + Venetoclax Group (Part D) | From start of study drug up to 30 days after permanent discontinuation of study drug or initiation of new anti-cancer therapy, whichever occurs first (maximum of 21 months). | Part D Incidence (frequency ≥ 2 participants) and severity (CTCAE grades) of serious treatment-emergent adverse events in ONO-7475 + Venetoclax Group (Part D), preferred term coded with MedDRA version 23.1. CTCAE = Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. |
| Overall Response Rate in ONO-7475 + Venetoclax Group (Part D) | From baseline up to maximum of 21 months | Part D Summary of best overall response in ONO-7475 + Venetoclax group. |
| Duration of Response in ONO-7475 + Venetoclax Group (Part D) | From baseline up to maximum of 21 months | Part D Duration of response in ONO-7475 6mg + Venetoclax group. |
| Event-Free Survival and Overall Survival in ONO-7475 + Venetoclax Group (Part D) | From baseline up to maximum of 21 months | Part D analysis of event free survival and overall survival in ONO-7475 6mg + Venetoclax group |
| Transfusion Independence Rate (Part D) | From baseline up to maximum of 21 months | Part D analysis of transfusion Independence rate. Rate of maintenance of transfusion independence = percentage of patients who were transfusion independent post-baseline based upon the patients who were transfusion independent at baseline. Calculated using the Clopper-Pearson method. |
| Pharmacokinetics (AUC) of Venetoclax in Treatment Group ONO-7475 + Venetoclax | Day 1 and Day 29 | Part D Pharmacokinetics (AUC) of Venetoclax in treatment group ONO-7475 + venetoclax. |
| Pharmacokinetics (Cmax and Ctrough) of ONO-7475 (Part A) | Day 1 and Day 28 | Part A Pharmacokinetics Cmax of ONO-7475 assessed on day 1 and day 28, and Ctrough of ONO-7475 assessed on day 28 (pre-dose). |
| Pharmacokinetics (Tmax) of ONO-7475 (Part A) | Day 1 and Day 28 | Part A Pharmacokinetics Tmax of ONO-7475 assessed on day 1 and day 28. |
| Overall Response Rate and Duration of Response in ONO-7475 Groups (Part A) | From baseline up to maximum of 32 months | Part A analysis of best overall response. Duration of response analysis was not performed as no response of complete remission, Morphologic complete remission with incomplete blood count recovery, morphologic leukemia-free state, or partial remission was observed. |
| Pharmacokinetics (AUC) of ONO-7475 (Part A) | Day 1 and Day 28 | Part A Pharmacokinetics (AUC0-10h) of ONO-7475 assessed on day 1 and day 28, (AUC0-24h) of ONO-7475 assessed on day 1. |
| Pharmacokinetics (T1/2) of ONO-7475 (Part A) | Day 1 and Day 28 | Part A Pharmacokinetics T1/2 of ONO-7475 assessed on day 1 and day 28. T1/2 was not calculable due to insufficient evaluable data. |
| Pharmacokinetics of the Food Effect on ONO-7475 (Part A) | Day 28 and Day 57 | Part A Pharmacokinetics (Cmax, Tmax, AUC, T1/2, Ctrough) of the food effect on ONO-7475 assessed as ratio of Day57/Day28 and comparing pharmacokinetic parameters from dosing under fasted and non-fasted conditions assessed in 6mg and 10mg dose groups. |
Countries
United States
Participant flow
Pre-assignment details
Part A study: a total of 29 participants signed informed consent form and were enrolled in the study. 9 participants were screen failures who did not meet eligibility criteria. 20 participants received at least 1 dose of study drug. Part D study: a total of 33 participants signed informed consent form and were enrolled in the study. 11 participants were screen failures who did not meet eligibility criteria. 22 participants received at least 1 dose of study drug. No dose escalation conducted.
Participants by arm
| Arm | Count |
|---|---|
| ONO-7475 3mg Part A initial dose level | 10 |
| ONO-7475 6mg Part A 2nd dose level | 3 |
| ONO-7475 10mg Part A 3rd dose level | 7 |
| ONO-7475 6mg + Venetoclax Part D combination of ONO-7475 + Venetoclax | 22 |
| Total | 42 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Part A Dose Escalation Study | Adverse Event | 1 | 0 | 1 | 0 |
| Part A Dose Escalation Study | Physician Decision | 1 | 1 | 2 | 0 |
| Part A Dose Escalation Study | Progressive disease | 3 | 1 | 3 | 0 |
| Part A Dose Escalation Study | Withdrawal by Subject | 5 | 1 | 1 | 0 |
Baseline characteristics
| Characteristic | ONO-7475 6mg | ONO-7475 6mg + Venetoclax | Total | ONO-7475 3mg | ONO-7475 10mg |
|---|---|---|---|---|---|
| Age, Continuous Age | 65.0 years | 65.5 years | 67.0 years | 56.0 years | 72.0 years |
| Age, Customized <=60 years | 1 Participants | 9 Participants | 15 Participants | 5 Participants | 0 Participants |
| Age, Customized >60 years | 2 Participants | 13 Participants | 27 Participants | 5 Participants | 7 Participants |
| AML classification at initial diagnosis 2008 2016 revisions to 2008 WHO classification ACUTE MEGAKARYOBLASTIC LEUKEMIA | 1 Participants | 1 Participants | 2 Participants | 0 Participants | 0 Participants |
| AML classification at initial diagnosis 2008 2016 revisions to 2008 WHO classification ACUTE MONOBLASTIC/MONOCYTIC LEUKEMIA | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| AML classification at initial diagnosis 2008 2016 revisions to 2008 WHO classification ACUTE MYELOID LEUKEMIA WITH MYELODYSPLASIA-RELATED CHANGES | 0 Participants | 9 Participants | 13 Participants | 3 Participants | 1 Participants |
| AML classification at initial diagnosis 2008 2016 revisions to 2008 WHO classification ACUTE MYELOMONOCYTIC LEUKEMIA | 1 Participants | 2 Participants | 3 Participants | 0 Participants | 0 Participants |
| AML classification at initial diagnosis 2008 2016 revisions to 2008 WHO classification AML, NOS | 1 Participants | 5 Participants | 8 Participants | 1 Participants | 1 Participants |
| AML classification at initial diagnosis 2008 2016 revisions to 2008 WHO classification AML WITH INV(16)(P13.1Q22) OR T(16;16)(P13.1;Q22); CBFB-MYH11 | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants |
| AML classification at initial diagnosis 2008 2016 revisions to 2008 WHO classification AML WITH MATURATION | 0 Participants | 1 Participants | 3 Participants | 2 Participants | 0 Participants |
| AML classification at initial diagnosis 2008 2016 revisions to 2008 WHO classification AML WITH MINIMAL DIFFERENTIATION | 0 Participants | 0 Participants | 3 Participants | 1 Participants | 2 Participants |
| AML classification at initial diagnosis 2008 2016 revisions to 2008 WHO classification AML WITH MUTATED RUNX1 | 0 Participants | 2 Participants | 3 Participants | 0 Participants | 1 Participants |
| AML classification at initial diagnosis 2008 2016 revisions to 2008 WHO classification AML Without Maturation | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| AML classification at initial diagnosis 2008 2016 revisions to 2008 WHO classification UNKNOWN | 0 Participants | 1 Participants | 4 Participants | 2 Participants | 1 Participants |
| AML classification performed according to WHO criteria 2016 completed at screening ACUTE MEGAKARYOBLASTIC LEUKEMIA | 1 Participants | 1 Participants | 2 Participants | 0 Participants | 0 Participants |
| AML classification performed according to WHO criteria 2016 completed at screening ACUTE MYELOBLASTIC/MONOCYTIC LEUKEMIA | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| AML classification performed according to WHO criteria 2016 completed at screening ACUTE MYELOID LEUKEMIA WITH MYELODYSPLASIA-RELATED CHANGES | 0 Participants | 6 Participants | 11 Participants | 5 Participants | 0 Participants |
| AML classification performed according to WHO criteria 2016 completed at screening ACUTE MYELOMONOCYTIC LEUKEMIA | 1 Participants | 2 Participants | 3 Participants | 0 Participants | 0 Participants |
| AML classification performed according to WHO criteria 2016 completed at screening AML, NOS | 1 Participants | 7 Participants | 11 Participants | 1 Participants | 2 Participants |
| AML classification performed according to WHO criteria 2016 completed at screening AML WITH INV(16)(P13.1Q22) OR T(16;16)(P13.1;Q22); CBFB-MYH11 | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants |
| AML classification performed according to WHO criteria 2016 completed at screening AML WITH MATURATION | 0 Participants | 1 Participants | 3 Participants | 2 Participants | 0 Participants |
| AML classification performed according to WHO criteria 2016 completed at screening AML WITH MINIMAL DIFFERENTIATION | 0 Participants | 0 Participants | 4 Participants | 1 Participants | 3 Participants |
| AML classification performed according to WHO criteria 2016 completed at screening AML WITH MUTATED RUNX1 | 0 Participants | 3 Participants | 4 Participants | 0 Participants | 1 Participants |
| AML classification performed according to WHO criteria 2016 completed at screening AML With Recurrent Genetic Abnormalities | 0 Participants | 2 Participants | 2 Participants | 0 Participants | 0 Participants |
| AML FAB classification at initial diagnosis Acute Myeloid Leukaemia With Cup Like Morphology | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| AML FAB classification at initial diagnosis M0 - Undifferentiated Acute Myeloblastic Leukemia | 0 Participants | 5 Participants | 5 Participants | 0 Participants | 0 Participants |
| AML FAB classification at initial diagnosis M1 - ACUTE MYELOBLASTIC LEUKEMIA WITH MINIMAL MATURATION | 0 Participants | 1 Participants | 3 Participants | 1 Participants | 1 Participants |
| AML FAB classification at initial diagnosis M2 - ACUTE MYELOBLASTIC LEUKEMIA WITH MATURATION | 1 Participants | 4 Participants | 9 Participants | 3 Participants | 1 Participants |
| AML FAB classification at initial diagnosis M4 - Acute Myelomonocytic Leukemia | 0 Participants | 2 Participants | 2 Participants | 0 Participants | 0 Participants |
| AML FAB classification at initial diagnosis M5 - ACUTE MONOCYTIC LEUKEMIA | 1 Participants | 0 Participants | 3 Participants | 1 Participants | 1 Participants |
| AML FAB classification at initial diagnosis M7 - ACUTE MEGAKARYOBLASTIC LEUKEMIA | 1 Participants | 1 Participants | 2 Participants | 0 Participants | 0 Participants |
| AML FAB classification at initial diagnosis MISSING | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants |
| AML FAB classification at initial diagnosis UNKNOWN | 0 Participants | 8 Participants | 16 Participants | 4 Participants | 4 Participants |
| BMI | 32.22 Kilogram per square meter | 24.03 Kilogram per square meter | 25.56 Kilogram per square meter | 29.25 Kilogram per square meter | 25.54 Kilogram per square meter |
| Current AML status De novo | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants |
| Current AML status Refractory | 3 Participants | 9 Participants | 23 Participants | 6 Participants | 5 Participants |
| Current AML status Relapsed | 0 Participants | 13 Participants | 18 Participants | 3 Participants | 2 Participants |
| ECOG performance status Grade 0 | 0 Participants | 1 Participants | 4 Participants | 2 Participants | 1 Participants |
| ECOG performance status Grade 1 | 2 Participants | 19 Participants | 32 Participants | 7 Participants | 4 Participants |
| ECOG performance status Grade 2 | 1 Participants | 2 Participants | 6 Participants | 1 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 2 Participants | 3 Participants | 1 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 Participants | 20 Participants | 39 Participants | 9 Participants | 7 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Extramedullary involvement at diagnosis No | 3 Participants | 19 Participants | 38 Participants | 9 Participants | 7 Participants |
| Extramedullary involvement at diagnosis Unknown | 0 Participants | 3 Participants | 4 Participants | 1 Participants | 0 Participants |
| Extramedullary involvement at present No | 0 Participants | 22 Participants | 31 Participants | 9 Participants | 0 Participants |
| Extramedullary involvement at present Unknown | 3 Participants | 0 Participants | 11 Participants | 1 Participants | 7 Participants |
| Extramedullary involvement at present Yes | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Height | 160.0 Centimeter | 168 Centimeter | 165 Centimeter | 158.0 Centimeter | 163.0 Centimeter |
| HLA-DR results available Missing | 0 Participants | 4 Participants | 4 Participants | 0 Participants | 0 Participants |
| HLA-DR results available Negative | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants |
| HLA-DR results available Positive | 3 Participants | 18 Participants | 37 Participants | 9 Participants | 7 Participants |
| HLA-DR risk group Adverse | 3 Participants | 0 Participants | 15 Participants | 6 Participants | 6 Participants |
| HLA-DR risk group Favorable | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants |
| HLA-DR risk group Intermediate | 0 Participants | 0 Participants | 3 Participants | 2 Participants | 1 Participants |
| HLA-DR risk group Missing | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants |
| Immunophenotyping results available CD34+ | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants |
| Immunophenotyping results available Missing | 0 Participants | 5 Participants | 6 Participants | 1 Participants | 0 Participants |
| Immunophenotyping results available Other | 3 Participants | 17 Participants | 35 Participants | 8 Participants | 7 Participants |
| Left ventricular ejection fraction (LVEF) | 62.0 Percent | 60.0 Percent | 60.0 Percent | 57.0 Percent | 61.0 Percent |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 4 Participants | 9 Participants | 3 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 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 |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 3 Participants | 5 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) White | 2 Participants | 15 Participants | 27 Participants | 5 Participants | 5 Participants |
| Region of Enrollment United States | 3 participants | 22 participants | 42 participants | 10 participants | 7 participants |
| Sex: Female, Male Female | 3 Participants | 9 Participants | 22 Participants | 6 Participants | 4 Participants |
| Sex: Female, Male Male | 0 Participants | 13 Participants | 20 Participants | 4 Participants | 3 Participants |
| Time from initial diagnosis to first dose of ONO-7475 | 17.7 Months | 12.1 Months | 14.7 Months | 24.3 Months | 12.2 Months |
| Weight | 82.50 Kilogram | 75.45 Kilogram | 74.25 Kilogram | 76.30 Kilogram | 64.10 Kilogram |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 10 / 10 | 3 / 3 | 5 / 7 | 15 / 22 |
| other Total, other adverse events | 10 / 10 | 3 / 3 | 7 / 7 | 21 / 22 |
| serious Total, serious adverse events | 9 / 10 | 2 / 3 | 6 / 7 | 13 / 22 |
Outcome results
Primary
Clinically Significant Changes in 12-Lead Electrocardiogram Parameters (Part A)
Participants with clinically significant changes in 12-lead Electrocardiogram (ECG) parameters.
Time frame: From start of study drug up to 30 days after permanent discontinuation of study drug or initiation of new anti-cancer therapy, whichever occurs first (maximum of 32 months).
Population: Safety analysis set, in participants who received at least 1 dose of ONO-7475.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| ONO-7475 3mg | Clinically Significant Changes in 12-Lead Electrocardiogram Parameters (Part A) | Participants with clinically significant changes in 12-lead ECG parameters | 0 Participants |
| ONO-7475 3mg | Clinically Significant Changes in 12-Lead Electrocardiogram Parameters (Part A) | Participants without clinically significant changes in 12-lead ECG parameters | 10 Participants |
| ONO-7475 6mg | Clinically Significant Changes in 12-Lead Electrocardiogram Parameters (Part A) | Participants without clinically significant changes in 12-lead ECG parameters | 3 Participants |
| ONO-7475 6mg | Clinically Significant Changes in 12-Lead Electrocardiogram Parameters (Part A) | Participants with clinically significant changes in 12-lead ECG parameters | 0 Participants |
| ONO-7475 10 mg | Clinically Significant Changes in 12-Lead Electrocardiogram Parameters (Part A) | Participants with clinically significant changes in 12-lead ECG parameters | 0 Participants |
| ONO-7475 10 mg | Clinically Significant Changes in 12-Lead Electrocardiogram Parameters (Part A) | Participants without clinically significant changes in 12-lead ECG parameters | 7 Participants |
| Total | Clinically Significant Changes in 12-Lead Electrocardiogram Parameters (Part A) | Participants with clinically significant changes in 12-lead ECG parameters | 0 Participants |
| Total | Clinically Significant Changes in 12-Lead Electrocardiogram Parameters (Part A) | Participants without clinically significant changes in 12-lead ECG parameters | 20 Participants |
Primary
Clinically Significant Changes in Ophthalmology Examination Parameters (Part A)
Incidence (all participants) of ophthalmological treatment-emergent adverse events (all CTCAE grades) by preferred terms coded with MedDRA Version 23.1. CTCAE = Common Terminology Criteria for Adverse Event version 4.03.
Time frame: From start of study drug up to 30 days after permanent discontinuation of study drug or initiation of new anti-cancer therapy, whichever occurs first (maximum of 32 months).
Population: Safety analysis set, in participants who received at least 1 dose of ONO-7475.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| ONO-7475 3mg | Clinically Significant Changes in Ophthalmology Examination Parameters (Part A) | Retinal thickening | 1 Participants |
| ONO-7475 3mg | Clinically Significant Changes in Ophthalmology Examination Parameters (Part A) | Vitreous floaters | 1 Participants |
| ONO-7475 3mg | Clinically Significant Changes in Ophthalmology Examination Parameters (Part A) | Scleral haemorrhage | 0 Participants |
| ONO-7475 3mg | Clinically Significant Changes in Ophthalmology Examination Parameters (Part A) | Retinopathy | 1 Participants |
| ONO-7475 3mg | Clinically Significant Changes in Ophthalmology Examination Parameters (Part A) | Eyelid ptosis | 1 Participants |
| ONO-7475 3mg | Clinically Significant Changes in Ophthalmology Examination Parameters (Part A) | Conjunctival haemorrhage | 0 Participants |
| ONO-7475 3mg | Clinically Significant Changes in Ophthalmology Examination Parameters (Part A) | Night blindness | 1 Participants |
| ONO-7475 3mg | Clinically Significant Changes in Ophthalmology Examination Parameters (Part A) | Cataract cortical | 0 Participants |
| ONO-7475 3mg | Clinically Significant Changes in Ophthalmology Examination Parameters (Part A) | Vision blurred | 1 Participants |
| ONO-7475 3mg | Clinically Significant Changes in Ophthalmology Examination Parameters (Part A) | Retinal aneurysm | 0 Participants |
| ONO-7475 6mg | Clinically Significant Changes in Ophthalmology Examination Parameters (Part A) | Scleral haemorrhage | 1 Participants |
| ONO-7475 6mg | Clinically Significant Changes in Ophthalmology Examination Parameters (Part A) | Retinal thickening | 0 Participants |
| ONO-7475 6mg | Clinically Significant Changes in Ophthalmology Examination Parameters (Part A) | Retinal aneurysm | 1 Participants |
| ONO-7475 6mg | Clinically Significant Changes in Ophthalmology Examination Parameters (Part A) | Cataract cortical | 0 Participants |
| ONO-7475 6mg | Clinically Significant Changes in Ophthalmology Examination Parameters (Part A) | Night blindness | 0 Participants |
| ONO-7475 6mg | Clinically Significant Changes in Ophthalmology Examination Parameters (Part A) | Retinopathy | 0 Participants |
| ONO-7475 6mg | Clinically Significant Changes in Ophthalmology Examination Parameters (Part A) | Conjunctival haemorrhage | 0 Participants |
| ONO-7475 6mg | Clinically Significant Changes in Ophthalmology Examination Parameters (Part A) | Eyelid ptosis | 0 Participants |
| ONO-7475 6mg | Clinically Significant Changes in Ophthalmology Examination Parameters (Part A) | Vitreous floaters | 0 Participants |
| ONO-7475 6mg | Clinically Significant Changes in Ophthalmology Examination Parameters (Part A) | Vision blurred | 0 Participants |
| ONO-7475 10 mg | Clinically Significant Changes in Ophthalmology Examination Parameters (Part A) | Cataract cortical | 1 Participants |
| ONO-7475 10 mg | Clinically Significant Changes in Ophthalmology Examination Parameters (Part A) | Conjunctival haemorrhage | 1 Participants |
| ONO-7475 10 mg | Clinically Significant Changes in Ophthalmology Examination Parameters (Part A) | Eyelid ptosis | 0 Participants |
| ONO-7475 10 mg | Clinically Significant Changes in Ophthalmology Examination Parameters (Part A) | Night blindness | 0 Participants |
| ONO-7475 10 mg | Clinically Significant Changes in Ophthalmology Examination Parameters (Part A) | Retinal aneurysm | 0 Participants |
| ONO-7475 10 mg | Clinically Significant Changes in Ophthalmology Examination Parameters (Part A) | Retinal thickening | 0 Participants |
| ONO-7475 10 mg | Clinically Significant Changes in Ophthalmology Examination Parameters (Part A) | Retinopathy | 0 Participants |
| ONO-7475 10 mg | Clinically Significant Changes in Ophthalmology Examination Parameters (Part A) | Scleral haemorrhage | 0 Participants |
| ONO-7475 10 mg | Clinically Significant Changes in Ophthalmology Examination Parameters (Part A) | Vision blurred | 0 Participants |
| ONO-7475 10 mg | Clinically Significant Changes in Ophthalmology Examination Parameters (Part A) | Vitreous floaters | 0 Participants |
| Total | Clinically Significant Changes in Ophthalmology Examination Parameters (Part A) | Cataract cortical | 1 Participants |
| Total | Clinically Significant Changes in Ophthalmology Examination Parameters (Part A) | Scleral haemorrhage | 1 Participants |
| Total | Clinically Significant Changes in Ophthalmology Examination Parameters (Part A) | Night blindness | 1 Participants |
| Total | Clinically Significant Changes in Ophthalmology Examination Parameters (Part A) | Eyelid ptosis | 1 Participants |
| Total | Clinically Significant Changes in Ophthalmology Examination Parameters (Part A) | Vitreous floaters | 1 Participants |
| Total | Clinically Significant Changes in Ophthalmology Examination Parameters (Part A) | Vision blurred | 1 Participants |
| Total | Clinically Significant Changes in Ophthalmology Examination Parameters (Part A) | Conjunctival haemorrhage | 1 Participants |
| Total | Clinically Significant Changes in Ophthalmology Examination Parameters (Part A) | Retinopathy | 1 Participants |
| Total | Clinically Significant Changes in Ophthalmology Examination Parameters (Part A) | Retinal thickening | 1 Participants |
| Total | Clinically Significant Changes in Ophthalmology Examination Parameters (Part A) | Retinal aneurysm | 1 Participants |
Primary
Complete Response (CR) / Complete Response With Partial Hematologic Recovery (CRh) Rate (Part D)
Summary of complete response (CR) and complete response with partial hematologic recovery (CRh) rate.
Time frame: From baseline up to maximum of 21 months
Population: Full analysis set
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| ONO-7475 3mg | Complete Response (CR) / Complete Response With Partial Hematologic Recovery (CRh) Rate (Part D) | Complete remission | 0 Participants |
| ONO-7475 3mg | Complete Response (CR) / Complete Response With Partial Hematologic Recovery (CRh) Rate (Part D) | Complete response with partial hematologic recovery | 0 Participants |
Primary
Incidence of Adverse Events (Part A)
Incidence of most common (frequency of \>20%) treatment-emergent adverse events (TEAEs) of CTCAE grade 3 or higher by preferred terms coded with MedDRA version 23.1. CTCAE = Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.
Time frame: From start of study drug up to 30 days after permanent discontinuation of study drug or initiation of new anti-cancer therapy, whichever occurs first (maximum of 32 months).
Population: Safety analysis set, in participants who received at least 1 dose of ONO-7475.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| ONO-7475 3mg | Incidence of Adverse Events (Part A) | Anaemia | 4 Participants |
| ONO-7475 3mg | Incidence of Adverse Events (Part A) | Pneumonia | 4 Participants |
| ONO-7475 3mg | Incidence of Adverse Events (Part A) | Febrile neutropenia | 2 Participants |
| ONO-7475 6mg | Incidence of Adverse Events (Part A) | Anaemia | 1 Participants |
| ONO-7475 6mg | Incidence of Adverse Events (Part A) | Pneumonia | 1 Participants |
| ONO-7475 6mg | Incidence of Adverse Events (Part A) | Febrile neutropenia | 1 Participants |
| ONO-7475 10 mg | Incidence of Adverse Events (Part A) | Febrile neutropenia | 4 Participants |
| ONO-7475 10 mg | Incidence of Adverse Events (Part A) | Anaemia | 2 Participants |
| ONO-7475 10 mg | Incidence of Adverse Events (Part A) | Pneumonia | 0 Participants |
| Total | Incidence of Adverse Events (Part A) | Anaemia | 7 Participants |
| Total | Incidence of Adverse Events (Part A) | Pneumonia | 5 Participants |
| Total | Incidence of Adverse Events (Part A) | Febrile neutropenia | 7 Participants |
Primary
Incidence of Adverse Events (Part D)
Incidence of most common (frequency \> 20%) treatment-emergent adverse events (TEAEs) of CTCAE grade 3 or higher by preferred term coded with MedDRA version 23.1. CTCAE = Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.
Time frame: From start of study drug up to 30 days after permanent discontinuation of study drug or initiation of new anti-cancer therapy, whichever occurs first (maximum of 21 months).
Population: Safety analysis set, in participants who received at least 1 dose of ONO-7475 and/or venetoclax.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| ONO-7475 3mg | Incidence of Adverse Events (Part D) | Febrile neutropenia | 7 Participants |
| ONO-7475 3mg | Incidence of Adverse Events (Part D) | Anaemia | 5 Participants |
| ONO-7475 3mg | Incidence of Adverse Events (Part D) | Thrombocytopenia | 5 Participants |
Primary
Incidence of Serious Adverse Events (Part A)
Incidence (frequency ≥ 2 participants) of serious treatment-emergent adverse events (all CTCAE grades) by preferred terms coded with MedDRA version 23.1. CTCAE = Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.
Time frame: From start of study drug up to 30 days after permanent discontinuation of study drug or initiation of new anti-cancer therapy, whichever occurs first (maximum of 32 months).
Population: Safety analysis set, in participants who received at least 1 dose of ONO-7475.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| ONO-7475 3mg | Incidence of Serious Adverse Events (Part A) | Pneumonia | 3 Participants |
| ONO-7475 3mg | Incidence of Serious Adverse Events (Part A) | Sepsis | 3 Participants |
| ONO-7475 3mg | Incidence of Serious Adverse Events (Part A) | Febrile neutropenia | 2 Participants |
| ONO-7475 3mg | Incidence of Serious Adverse Events (Part A) | Klebsiella bacteraemia | 2 Participants |
| ONO-7475 6mg | Incidence of Serious Adverse Events (Part A) | Sepsis | 1 Participants |
| ONO-7475 6mg | Incidence of Serious Adverse Events (Part A) | Febrile neutropenia | 1 Participants |
| ONO-7475 6mg | Incidence of Serious Adverse Events (Part A) | Klebsiella bacteraemia | 0 Participants |
| ONO-7475 6mg | Incidence of Serious Adverse Events (Part A) | Pneumonia | 1 Participants |
| ONO-7475 10 mg | Incidence of Serious Adverse Events (Part A) | Febrile neutropenia | 4 Participants |
| ONO-7475 10 mg | Incidence of Serious Adverse Events (Part A) | Sepsis | 0 Participants |
| ONO-7475 10 mg | Incidence of Serious Adverse Events (Part A) | Klebsiella bacteraemia | 0 Participants |
| ONO-7475 10 mg | Incidence of Serious Adverse Events (Part A) | Pneumonia | 0 Participants |
| Total | Incidence of Serious Adverse Events (Part A) | Klebsiella bacteraemia | 2 Participants |
| Total | Incidence of Serious Adverse Events (Part A) | Sepsis | 4 Participants |
| Total | Incidence of Serious Adverse Events (Part A) | Pneumonia | 4 Participants |
| Total | Incidence of Serious Adverse Events (Part A) | Febrile neutropenia | 7 Participants |
Primary
Incidence of Serious Adverse Events (Part D)
Incidence (frequency ≥ 2 participants) of serious treatment-emergent adverse events (all CTCAE grades) by preferred terms coded with MedDRA version 23.1. CTCAE = Common Terminology Criteria for Adverse Events (CTXAE) Version 4.03.
Time frame: From start of study drug up to 30 days after permanent discontinuation of study drug or initiation of new anti-cancer therapy, whichever occurs first (maximum of 21 months).
Population: Safety analysis set, in participants who received at least 1 dose of ONO-7475 and/or venetoclax.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| ONO-7475 3mg | Incidence of Serious Adverse Events (Part D) | Gastrointestinal haemorrhage | 2 Participants |
| ONO-7475 3mg | Incidence of Serious Adverse Events (Part D) | Sepsis | 3 Participants |
| ONO-7475 3mg | Incidence of Serious Adverse Events (Part D) | Febrile neutropenia | 7 Participants |
Secondary
Determination of Maximum Tolerated Dose (MTD) by Assessing Dose Limiting Toxicities (DLT) (Part A)
Dose Limiting Toxicities (DLT) Criteria: 1) ONO-7475-related ≥Grade 4 hematologic toxicity, 2) any pre-existing condition that worsens by more than 1 grade or to Grade 4, not caused by AML, 3) any ≥Grade 3 non-hematologic toxicity not caused by AML (exception: alopecia, nausea, vomiting, fatigue, headache, chills, electrolyte disturbances), 4) ≥Grade 2 blurred vision (confirmed by loss of 15 letters or more on Early Treatment Diabetic Retinopathy chart and by ophthalmological and retinal assessments) not caused by AML, 5) ≥Grade 2 clinically significant changes in night blindness not caused by AML, 6) ≥Grade 3 differentiation syndrome, 7) death not caused by AML, and 8) any other event determined by the Safety Review Committee for dosing stop. Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 was applied for toxicity grading.
Time frame: 28 days
Population: Analysis set included participants evaluable for DLT, defined as participants received ONO-7475 with a minimum dose intensity of 75% within DLT evaluation period \[from first dose to Day 28\] and had completed Day 28 assessments.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| ONO-7475 3mg | Determination of Maximum Tolerated Dose (MTD) by Assessing Dose Limiting Toxicities (DLT) (Part A) | Numbers of participants experienced DLT | 0 Participants |
| ONO-7475 3mg | Determination of Maximum Tolerated Dose (MTD) by Assessing Dose Limiting Toxicities (DLT) (Part A) | Numbers of participants not experienced DLT | 10 Participants |
| ONO-7475 6mg | Determination of Maximum Tolerated Dose (MTD) by Assessing Dose Limiting Toxicities (DLT) (Part A) | Numbers of participants not experienced DLT | 3 Participants |
| ONO-7475 6mg | Determination of Maximum Tolerated Dose (MTD) by Assessing Dose Limiting Toxicities (DLT) (Part A) | Numbers of participants experienced DLT | 0 Participants |
| ONO-7475 10 mg | Determination of Maximum Tolerated Dose (MTD) by Assessing Dose Limiting Toxicities (DLT) (Part A) | Numbers of participants experienced DLT | 0 Participants |
| ONO-7475 10 mg | Determination of Maximum Tolerated Dose (MTD) by Assessing Dose Limiting Toxicities (DLT) (Part A) | Numbers of participants not experienced DLT | 7 Participants |
| Total | Determination of Maximum Tolerated Dose (MTD) by Assessing Dose Limiting Toxicities (DLT) (Part A) | Numbers of participants experienced DLT | 0 Participants |
| Total | Determination of Maximum Tolerated Dose (MTD) by Assessing Dose Limiting Toxicities (DLT) (Part A) | Numbers of participants not experienced DLT | 20 Participants |
Secondary
Duration of Response in ONO-7475 + Venetoclax Group (Part D)
Part D Duration of response in ONO-7475 6mg + Venetoclax group.
Time frame: From baseline up to maximum of 21 months
Population: Full analysis set. Participants with best response assessed as complete remission, complete remission with partial hematologic recovery, complete remission with incomplete hematologic recovery, morphologic leukemia free state and partial remission were included in analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| ONO-7475 3mg | Duration of Response in ONO-7475 + Venetoclax Group (Part D) | 1.881 Months | Standard Deviation 2.5073 |
Secondary
Event-Free Survival and Overall Survival in ONO-7475 + Venetoclax Group (Part D)
Part D analysis of event free survival and overall survival in ONO-7475 6mg + Venetoclax group
Time frame: From baseline up to maximum of 21 months
Population: Full analysis set
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| ONO-7475 3mg | Event-Free Survival and Overall Survival in ONO-7475 + Venetoclax Group (Part D) | Event free survival | 0.99 Months |
| ONO-7475 3mg | Event-Free Survival and Overall Survival in ONO-7475 + Venetoclax Group (Part D) | Overall survival | 4.01 Months |
Secondary
Event Free Survival in ONO-7475 Groups (Part A)
Part A analysis of event free survival in ONO-7475 treatment groups
Time frame: From baseline up to maximum of 32 months
Population: Full analysis set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| ONO-7475 3mg | Event Free Survival in ONO-7475 Groups (Part A) | 1.0 Months |
| ONO-7475 6mg | Event Free Survival in ONO-7475 Groups (Part A) | 0.9 Months |
| ONO-7475 10 mg | Event Free Survival in ONO-7475 Groups (Part A) | 0.9 Months |
| Total | Event Free Survival in ONO-7475 Groups (Part A) | 1.0 Months |
Secondary
Incidence of Adverse Events in ONO-7475 + Venetoclax Group (Part D)
Part D Incidence (frequency \> 20%) and severity (CTCAE grades) of treatment-emergent adverse events in ONO-7475 + Venetoclax Group, in preferred terms coded MedDRA version 23.1. CTCAE = common terminology criteria for adverse events (CTCAE) version 4.03.
Time frame: From start of study drug up to 30 days after permanent discontinuation of study drug or initiation of new anti-cancer therapy, whichever occurs first (maximum of 21 months).
Population: Safety analysis set, in participants who received at least 1 dose of ONO-7475 and/or venetoclax.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| ONO-7475 3mg | Incidence of Adverse Events in ONO-7475 + Venetoclax Group (Part D) | Participants with treatment-emergent adverse events | 21 Participants |
| ONO-7475 3mg | Incidence of Adverse Events in ONO-7475 + Venetoclax Group (Part D) | Fatigue | 10 Participants |
| ONO-7475 3mg | Incidence of Adverse Events in ONO-7475 + Venetoclax Group (Part D) | Diarrhoea | 7 Participants |
| ONO-7475 3mg | Incidence of Adverse Events in ONO-7475 + Venetoclax Group (Part D) | Febrile neutropenia | 7 Participants |
| ONO-7475 3mg | Incidence of Adverse Events in ONO-7475 + Venetoclax Group (Part D) | Hypophosphataemia | 7 Participants |
| ONO-7475 3mg | Incidence of Adverse Events in ONO-7475 + Venetoclax Group (Part D) | Anaemia | 6 Participants |
| ONO-7475 3mg | Incidence of Adverse Events in ONO-7475 + Venetoclax Group (Part D) | Nausea | 6 Participants |
| ONO-7475 3mg | Incidence of Adverse Events in ONO-7475 + Venetoclax Group (Part D) | Constipation | 5 Participants |
| ONO-7475 3mg | Incidence of Adverse Events in ONO-7475 + Venetoclax Group (Part D) | Headache | 5 Participants |
| ONO-7475 3mg | Incidence of Adverse Events in ONO-7475 + Venetoclax Group (Part D) | Hypokalaemia | 5 Participants |
| ONO-7475 3mg | Incidence of Adverse Events in ONO-7475 + Venetoclax Group (Part D) | Thrombocytopenia | 5 Participants |
| ONO-7475 3mg | Incidence of Adverse Events in ONO-7475 + Venetoclax Group (Part D) | Vomiting | 5 Participants |
| ONO-7475 6mg | Incidence of Adverse Events in ONO-7475 + Venetoclax Group (Part D) | Thrombocytopenia | 5 Participants |
| ONO-7475 6mg | Incidence of Adverse Events in ONO-7475 + Venetoclax Group (Part D) | Participants with treatment-emergent adverse events | 20 Participants |
| ONO-7475 6mg | Incidence of Adverse Events in ONO-7475 + Venetoclax Group (Part D) | Nausea | 0 Participants |
| ONO-7475 6mg | Incidence of Adverse Events in ONO-7475 + Venetoclax Group (Part D) | Fatigue | 0 Participants |
| ONO-7475 6mg | Incidence of Adverse Events in ONO-7475 + Venetoclax Group (Part D) | Hypokalaemia | 0 Participants |
| ONO-7475 6mg | Incidence of Adverse Events in ONO-7475 + Venetoclax Group (Part D) | Diarrhoea | 0 Participants |
| ONO-7475 6mg | Incidence of Adverse Events in ONO-7475 + Venetoclax Group (Part D) | Constipation | 0 Participants |
| ONO-7475 6mg | Incidence of Adverse Events in ONO-7475 + Venetoclax Group (Part D) | Febrile neutropenia | 7 Participants |
| ONO-7475 6mg | Incidence of Adverse Events in ONO-7475 + Venetoclax Group (Part D) | Vomiting | 0 Participants |
| ONO-7475 6mg | Incidence of Adverse Events in ONO-7475 + Venetoclax Group (Part D) | Hypophosphataemia | 0 Participants |
| ONO-7475 6mg | Incidence of Adverse Events in ONO-7475 + Venetoclax Group (Part D) | Headache | 0 Participants |
| ONO-7475 6mg | Incidence of Adverse Events in ONO-7475 + Venetoclax Group (Part D) | Anaemia | 5 Participants |
Secondary
Incidence of Serious Adverse Events in ONO-7475 + Venetoclax Group (Part D)
Part D Incidence (frequency ≥ 2 participants) and severity (CTCAE grades) of serious treatment-emergent adverse events in ONO-7475 + Venetoclax Group (Part D), preferred term coded with MedDRA version 23.1. CTCAE = Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.
Time frame: From start of study drug up to 30 days after permanent discontinuation of study drug or initiation of new anti-cancer therapy, whichever occurs first (maximum of 21 months).
Population: Safety analysis set, in participants who received at least 1 dose of ONO-7475 and/or venetoclax
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| ONO-7475 3mg | Incidence of Serious Adverse Events in ONO-7475 + Venetoclax Group (Part D) | Participants with serious adverse events | 13 Participants |
| ONO-7475 3mg | Incidence of Serious Adverse Events in ONO-7475 + Venetoclax Group (Part D) | Sepsis | 3 Participants |
| ONO-7475 3mg | Incidence of Serious Adverse Events in ONO-7475 + Venetoclax Group (Part D) | Febrile neutropenia | 7 Participants |
| ONO-7475 3mg | Incidence of Serious Adverse Events in ONO-7475 + Venetoclax Group (Part D) | Gastrointestinal hemorrhage | 2 Participants |
| ONO-7475 6mg | Incidence of Serious Adverse Events in ONO-7475 + Venetoclax Group (Part D) | Gastrointestinal hemorrhage | 2 Participants |
| ONO-7475 6mg | Incidence of Serious Adverse Events in ONO-7475 + Venetoclax Group (Part D) | Participants with serious adverse events | 13 Participants |
| ONO-7475 6mg | Incidence of Serious Adverse Events in ONO-7475 + Venetoclax Group (Part D) | Febrile neutropenia | 7 Participants |
| ONO-7475 6mg | Incidence of Serious Adverse Events in ONO-7475 + Venetoclax Group (Part D) | Sepsis | 3 Participants |
Secondary
Overall Response Rate and Duration of Response in ONO-7475 Groups (Part A)
Part A analysis of best overall response. Duration of response analysis was not performed as no response of complete remission, Morphologic complete remission with incomplete blood count recovery, morphologic leukemia-free state, or partial remission was observed.
Time frame: From baseline up to maximum of 32 months
Population: Full analysis set
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| ONO-7475 3mg | Overall Response Rate and Duration of Response in ONO-7475 Groups (Part A) | Complete response | 0 Participants |
| ONO-7475 3mg | Overall Response Rate and Duration of Response in ONO-7475 Groups (Part A) | Morphologic complete remission with incomplete blood count recovery | 0 Participants |
| ONO-7475 3mg | Overall Response Rate and Duration of Response in ONO-7475 Groups (Part A) | Morphologic leukemia-free state | 0 Participants |
| ONO-7475 3mg | Overall Response Rate and Duration of Response in ONO-7475 Groups (Part A) | Partial remission | 0 Participants |
| ONO-7475 3mg | Overall Response Rate and Duration of Response in ONO-7475 Groups (Part A) | Treatment failure | 5 Participants |
| ONO-7475 3mg | Overall Response Rate and Duration of Response in ONO-7475 Groups (Part A) | Not evaluated / assessed | 5 Participants |
| ONO-7475 6mg | Overall Response Rate and Duration of Response in ONO-7475 Groups (Part A) | Not evaluated / assessed | 0 Participants |
| ONO-7475 6mg | Overall Response Rate and Duration of Response in ONO-7475 Groups (Part A) | Partial remission | 0 Participants |
| ONO-7475 6mg | Overall Response Rate and Duration of Response in ONO-7475 Groups (Part A) | Complete response | 0 Participants |
| ONO-7475 6mg | Overall Response Rate and Duration of Response in ONO-7475 Groups (Part A) | Morphologic leukemia-free state | 0 Participants |
| ONO-7475 6mg | Overall Response Rate and Duration of Response in ONO-7475 Groups (Part A) | Morphologic complete remission with incomplete blood count recovery | 0 Participants |
| ONO-7475 6mg | Overall Response Rate and Duration of Response in ONO-7475 Groups (Part A) | Treatment failure | 3 Participants |
| ONO-7475 10 mg | Overall Response Rate and Duration of Response in ONO-7475 Groups (Part A) | Morphologic complete remission with incomplete blood count recovery | 0 Participants |
| ONO-7475 10 mg | Overall Response Rate and Duration of Response in ONO-7475 Groups (Part A) | Morphologic leukemia-free state | 0 Participants |
| ONO-7475 10 mg | Overall Response Rate and Duration of Response in ONO-7475 Groups (Part A) | Partial remission | 0 Participants |
| ONO-7475 10 mg | Overall Response Rate and Duration of Response in ONO-7475 Groups (Part A) | Not evaluated / assessed | 2 Participants |
| ONO-7475 10 mg | Overall Response Rate and Duration of Response in ONO-7475 Groups (Part A) | Treatment failure | 5 Participants |
| ONO-7475 10 mg | Overall Response Rate and Duration of Response in ONO-7475 Groups (Part A) | Complete response | 0 Participants |
| Total | Overall Response Rate and Duration of Response in ONO-7475 Groups (Part A) | Treatment failure | 13 Participants |
| Total | Overall Response Rate and Duration of Response in ONO-7475 Groups (Part A) | Not evaluated / assessed | 7 Participants |
| Total | Overall Response Rate and Duration of Response in ONO-7475 Groups (Part A) | Morphologic complete remission with incomplete blood count recovery | 0 Participants |
| Total | Overall Response Rate and Duration of Response in ONO-7475 Groups (Part A) | Partial remission | 0 Participants |
| Total | Overall Response Rate and Duration of Response in ONO-7475 Groups (Part A) | Complete response | 0 Participants |
| Total | Overall Response Rate and Duration of Response in ONO-7475 Groups (Part A) | Morphologic leukemia-free state | 0 Participants |
Secondary
Overall Response Rate in ONO-7475 + Venetoclax Group (Part D)
Part D Summary of best overall response in ONO-7475 + Venetoclax group.
Time frame: From baseline up to maximum of 21 months
Population: Full analysis set
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| ONO-7475 3mg | Overall Response Rate in ONO-7475 + Venetoclax Group (Part D) | Complete remission | 0 Participants |
| ONO-7475 3mg | Overall Response Rate in ONO-7475 + Venetoclax Group (Part D) | Complete remission with incomplete hematologic recovery | 1 Participants |
| ONO-7475 3mg | Overall Response Rate in ONO-7475 + Venetoclax Group (Part D) | Morphologic leukemia free state | 1 Participants |
| ONO-7475 3mg | Overall Response Rate in ONO-7475 + Venetoclax Group (Part D) | Partial remission | 2 Participants |
| ONO-7475 3mg | Overall Response Rate in ONO-7475 + Venetoclax Group (Part D) | Treatment failure | 16 Participants |
| ONO-7475 3mg | Overall Response Rate in ONO-7475 + Venetoclax Group (Part D) | Not evaluated / assessed | 2 Participants |
Secondary
Pharmacodynamics (Axl and Mer Inhibition) of ONO-7475 (Part A)
Assessment of the pharmacodynamic activity by measurement of Axl and Mer inhibition using a Plasma Inhibitory Activity (PIA) assay. PIA is a flow cytometry assay measuring auto-phosphorylation in Axl-expressing Ba/F3 and Mer-expressing Ba/F3 cells, respectively the percentage of inhibition. Pre-dose samples were collected for the analysis on day 2 and day 28.
Time frame: Day 2 and Day 28
Population: Pharmacodynamic (PD) analysis set, in participants who received at least 1 dose of ONO-7475 and with evaluable PD parameter results were summarised.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| ONO-7475 3mg | Pharmacodynamics (Axl and Mer Inhibition) of ONO-7475 (Part A) | Axl %inhibition Day 2 Pre-dose | 53.13 percentage | Standard Deviation 20.971 |
| ONO-7475 3mg | Pharmacodynamics (Axl and Mer Inhibition) of ONO-7475 (Part A) | Mer %Inhibition Day 28 Pre-Dose | 42.60 percentage | — |
| ONO-7475 3mg | Pharmacodynamics (Axl and Mer Inhibition) of ONO-7475 (Part A) | Axl %Inhibition Day 28 Pre-Dose | 82.50 percentage | Standard Deviation 11.811 |
| ONO-7475 3mg | Pharmacodynamics (Axl and Mer Inhibition) of ONO-7475 (Part A) | Mer %inhibition Day 2 Pre-dose | 31.40 percentage | Standard Deviation 9.475 |
| ONO-7475 6mg | Pharmacodynamics (Axl and Mer Inhibition) of ONO-7475 (Part A) | Axl %Inhibition Day 28 Pre-Dose | 99.5 percentage | — |
| ONO-7475 6mg | Pharmacodynamics (Axl and Mer Inhibition) of ONO-7475 (Part A) | Mer %Inhibition Day 28 Pre-Dose | 69.1 percentage | — |
| ONO-7475 6mg | Pharmacodynamics (Axl and Mer Inhibition) of ONO-7475 (Part A) | Axl %inhibition Day 2 Pre-dose | 19.10 percentage | — |
| ONO-7475 10 mg | Pharmacodynamics (Axl and Mer Inhibition) of ONO-7475 (Part A) | Mer %Inhibition Day 28 Pre-Dose | 91.5 percentage | Standard Deviation 10.209 |
| ONO-7475 10 mg | Pharmacodynamics (Axl and Mer Inhibition) of ONO-7475 (Part A) | Axl %inhibition Day 2 Pre-dose | 88.57 percentage | Standard Deviation 4.876 |
| ONO-7475 10 mg | Pharmacodynamics (Axl and Mer Inhibition) of ONO-7475 (Part A) | Axl %Inhibition Day 28 Pre-Dose | 90.30 percentage | Standard Deviation 8.344 |
| ONO-7475 10 mg | Pharmacodynamics (Axl and Mer Inhibition) of ONO-7475 (Part A) | Mer %inhibition Day 2 Pre-dose | 55.78 percentage | Standard Deviation 11.932 |
Secondary
Pharmacokinetics (AUC) of ONO-7475 in Treatment Group ONO-7475 + Venetoclax (Part D)
Part D Pharmacokinetics (AUC) of ONO-7475 in treatment group ONO-7475 + venetoclax.
Time frame: Day 29
Population: Pharmacokinetic (PK) analysis set, in participants who received at least 1 dose of ONO-7475 and with evaluable PK parameter results.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| ONO-7475 3mg | Pharmacokinetics (AUC) of ONO-7475 in Treatment Group ONO-7475 + Venetoclax (Part D) | AUC (0-10h) (ng*h/mL) of ONO-7475 Day 29 | 4810 ng*h/mL | Standard Deviation 1990 |
| ONO-7475 3mg | Pharmacokinetics (AUC) of ONO-7475 in Treatment Group ONO-7475 + Venetoclax (Part D) | AUC (0-24h) (ng*h/mL) of ONO-7475 Day 29 | 11100 ng*h/mL | Standard Deviation 4820 |
Secondary
Pharmacokinetics (AUC) of ONO-7475 (Part A)
Part A Pharmacokinetics (AUC0-10h) of ONO-7475 assessed on day 1 and day 28, (AUC0-24h) of ONO-7475 assessed on day 1.
Time frame: Day 1 and Day 28
Population: Pharmacokinetic (PK) analysis set, in participants who received at least 1 dose of ONO-7475 and with evaluable PK parameter resulted were summarised.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| ONO-7475 3mg | Pharmacokinetics (AUC) of ONO-7475 (Part A) | AUC(0-10h) (ng*h/mL) day 28 | 2534 ng*h/mL | — |
| ONO-7475 3mg | Pharmacokinetics (AUC) of ONO-7475 (Part A) | AUC(0-10h) (ng*h/mL) day 1 | 559.3 ng*h/mL | Standard Deviation 247.66 |
| ONO-7475 3mg | Pharmacokinetics (AUC) of ONO-7475 (Part A) | AUC(0-24h) (ng*h/mL) day 1 | 1358.4 ng*h/mL | Standard Deviation 198.56 |
| ONO-7475 6mg | Pharmacokinetics (AUC) of ONO-7475 (Part A) | AUC(0-10h) (ng*h/mL) day 28 | 1124.9 ng*h/mL | Standard Deviation 654.75 |
| ONO-7475 6mg | Pharmacokinetics (AUC) of ONO-7475 (Part A) | AUC(0-10h) (ng*h/mL) day 1 | 649.3 ng*h/mL | Standard Deviation 296.73 |
| ONO-7475 6mg | Pharmacokinetics (AUC) of ONO-7475 (Part A) | AUC(0-24h) (ng*h/mL) day 1 | 1506.9 ng*h/mL | — |
| ONO-7475 10 mg | Pharmacokinetics (AUC) of ONO-7475 (Part A) | AUC(0-10h) (ng*h/mL) day 1 | 2086.2 ng*h/mL | Standard Deviation 767.91 |
| ONO-7475 10 mg | Pharmacokinetics (AUC) of ONO-7475 (Part A) | AUC(0-24h) (ng*h/mL) day 1 | 4870.3 ng*h/mL | Standard Deviation 1147.48 |
| ONO-7475 10 mg | Pharmacokinetics (AUC) of ONO-7475 (Part A) | AUC(0-10h) (ng*h/mL) day 28 | 6202.5 ng*h/mL | Standard Deviation 2406.09 |
Secondary
Pharmacokinetics (AUC) of Venetoclax in Treatment Group ONO-7475 + Venetoclax
Part D Pharmacokinetics (AUC) of Venetoclax in treatment group ONO-7475 + venetoclax.
Time frame: Day 1 and Day 29
Population: Pharmacokinetic (PK) analysis set, in participants who received at least 1 dose of venetoclax and with evaluable PK parameter results.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| ONO-7475 3mg | Pharmacokinetics (AUC) of Venetoclax in Treatment Group ONO-7475 + Venetoclax | AUC (0-10h) day 1 | 1330 ng*h/mL | Standard Deviation 1220 |
| ONO-7475 3mg | Pharmacokinetics (AUC) of Venetoclax in Treatment Group ONO-7475 + Venetoclax | AUC (0-10h) day 29 | 14700 ng*h/mL | Standard Deviation 8650 |
| ONO-7475 3mg | Pharmacokinetics (AUC) of Venetoclax in Treatment Group ONO-7475 + Venetoclax | AUC (0-24h) day day 29 | 32900 ng*h/mL | Standard Deviation 19200 |
Secondary
Pharmacokinetics (Cmax and Ctrough) of ONO-7475 (Part A)
Part A Pharmacokinetics Cmax of ONO-7475 assessed on day 1 and day 28, and Ctrough of ONO-7475 assessed on day 28 (pre-dose).
Time frame: Day 1 and Day 28
Population: Pharmacokinetic (PK) analysis set, in participants who received at least 1 dose of ONO-7475 and with evaluable PK parameter resulted were summarised.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| ONO-7475 3mg | Pharmacokinetics (Cmax and Ctrough) of ONO-7475 (Part A) | Cmax (ng/mL) day 28 | 369.0 ng/mL | — |
| ONO-7475 3mg | Pharmacokinetics (Cmax and Ctrough) of ONO-7475 (Part A) | Cmax (ng/mL) day 1 | 90.8 ng/mL | Standard Deviation 17.49 |
| ONO-7475 3mg | Pharmacokinetics (Cmax and Ctrough) of ONO-7475 (Part A) | Ctrough (ng/mL) day 28 | 192.7 ng/mL | Standard Deviation 154.23 |
| ONO-7475 6mg | Pharmacokinetics (Cmax and Ctrough) of ONO-7475 (Part A) | Cmax (ng/mL) day 28 | 189.5 ng/mL | Standard Deviation 96.87 |
| ONO-7475 6mg | Pharmacokinetics (Cmax and Ctrough) of ONO-7475 (Part A) | Cmax (ng/mL) day 1 | 86 ng/mL | — |
| ONO-7475 6mg | Pharmacokinetics (Cmax and Ctrough) of ONO-7475 (Part A) | Ctrough (ng/mL) day 28 | 353.0 ng/mL | Standard Deviation 347.89 |
| ONO-7475 10 mg | Pharmacokinetics (Cmax and Ctrough) of ONO-7475 (Part A) | Cmax (ng/mL) day 1 | 319.8 ng/mL | Standard Deviation 73.99 |
| ONO-7475 10 mg | Pharmacokinetics (Cmax and Ctrough) of ONO-7475 (Part A) | Ctrough (ng/mL) day 28 | 588.4 ng/mL | Standard Deviation 250.9 |
| ONO-7475 10 mg | Pharmacokinetics (Cmax and Ctrough) of ONO-7475 (Part A) | Cmax (ng/mL) day 28 | 1037 ng/mL | Standard Deviation 229.58 |
Secondary
Pharmacokinetics (Cmax) of ONO-7475 in Treatment Group ONO-7475 + Venetoclax (Part D)
Part D Pharmacokinetics (Cmax) of ONO-7475 in treatment group ONO-7475 + venetoclax.
Time frame: Day 29
Population: Pharmacokinetic (PK) analysis set, in participants who received at least 1 dose of ONO-7475 and with evaluable PK parameter results.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| ONO-7475 3mg | Pharmacokinetics (Cmax) of ONO-7475 in Treatment Group ONO-7475 + Venetoclax (Part D) | 622 ng/mL | Standard Deviation 236 |
Secondary
Pharmacokinetics (Cmax) of Venetoclax in Treatment Group ONO-7475 + Venetoclax (Part D)
Part D Pharmacokinetics (Cmax) of Venetoclax in treatment group ONO-7475 + Venetoclax.
Time frame: Day 1 and Day 29
Population: Pharmacokinetic (PK) analysis set, in participants who received at least 1 dose of venetoclax and with evaluable PK parameter results.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| ONO-7475 3mg | Pharmacokinetics (Cmax) of Venetoclax in Treatment Group ONO-7475 + Venetoclax (Part D) | Cmax (ng/mL) Day 1 | 310 ng/mL | Standard Deviation 281 |
| ONO-7475 3mg | Pharmacokinetics (Cmax) of Venetoclax in Treatment Group ONO-7475 + Venetoclax (Part D) | Cmax (ng/mL) Day 29 | 1870 ng/mL | Standard Deviation 846 |
Secondary
Pharmacokinetics of the Food Effect on ONO-7475 (Part A)
Part A Pharmacokinetics (Cmax, Tmax, AUC, T1/2, Ctrough) of the food effect on ONO-7475 assessed as ratio of Day57/Day28 and comparing pharmacokinetic parameters from dosing under fasted and non-fasted conditions assessed in 6mg and 10mg dose groups.
Time frame: Day 28 and Day 57
Population: Pharmacokinetic analysis set, in participants who received at least 1 dose of ONO-7475 and with evaluable PK parameter results. Food effect was not evaluated in 3mg dose group. Tmax, T1/2 and Ctrough ratios were not calculable due to insufficient data.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| ONO-7475 6mg | Pharmacokinetics of the Food Effect on ONO-7475 (Part A) | Day 57/Day 28 ratio of Cmax | 0.89 ratio |
| ONO-7475 6mg | Pharmacokinetics of the Food Effect on ONO-7475 (Part A) | Day 57/Day 28 ratio of AUC (0-10h) | 0.88 ratio |
| ONO-7475 10 mg | Pharmacokinetics of the Food Effect on ONO-7475 (Part A) | Day 57/Day 28 ratio of Cmax | 1.13 ratio |
| ONO-7475 10 mg | Pharmacokinetics of the Food Effect on ONO-7475 (Part A) | Day 57/Day 28 ratio of AUC (0-10h) | 1.69 ratio |
Secondary
Pharmacokinetics (T1/2) of ONO-7475 in Treatment Group ONO-7475 + Venetoclax (Part D)
Part D Pharmacokinetics (T1/2) of ONO-7475 in treatment group ONO-7475 + venetoclax.
Time frame: Day 29
Population: Pharmacokinetic (PK) analysis set, in participants who received at least 1 dose of ONO-7475 and with evaluable PK parameter results. T1/2 of ONO-7475 was not calculable due to insufficient evaluable data.
Secondary
Pharmacokinetics (T1/2) of ONO-7475 (Part A)
Part A Pharmacokinetics T1/2 of ONO-7475 assessed on day 1 and day 28. T1/2 was not calculable due to insufficient evaluable data.
Time frame: Day 1 and Day 28
Population: Pharmacokinetic (PK) analysis set, in participants who received at least 1 dose of ONO-7475 and with evaluable PK parameter resulted were summarised. T1/2 was not calculable due to insufficient evaluable data.
Secondary
Pharmacokinetics (T1/2) of Venetoclax in Treatment Group ONO-7475 + Venetoclax (Part D)
Part D Pharmacokinetics (T1/2) of Venetoclax in treatment group ONO-7475 + venetoclax.
Time frame: Day 29
Population: Pharmacokinetic (PK) analysis set, in participants who received at least 1 dose of Venetoclax and with evaluable PK parameter results.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| ONO-7475 3mg | Pharmacokinetics (T1/2) of Venetoclax in Treatment Group ONO-7475 + Venetoclax (Part D) | 5.8 Hour (h) |
Secondary
Pharmacokinetics (Tmax) of ONO-7475 in Treatment Group ONO-7475 + Venetoclax (Part D)
Part D Pharmacokinetics (Tmax) of ONO-7475 in treatment group ONO-7475 + venetoclax.
Time frame: Day 29
Population: Pharmacokinetic (PK) analysis set, in participants who received at least 1 dose of ONO-7475 and with evaluable PK parameter results.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| ONO-7475 3mg | Pharmacokinetics (Tmax) of ONO-7475 in Treatment Group ONO-7475 + Venetoclax (Part D) | 5.58 Hour (h) | Standard Deviation 5.84 |
Secondary
Pharmacokinetics (Tmax) of ONO-7475 (Part A)
Part A Pharmacokinetics Tmax of ONO-7475 assessed on day 1 and day 28.
Time frame: Day 1 and Day 28
Population: Pharmacokinetic (PK) analysis set, in participants who received at least 1 dose of ONO-7475 and with evaluable PK parameter resulted were summarised. Insufficient evaluable data available for day 28 Tmax values in 3 mg dose group.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| ONO-7475 3mg | Pharmacokinetics (Tmax) of ONO-7475 (Part A) | Tmax (h) day 1 | 3.5 Hour (h) | Standard Deviation 2.18 |
| ONO-7475 6mg | Pharmacokinetics (Tmax) of ONO-7475 (Part A) | Tmax (h) day 28 | 1.5 Hour (h) | Standard Deviation 2.12 |
| ONO-7475 6mg | Pharmacokinetics (Tmax) of ONO-7475 (Part A) | Tmax (h) day 1 | 5.6 Hour (h) | — |
| ONO-7475 10 mg | Pharmacokinetics (Tmax) of ONO-7475 (Part A) | Tmax (h) day 1 | 3.2 Hour (h) | Standard Deviation 2.4 |
| ONO-7475 10 mg | Pharmacokinetics (Tmax) of ONO-7475 (Part A) | Tmax (h) day 28 | 4.3 Hour (h) | Standard Deviation 3.22 |
Secondary
Pharmacokinetics (Tmax) of Venetoclax in Treatment Group ONO-7475 + Venetoclax (Part D)
Part D Pharmacokinetics (Tmax) of Venetoclax in treatment group ONO-7475 + venetoclax.
Time frame: Day 1 and Day 29
Population: Pharmacokinetic (PK) analysis set, in participants who received at least 1 dose of ONO-7475 and with evaluable PK parameter results.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| ONO-7475 3mg | Pharmacokinetics (Tmax) of Venetoclax in Treatment Group ONO-7475 + Venetoclax (Part D) | Tmax day 1 | 6.72 Hour (h) | Standard Deviation 1.99 |
| ONO-7475 3mg | Pharmacokinetics (Tmax) of Venetoclax in Treatment Group ONO-7475 + Venetoclax (Part D) | Tmax day 29 | 7.07 Hour (h) | Standard Deviation 4.85 |
Secondary
Transfusion Independence Rate (Part D)
Part D analysis of transfusion Independence rate. Rate of maintenance of transfusion independence = percentage of patients who were transfusion independent post-baseline based upon the patients who were transfusion independent at baseline. Calculated using the Clopper-Pearson method.
Time frame: From baseline up to maximum of 21 months
Population: Full analysis set and in participants who were transfusion independent at baseline.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ONO-7475 3mg | Transfusion Independence Rate (Part D) | 87.5 percentage of participants |