Leukemia, Myeloid, Acute, Myelodysplastic Syndromes
Conditions
Keywords
Myelodysplastic Syndromes, Acute Myeloid Leukemia, AML, MDS, Hematologic Cancers, Leukemia, Anti-SIRPa antibody, CC-95251
Brief summary
The purpose of this study is to evaluate the safety, tolerability, and preliminary clinical activity of CC-95251 alone and in combination with antineoplastic agents in participants with relapsed or refractory acute myeloid leukemia and relapsed or refractory and treatment-naive higher risk melodysplastic syndromes.
Interventions
DRUGVenetoclax
Specified dose on specified days
DRUGCC-95251
Specified dose on specified days
DRUGAzacitidine
Specified dose on specified days
Sponsors
Bristol-Myers Squibb
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
• Eastern Cooperative Oncology Group Performance Status of 0 to 2 For Parts A & B: * Relapsed or refractory (R/R) acute myeloid leukemia (AML) as defined by the 2016 WHO Classification * R/R myelodysplastic syndromes (MDS) as defined by the 2016 WHO Classification with intermediate, high or very high risk by Revised International Prognostic Scoring System (IPSS-R) For Part C: • Treatment-naïve (TN) (ie, previously untreated) MDS as defined by the 2016 WHO Classification with intermediate, high or very high risk by IPSS-R For Part D: • TN AML as defined by the 2016 WHO Classification, including secondary AML and therapy-related AML in participants who are ineligible (IE) for intensive chemotherapy (IC) and allogeneic hematopoietic stem cell transplant (HSCT)
Exclusion criteria
* Acute promyelocytic leukemia * Immediately life-threatening, severe complications of leukemia such as disseminated/uncontrolled infection, uncontrolled bleeding, and/or uncontrolled disseminated intravascular coagulation * Participants who have received prior treatment with a CD47 or SIRPα targeting agent * Participant is on chronic systemic immunosuppressive therapy or corticosteroids * Prior systemic cancer-directed treatments or investigational modalities ≤ 5 half-lives or 4 weeks prior to starting study treatment, whichever is shorter (relapsed or refractory participants only). * Any condition including, active or uncontrolled infection, or the presence of laboratory abnormalities, which places the participant at unacceptable risk if he/she were to participate in the study * Pregnant or nursing participants. Other protocol-defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Clinically Significant Changes in Vital Signs Presented as AEs | From signing informed consent to 56 days post last dose (Approximately 30 months) | Vital sign measurements include: Weight (kg), Temperature (°C), Systolic Blood Pressure (mmHg), Diastolic Blood Pressure (mmHg), Pulse (beats/min), Respiration Rate (breaths/min). |
| Number of Participants With DLTs | From Cycle 1 Day 1 to Cycle 1 Day 28 up to 42 post first dose of cycle 1 (upto 42 days) | A dose-limiting toxicity (DLT) is any treatment-related toxicity during Cycle 1 (Days 1-28, up to 42) not clearly due to illness or external causes. DLTs include: * Any Grade ≥3 non-hematologic toxicity, except specific reversible or manageable cases (e.g., IRR, nausea, diarrhea, fatigue, infection with leukemia, TLS, electrolyte imbalance, liver enzyme elevations, or rash). * Any confirmed Hy's law case (ALT/AST ≥3× ULN + bilirubin \>2× ULN without cholestasis). * Hematologic toxicities: Grade 4 neutropenia/thrombocytopenia persisting at Day 28 without active AML/MDS; febrile neutropenia or Grade ≥3 thrombocytopenia with severe bleeding and prolonged myelosuppression (\>42 days) without active leukemia. * Any adverse event requiring dose reduction in Cycle 1 unless clearly unrelated to the drug. |
| Number of Participants With Treatment Emergent Adverse Events | From signing informed consent to 56 days post last dose (Approximately 30 months) | An AE is any noxious, unintended, or untoward medical occurrence that may appear or worsen in a participant during the course of a study. It may be a new intercurrent illness, a worsening concomitant illness, an injury, or any concomitant impairment of the subject's health, including laboratory test values, regardless of etiology. Any worsening (ie, any clinically significant adverse change in the frequency or intensity of a pre-existing condition) should be considered an AE. |
| Number of Participants With With Grade 3 or Higher Laboratory Abnormalities | From signing informed consent to 56 days post last dose (Approximately 30 months) | Clinical laboratory values from laboratories will be graded according to CTCAE Version 5 for applicable tests programmatically. For laboratory values that fall outside of the grade criteria of CTCAE Version 5, a Grade of 0 will be assigned. In addition, normal ranges will be used to determine the categories of High, Low, and Normal for laboratory tests that have no severity grade. |
| Number of Participants With Clinically Significant ECG Abnormalities Presented as Adverse Events | From screening to 56 days post last dose (Approximately 29 months) | A single ECG will be performed in Screening, Cycle 1 Day 1 and 15, and Day 1 of Cycles ≥ 2. Investigators will make immediate clinical decisions based on their interpretation of the ECG results and provide their overall assessment. |
| Number of ECOG Evaluations With Shift of ECOG Score of 3 or Greater. | From screening to 56 days post last dose (Approximately 29 months) | ECOG Scale was used to assess performance status. Grades: 0: Fully active, able to carry on all pre-disease performance without estriction. 1: Restricted in physically strenuous activity but ambulatory, able to carry out work of light nature. 2: Ambulatory, capable of self-care, unable to carry out work activities. Up and about more than 50% waking hours. 3: Capable of limited self-care, confined to bed/chair more than 50% waking hours. 4: Completely disabled. Cannot carry on any self-care. Totally confined to bed/chair. 5: Dead. Baseline value was defined as the last non-missing value on or before the day that first dose of study drug is administered; if multiple values are present for the same date, the average of these values will be used as the baseline. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Tmax | On Cycle 1 Day 1, C1D22 and C2D22. | Time to maximum plasma concentration (Tmax) |
| AUC(0-T) | On Cycle 1 Day 1, C1D22 and C2D22. | Area under the plasma concentration time-curve up to the last measurable concentration (AUC0-t) |
| AUC(TAU) | On Cycle 1 Day 1, C1D22 and C2D22. | Area under the plasma concentration time-curve during a dosing interval (AUCtau) |
| Cmin | On Cycle 1 Day 1, C1D22 and C2D22. | Minimum serum concentration |
| Cmax | On Cycle 1 Day 1, C1D22 and C2D22. | Maximum plasma concentration of drug |
Countries
Australia, Canada, France, Italy, Norway, Spain, Sweden, United Kingdom, United States
Participant flow
Pre-assignment details
Due to a strategic re-evaluation and prioritization of the company's portfolio, this study was terminated early during dose escalation (Part A). No participants were enrolled in Parts B, C, and D because the study was terminated prior to the start of dose expansion.
Participants by arm
| Arm | Count |
|---|---|
| Part A: Treatment 1 Monotherapy: CC-95251 20mg/kg | 6 |
| Part A: Treatment 2 Monotherapy : CC-95251 30mg/kg | 8 |
| Part A: Treatment 3 Combination : CC-95251 10mg/kg + Azacitidine 75 mg/m2 | 9 |
| Part A: Treatment 4 Combination : CC-95251 20mg/kg + Azacitidine 75 mg/m2 | 10 |
| Part A: Treatment 5 Combination : CC-95251 30mg/kg + Azacitidine 75 mg/m2 | 8 |
| Part A: Treatment 6 Triplet Combination : CC-95251 20mg/kg + Azacitidine 75 mg/m2 + Venetoclax | 10 |
| Part A: Treatment 7 Triplet Combination : CC-95251 30mg/kg + Azacitidine 75 mg/m2 + Venetoclax | 5 |
| Total | 56 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 |
|---|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 2 | 1 | 4 | 4 | 3 | 2 | 0 |
| Overall Study | Disease Relapse | 0 | 1 | 0 | 1 | 1 | 0 | 0 |
| Overall Study | Lack of Efficacy | 0 | 1 | 1 | 0 | 1 | 2 | 2 |
| Overall Study | Other Reasons | 0 | 0 | 0 | 0 | 0 | 2 | 1 |
| Overall Study | Physician Decision | 0 | 1 | 1 | 0 | 0 | 0 | 0 |
| Overall Study | Progressive Disease | 4 | 4 | 2 | 3 | 2 | 3 | 2 |
| Overall Study | Study Terminated by Sponsor | 0 | 0 | 0 | 1 | 0 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 1 | 1 | 1 | 1 | 0 |
Baseline characteristics
| Characteristic | Part A: Treatment 7 | Total | Part A: Treatment 1 | Part A: Treatment 2 | Part A: Treatment 3 | Part A: Treatment 4 | Part A: Treatment 5 | Part A: Treatment 6 |
|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 65.4 Years STANDARD_DEVIATION 13.37 | 66.3 Years STANDARD_DEVIATION 12.31 | 67.0 Years STANDARD_DEVIATION 13.5 | 69.4 Years STANDARD_DEVIATION 10.82 | 68.3 Years STANDARD_DEVIATION 8.59 | 70.6 Years STANDARD_DEVIATION 4.25 | 67.5 Years STANDARD_DEVIATION 14.09 | 56.6 Years STANDARD_DEVIATION 16.53 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 7 Participants | 1 Participants | 0 Participants | 1 Participants | 2 Participants | 2 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 4 Participants | 31 Participants | 3 Participants | 5 Participants | 6 Participants | 4 Participants | 3 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 18 Participants | 2 Participants | 3 Participants | 2 Participants | 4 Participants | 3 Participants | 3 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 |
| Race (NIH/OMB) Asian | 1 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 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 |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 16 Participants | 2 Participants | 3 Participants | 2 Participants | 3 Participants | 2 Participants | 3 Participants |
| Race (NIH/OMB) White | 2 Participants | 37 Participants | 4 Participants | 5 Participants | 7 Participants | 7 Participants | 5 Participants | 7 Participants |
| Sex: Female, Male Female | 2 Participants | 26 Participants | 4 Participants | 2 Participants | 4 Participants | 5 Participants | 3 Participants | 6 Participants |
| Sex: Female, Male Male | 3 Participants | 30 Participants | 2 Participants | 6 Participants | 5 Participants | 5 Participants | 5 Participants | 4 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 |
|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 6 / 6 | 7 / 8 | 6 / 9 | 9 / 10 | 6 / 8 | 8 / 10 | 3 / 5 |
| other Total, other adverse events | 6 / 6 | 8 / 8 | 7 / 9 | 9 / 10 | 7 / 8 | 10 / 10 | 5 / 5 |
| serious Total, serious adverse events | 6 / 6 | 7 / 8 | 8 / 9 | 7 / 10 | 7 / 8 | 10 / 10 | 5 / 5 |
Outcome results
Primary
Number of ECOG Evaluations With Shift of ECOG Score of 3 or Greater.
ECOG Scale was used to assess performance status. Grades: 0: Fully active, able to carry on all pre-disease performance without estriction. 1: Restricted in physically strenuous activity but ambulatory, able to carry out work of light nature. 2: Ambulatory, capable of self-care, unable to carry out work activities. Up and about more than 50% waking hours. 3: Capable of limited self-care, confined to bed/chair more than 50% waking hours. 4: Completely disabled. Cannot carry on any self-care. Totally confined to bed/chair. 5: Dead. Baseline value was defined as the last non-missing value on or before the day that first dose of study drug is administered; if multiple values are present for the same date, the average of these values will be used as the baseline.
Time frame: From screening to 56 days post last dose (Approximately 29 months)
Population: Safety Population - Multiple ECOG evaluations were done throughout the study at different timepoints
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part A: Treatment 1 | Number of ECOG Evaluations With Shift of ECOG Score of 3 or Greater. | 3 ECOG Evaluations |
| Part A: Treatment 2 | Number of ECOG Evaluations With Shift of ECOG Score of 3 or Greater. | 1 ECOG Evaluations |
| Part A: Treatment 3 | Number of ECOG Evaluations With Shift of ECOG Score of 3 or Greater. | 0 ECOG Evaluations |
| Part A: Treatment 4 | Number of ECOG Evaluations With Shift of ECOG Score of 3 or Greater. | 1 ECOG Evaluations |
| Part A: Treatment 5 | Number of ECOG Evaluations With Shift of ECOG Score of 3 or Greater. | 0 ECOG Evaluations |
| Part A: Treatment 6 | Number of ECOG Evaluations With Shift of ECOG Score of 3 or Greater. | 1 ECOG Evaluations |
| Part A: Treatment 7 | Number of ECOG Evaluations With Shift of ECOG Score of 3 or Greater. | 1 ECOG Evaluations |
Primary
Number of Participants With Clinically Significant Changes in Vital Signs Presented as AEs
Vital sign measurements include: Weight (kg), Temperature (°C), Systolic Blood Pressure (mmHg), Diastolic Blood Pressure (mmHg), Pulse (beats/min), Respiration Rate (breaths/min).
Time frame: From signing informed consent to 56 days post last dose (Approximately 30 months)
Population: Safety Population
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part A: Treatment 1 | Number of Participants With Clinically Significant Changes in Vital Signs Presented as AEs | hypotension | 0 Participants |
| Part A: Treatment 1 | Number of Participants With Clinically Significant Changes in Vital Signs Presented as AEs | hypertension | 0 Participants |
| Part A: Treatment 1 | Number of Participants With Clinically Significant Changes in Vital Signs Presented as AEs | weight decreased | 0 Participants |
| Part A: Treatment 1 | Number of Participants With Clinically Significant Changes in Vital Signs Presented as AEs | Pyrexia | 0 Participants |
| Part A: Treatment 1 | Number of Participants With Clinically Significant Changes in Vital Signs Presented as AEs | hypothermia | 0 Participants |
| Part A: Treatment 2 | Number of Participants With Clinically Significant Changes in Vital Signs Presented as AEs | hypothermia | 0 Participants |
| Part A: Treatment 2 | Number of Participants With Clinically Significant Changes in Vital Signs Presented as AEs | hypertension | 0 Participants |
| Part A: Treatment 2 | Number of Participants With Clinically Significant Changes in Vital Signs Presented as AEs | weight decreased | 0 Participants |
| Part A: Treatment 2 | Number of Participants With Clinically Significant Changes in Vital Signs Presented as AEs | hypotension | 1 Participants |
| Part A: Treatment 2 | Number of Participants With Clinically Significant Changes in Vital Signs Presented as AEs | Pyrexia | 1 Participants |
| Part A: Treatment 3 | Number of Participants With Clinically Significant Changes in Vital Signs Presented as AEs | hypotension | 3 Participants |
| Part A: Treatment 3 | Number of Participants With Clinically Significant Changes in Vital Signs Presented as AEs | Pyrexia | 1 Participants |
| Part A: Treatment 3 | Number of Participants With Clinically Significant Changes in Vital Signs Presented as AEs | weight decreased | 0 Participants |
| Part A: Treatment 3 | Number of Participants With Clinically Significant Changes in Vital Signs Presented as AEs | hypothermia | 0 Participants |
| Part A: Treatment 3 | Number of Participants With Clinically Significant Changes in Vital Signs Presented as AEs | hypertension | 1 Participants |
| Part A: Treatment 4 | Number of Participants With Clinically Significant Changes in Vital Signs Presented as AEs | weight decreased | 0 Participants |
| Part A: Treatment 4 | Number of Participants With Clinically Significant Changes in Vital Signs Presented as AEs | hypotension | 0 Participants |
| Part A: Treatment 4 | Number of Participants With Clinically Significant Changes in Vital Signs Presented as AEs | hypertension | 0 Participants |
| Part A: Treatment 4 | Number of Participants With Clinically Significant Changes in Vital Signs Presented as AEs | Pyrexia | 2 Participants |
| Part A: Treatment 4 | Number of Participants With Clinically Significant Changes in Vital Signs Presented as AEs | hypothermia | 0 Participants |
| Part A: Treatment 5 | Number of Participants With Clinically Significant Changes in Vital Signs Presented as AEs | hypothermia | 1 Participants |
| Part A: Treatment 5 | Number of Participants With Clinically Significant Changes in Vital Signs Presented as AEs | Pyrexia | 3 Participants |
| Part A: Treatment 5 | Number of Participants With Clinically Significant Changes in Vital Signs Presented as AEs | hypertension | 1 Participants |
| Part A: Treatment 5 | Number of Participants With Clinically Significant Changes in Vital Signs Presented as AEs | hypotension | 2 Participants |
| Part A: Treatment 5 | Number of Participants With Clinically Significant Changes in Vital Signs Presented as AEs | weight decreased | 1 Participants |
| Part A: Treatment 6 | Number of Participants With Clinically Significant Changes in Vital Signs Presented as AEs | hypertension | 2 Participants |
| Part A: Treatment 6 | Number of Participants With Clinically Significant Changes in Vital Signs Presented as AEs | hypotension | 0 Participants |
| Part A: Treatment 6 | Number of Participants With Clinically Significant Changes in Vital Signs Presented as AEs | hypothermia | 0 Participants |
| Part A: Treatment 6 | Number of Participants With Clinically Significant Changes in Vital Signs Presented as AEs | Pyrexia | 4 Participants |
| Part A: Treatment 6 | Number of Participants With Clinically Significant Changes in Vital Signs Presented as AEs | weight decreased | 0 Participants |
| Part A: Treatment 7 | Number of Participants With Clinically Significant Changes in Vital Signs Presented as AEs | hypertension | 0 Participants |
| Part A: Treatment 7 | Number of Participants With Clinically Significant Changes in Vital Signs Presented as AEs | weight decreased | 0 Participants |
| Part A: Treatment 7 | Number of Participants With Clinically Significant Changes in Vital Signs Presented as AEs | Pyrexia | 1 Participants |
| Part A: Treatment 7 | Number of Participants With Clinically Significant Changes in Vital Signs Presented as AEs | hypotension | 0 Participants |
| Part A: Treatment 7 | Number of Participants With Clinically Significant Changes in Vital Signs Presented as AEs | hypothermia | 0 Participants |
Primary
Number of Participants With Clinically Significant ECG Abnormalities Presented as Adverse Events
A single ECG will be performed in Screening, Cycle 1 Day 1 and 15, and Day 1 of Cycles ≥ 2. Investigators will make immediate clinical decisions based on their interpretation of the ECG results and provide their overall assessment.
Time frame: From screening to 56 days post last dose (Approximately 29 months)
Population: Safety Population
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part A: Treatment 1 | Number of Participants With Clinically Significant ECG Abnormalities Presented as Adverse Events | Sinus Tachycardia | 1 Participants |
| Part A: Treatment 1 | Number of Participants With Clinically Significant ECG Abnormalities Presented as Adverse Events | Sinus Bradycardia | 0 Participants |
| Part A: Treatment 1 | Number of Participants With Clinically Significant ECG Abnormalities Presented as Adverse Events | Atrial Fibrillation | 0 Participants |
| Part A: Treatment 1 | Number of Participants With Clinically Significant ECG Abnormalities Presented as Adverse Events | Tachycardia | 0 Participants |
| Part A: Treatment 2 | Number of Participants With Clinically Significant ECG Abnormalities Presented as Adverse Events | Tachycardia | 0 Participants |
| Part A: Treatment 2 | Number of Participants With Clinically Significant ECG Abnormalities Presented as Adverse Events | Sinus Bradycardia | 0 Participants |
| Part A: Treatment 2 | Number of Participants With Clinically Significant ECG Abnormalities Presented as Adverse Events | Sinus Tachycardia | 0 Participants |
| Part A: Treatment 2 | Number of Participants With Clinically Significant ECG Abnormalities Presented as Adverse Events | Atrial Fibrillation | 1 Participants |
| Part A: Treatment 3 | Number of Participants With Clinically Significant ECG Abnormalities Presented as Adverse Events | Sinus Bradycardia | 0 Participants |
| Part A: Treatment 3 | Number of Participants With Clinically Significant ECG Abnormalities Presented as Adverse Events | Tachycardia | 0 Participants |
| Part A: Treatment 3 | Number of Participants With Clinically Significant ECG Abnormalities Presented as Adverse Events | Atrial Fibrillation | 0 Participants |
| Part A: Treatment 3 | Number of Participants With Clinically Significant ECG Abnormalities Presented as Adverse Events | Sinus Tachycardia | 0 Participants |
| Part A: Treatment 4 | Number of Participants With Clinically Significant ECG Abnormalities Presented as Adverse Events | Tachycardia | 0 Participants |
| Part A: Treatment 4 | Number of Participants With Clinically Significant ECG Abnormalities Presented as Adverse Events | Sinus Tachycardia | 0 Participants |
| Part A: Treatment 4 | Number of Participants With Clinically Significant ECG Abnormalities Presented as Adverse Events | Atrial Fibrillation | 0 Participants |
| Part A: Treatment 4 | Number of Participants With Clinically Significant ECG Abnormalities Presented as Adverse Events | Sinus Bradycardia | 0 Participants |
| Part A: Treatment 5 | Number of Participants With Clinically Significant ECG Abnormalities Presented as Adverse Events | Tachycardia | 0 Participants |
| Part A: Treatment 5 | Number of Participants With Clinically Significant ECG Abnormalities Presented as Adverse Events | Atrial Fibrillation | 1 Participants |
| Part A: Treatment 5 | Number of Participants With Clinically Significant ECG Abnormalities Presented as Adverse Events | Sinus Tachycardia | 0 Participants |
| Part A: Treatment 5 | Number of Participants With Clinically Significant ECG Abnormalities Presented as Adverse Events | Sinus Bradycardia | 1 Participants |
| Part A: Treatment 6 | Number of Participants With Clinically Significant ECG Abnormalities Presented as Adverse Events | Sinus Tachycardia | 2 Participants |
| Part A: Treatment 6 | Number of Participants With Clinically Significant ECG Abnormalities Presented as Adverse Events | Sinus Bradycardia | 0 Participants |
| Part A: Treatment 6 | Number of Participants With Clinically Significant ECG Abnormalities Presented as Adverse Events | Atrial Fibrillation | 0 Participants |
| Part A: Treatment 6 | Number of Participants With Clinically Significant ECG Abnormalities Presented as Adverse Events | Tachycardia | 2 Participants |
| Part A: Treatment 7 | Number of Participants With Clinically Significant ECG Abnormalities Presented as Adverse Events | Sinus Bradycardia | 0 Participants |
| Part A: Treatment 7 | Number of Participants With Clinically Significant ECG Abnormalities Presented as Adverse Events | Sinus Tachycardia | 0 Participants |
| Part A: Treatment 7 | Number of Participants With Clinically Significant ECG Abnormalities Presented as Adverse Events | Tachycardia | 0 Participants |
| Part A: Treatment 7 | Number of Participants With Clinically Significant ECG Abnormalities Presented as Adverse Events | Atrial Fibrillation | 0 Participants |
Primary
Number of Participants With DLTs
A dose-limiting toxicity (DLT) is any treatment-related toxicity during Cycle 1 (Days 1-28, up to 42) not clearly due to illness or external causes. DLTs include: * Any Grade ≥3 non-hematologic toxicity, except specific reversible or manageable cases (e.g., IRR, nausea, diarrhea, fatigue, infection with leukemia, TLS, electrolyte imbalance, liver enzyme elevations, or rash). * Any confirmed Hy's law case (ALT/AST ≥3× ULN + bilirubin \>2× ULN without cholestasis). * Hematologic toxicities: Grade 4 neutropenia/thrombocytopenia persisting at Day 28 without active AML/MDS; febrile neutropenia or Grade ≥3 thrombocytopenia with severe bleeding and prolonged myelosuppression (\>42 days) without active leukemia. * Any adverse event requiring dose reduction in Cycle 1 unless clearly unrelated to the drug.
Time frame: From Cycle 1 Day 1 to Cycle 1 Day 28 up to 42 post first dose of cycle 1 (upto 42 days)
Population: Safety Population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part A: Treatment 1 | Number of Participants With DLTs | 0 Participants |
| Part A: Treatment 2 | Number of Participants With DLTs | 1 Participants |
| Part A: Treatment 3 | Number of Participants With DLTs | 0 Participants |
| Part A: Treatment 4 | Number of Participants With DLTs | 0 Participants |
| Part A: Treatment 5 | Number of Participants With DLTs | 0 Participants |
| Part A: Treatment 6 | Number of Participants With DLTs | 2 Participants |
| Part A: Treatment 7 | Number of Participants With DLTs | 4 Participants |
Primary
Number of Participants With Treatment Emergent Adverse Events
An AE is any noxious, unintended, or untoward medical occurrence that may appear or worsen in a participant during the course of a study. It may be a new intercurrent illness, a worsening concomitant illness, an injury, or any concomitant impairment of the subject's health, including laboratory test values, regardless of etiology. Any worsening (ie, any clinically significant adverse change in the frequency or intensity of a pre-existing condition) should be considered an AE.
Time frame: From signing informed consent to 56 days post last dose (Approximately 30 months)
Population: Safety Population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part A: Treatment 1 | Number of Participants With Treatment Emergent Adverse Events | 6 Participants |
| Part A: Treatment 2 | Number of Participants With Treatment Emergent Adverse Events | 8 Participants |
| Part A: Treatment 3 | Number of Participants With Treatment Emergent Adverse Events | 8 Participants |
| Part A: Treatment 4 | Number of Participants With Treatment Emergent Adverse Events | 9 Participants |
| Part A: Treatment 5 | Number of Participants With Treatment Emergent Adverse Events | 8 Participants |
| Part A: Treatment 6 | Number of Participants With Treatment Emergent Adverse Events | 10 Participants |
| Part A: Treatment 7 | Number of Participants With Treatment Emergent Adverse Events | 5 Participants |
Primary
Number of Participants With With Grade 3 or Higher Laboratory Abnormalities
Clinical laboratory values from laboratories will be graded according to CTCAE Version 5 for applicable tests programmatically. For laboratory values that fall outside of the grade criteria of CTCAE Version 5, a Grade of 0 will be assigned. In addition, normal ranges will be used to determine the categories of High, Low, and Normal for laboratory tests that have no severity grade.
Time frame: From signing informed consent to 56 days post last dose (Approximately 30 months)
Population: Safety Population
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part A: Treatment 1 | Number of Participants With With Grade 3 or Higher Laboratory Abnormalities | platelet count | 5 Participants |
| Part A: Treatment 1 | Number of Participants With With Grade 3 or Higher Laboratory Abnormalities | hypocalcemia | 0 Participants |
| Part A: Treatment 1 | Number of Participants With With Grade 3 or Higher Laboratory Abnormalities | alkaline phosphatase | 0 Participants |
| Part A: Treatment 1 | Number of Participants With With Grade 3 or Higher Laboratory Abnormalities | hyperkalemia | 0 Participants |
| Part A: Treatment 1 | Number of Participants With With Grade 3 or Higher Laboratory Abnormalities | hemoglobin | 4 Participants |
| Part A: Treatment 1 | Number of Participants With With Grade 3 or Higher Laboratory Abnormalities | lymphocytes | 4 Participants |
| Part A: Treatment 1 | Number of Participants With With Grade 3 or Higher Laboratory Abnormalities | hyponatremia | 0 Participants |
| Part A: Treatment 1 | Number of Participants With With Grade 3 or Higher Laboratory Abnormalities | asparatate aminotransferase | 0 Participants |
| Part A: Treatment 1 | Number of Participants With With Grade 3 or Higher Laboratory Abnormalities | calcium, total | 0 Participants |
| Part A: Treatment 1 | Number of Participants With With Grade 3 or Higher Laboratory Abnormalities | hypokalemia | 0 Participants |
| Part A: Treatment 1 | Number of Participants With With Grade 3 or Higher Laboratory Abnormalities | albumin | 0 Participants |
| Part A: Treatment 1 | Number of Participants With With Grade 3 or Higher Laboratory Abnormalities | potassium | 0 Participants |
| Part A: Treatment 1 | Number of Participants With With Grade 3 or Higher Laboratory Abnormalities | neutrophils | 3 Participants |
| Part A: Treatment 1 | Number of Participants With With Grade 3 or Higher Laboratory Abnormalities | leukocytes | 5 Participants |
| Part A: Treatment 1 | Number of Participants With With Grade 3 or Higher Laboratory Abnormalities | creatinine | 0 Participants |
| Part A: Treatment 1 | Number of Participants With With Grade 3 or Higher Laboratory Abnormalities | sodium | 0 Participants |
| Part A: Treatment 1 | Number of Participants With With Grade 3 or Higher Laboratory Abnormalities | bilirubin, total | 0 Participants |
| Part A: Treatment 1 | Number of Participants With With Grade 3 or Higher Laboratory Abnormalities | Alanine aminotransferase | 0 Participants |
| Part A: Treatment 2 | Number of Participants With With Grade 3 or Higher Laboratory Abnormalities | hemoglobin | 6 Participants |
| Part A: Treatment 2 | Number of Participants With With Grade 3 or Higher Laboratory Abnormalities | asparatate aminotransferase | 1 Participants |
| Part A: Treatment 2 | Number of Participants With With Grade 3 or Higher Laboratory Abnormalities | alkaline phosphatase | 1 Participants |
| Part A: Treatment 2 | Number of Participants With With Grade 3 or Higher Laboratory Abnormalities | potassium | 2 Participants |
| Part A: Treatment 2 | Number of Participants With With Grade 3 or Higher Laboratory Abnormalities | hyponatremia | 0 Participants |
| Part A: Treatment 2 | Number of Participants With With Grade 3 or Higher Laboratory Abnormalities | platelet count | 8 Participants |
| Part A: Treatment 2 | Number of Participants With With Grade 3 or Higher Laboratory Abnormalities | hypokalemia | 2 Participants |
| Part A: Treatment 2 | Number of Participants With With Grade 3 or Higher Laboratory Abnormalities | hypocalcemia | 0 Participants |
| Part A: Treatment 2 | Number of Participants With With Grade 3 or Higher Laboratory Abnormalities | leukocytes | 5 Participants |
| Part A: Treatment 2 | Number of Participants With With Grade 3 or Higher Laboratory Abnormalities | Alanine aminotransferase | 1 Participants |
| Part A: Treatment 2 | Number of Participants With With Grade 3 or Higher Laboratory Abnormalities | hyperkalemia | 0 Participants |
| Part A: Treatment 2 | Number of Participants With With Grade 3 or Higher Laboratory Abnormalities | calcium, total | 0 Participants |
| Part A: Treatment 2 | Number of Participants With With Grade 3 or Higher Laboratory Abnormalities | lymphocytes | 5 Participants |
| Part A: Treatment 2 | Number of Participants With With Grade 3 or Higher Laboratory Abnormalities | sodium | 0 Participants |
| Part A: Treatment 2 | Number of Participants With With Grade 3 or Higher Laboratory Abnormalities | albumin | 0 Participants |
| Part A: Treatment 2 | Number of Participants With With Grade 3 or Higher Laboratory Abnormalities | creatinine | 0 Participants |
| Part A: Treatment 2 | Number of Participants With With Grade 3 or Higher Laboratory Abnormalities | neutrophils | 6 Participants |
| Part A: Treatment 2 | Number of Participants With With Grade 3 or Higher Laboratory Abnormalities | bilirubin, total | 0 Participants |
| Part A: Treatment 3 | Number of Participants With With Grade 3 or Higher Laboratory Abnormalities | neutrophils | 8 Participants |
| Part A: Treatment 3 | Number of Participants With With Grade 3 or Higher Laboratory Abnormalities | hemoglobin | 7 Participants |
| Part A: Treatment 3 | Number of Participants With With Grade 3 or Higher Laboratory Abnormalities | platelet count | 9 Participants |
| Part A: Treatment 3 | Number of Participants With With Grade 3 or Higher Laboratory Abnormalities | leukocytes | 6 Participants |
| Part A: Treatment 3 | Number of Participants With With Grade 3 or Higher Laboratory Abnormalities | lymphocytes | 4 Participants |
| Part A: Treatment 3 | Number of Participants With With Grade 3 or Higher Laboratory Abnormalities | Alanine aminotransferase | 1 Participants |
| Part A: Treatment 3 | Number of Participants With With Grade 3 or Higher Laboratory Abnormalities | alkaline phosphatase | 0 Participants |
| Part A: Treatment 3 | Number of Participants With With Grade 3 or Higher Laboratory Abnormalities | asparatate aminotransferase | 0 Participants |
| Part A: Treatment 3 | Number of Participants With With Grade 3 or Higher Laboratory Abnormalities | bilirubin, total | 1 Participants |
| Part A: Treatment 3 | Number of Participants With With Grade 3 or Higher Laboratory Abnormalities | creatinine | 0 Participants |
| Part A: Treatment 3 | Number of Participants With With Grade 3 or Higher Laboratory Abnormalities | albumin | 1 Participants |
| Part A: Treatment 3 | Number of Participants With With Grade 3 or Higher Laboratory Abnormalities | calcium, total | 0 Participants |
| Part A: Treatment 3 | Number of Participants With With Grade 3 or Higher Laboratory Abnormalities | hyperkalemia | 0 Participants |
| Part A: Treatment 3 | Number of Participants With With Grade 3 or Higher Laboratory Abnormalities | hypocalcemia | 0 Participants |
| Part A: Treatment 3 | Number of Participants With With Grade 3 or Higher Laboratory Abnormalities | hypokalemia | 0 Participants |
| Part A: Treatment 3 | Number of Participants With With Grade 3 or Higher Laboratory Abnormalities | hyponatremia | 0 Participants |
| Part A: Treatment 3 | Number of Participants With With Grade 3 or Higher Laboratory Abnormalities | potassium | 0 Participants |
| Part A: Treatment 3 | Number of Participants With With Grade 3 or Higher Laboratory Abnormalities | sodium | 0 Participants |
| Part A: Treatment 4 | Number of Participants With With Grade 3 or Higher Laboratory Abnormalities | hyperkalemia | 1 Participants |
| Part A: Treatment 4 | Number of Participants With With Grade 3 or Higher Laboratory Abnormalities | albumin | 1 Participants |
| Part A: Treatment 4 | Number of Participants With With Grade 3 or Higher Laboratory Abnormalities | potassium | 2 Participants |
| Part A: Treatment 4 | Number of Participants With With Grade 3 or Higher Laboratory Abnormalities | neutrophils | 8 Participants |
| Part A: Treatment 4 | Number of Participants With With Grade 3 or Higher Laboratory Abnormalities | calcium, total | 1 Participants |
| Part A: Treatment 4 | Number of Participants With With Grade 3 or Higher Laboratory Abnormalities | lymphocytes | 7 Participants |
| Part A: Treatment 4 | Number of Participants With With Grade 3 or Higher Laboratory Abnormalities | hemoglobin | 8 Participants |
| Part A: Treatment 4 | Number of Participants With With Grade 3 or Higher Laboratory Abnormalities | alkaline phosphatase | 0 Participants |
| Part A: Treatment 4 | Number of Participants With With Grade 3 or Higher Laboratory Abnormalities | hyponatremia | 1 Participants |
| Part A: Treatment 4 | Number of Participants With With Grade 3 or Higher Laboratory Abnormalities | Alanine aminotransferase | 0 Participants |
| Part A: Treatment 4 | Number of Participants With With Grade 3 or Higher Laboratory Abnormalities | platelet count | 10 Participants |
| Part A: Treatment 4 | Number of Participants With With Grade 3 or Higher Laboratory Abnormalities | hypokalemia | 1 Participants |
| Part A: Treatment 4 | Number of Participants With With Grade 3 or Higher Laboratory Abnormalities | creatinine | 1 Participants |
| Part A: Treatment 4 | Number of Participants With With Grade 3 or Higher Laboratory Abnormalities | asparatate aminotransferase | 0 Participants |
| Part A: Treatment 4 | Number of Participants With With Grade 3 or Higher Laboratory Abnormalities | sodium | 1 Participants |
| Part A: Treatment 4 | Number of Participants With With Grade 3 or Higher Laboratory Abnormalities | hypocalcemia | 1 Participants |
| Part A: Treatment 4 | Number of Participants With With Grade 3 or Higher Laboratory Abnormalities | leukocytes | 9 Participants |
| Part A: Treatment 4 | Number of Participants With With Grade 3 or Higher Laboratory Abnormalities | bilirubin, total | 0 Participants |
| Part A: Treatment 5 | Number of Participants With With Grade 3 or Higher Laboratory Abnormalities | sodium | 0 Participants |
| Part A: Treatment 5 | Number of Participants With With Grade 3 or Higher Laboratory Abnormalities | potassium | 0 Participants |
| Part A: Treatment 5 | Number of Participants With With Grade 3 or Higher Laboratory Abnormalities | bilirubin, total | 0 Participants |
| Part A: Treatment 5 | Number of Participants With With Grade 3 or Higher Laboratory Abnormalities | neutrophils | 8 Participants |
| Part A: Treatment 5 | Number of Participants With With Grade 3 or Higher Laboratory Abnormalities | creatinine | 0 Participants |
| Part A: Treatment 5 | Number of Participants With With Grade 3 or Higher Laboratory Abnormalities | lymphocytes | 7 Participants |
| Part A: Treatment 5 | Number of Participants With With Grade 3 or Higher Laboratory Abnormalities | albumin | 0 Participants |
| Part A: Treatment 5 | Number of Participants With With Grade 3 or Higher Laboratory Abnormalities | calcium, total | 0 Participants |
| Part A: Treatment 5 | Number of Participants With With Grade 3 or Higher Laboratory Abnormalities | leukocytes | 7 Participants |
| Part A: Treatment 5 | Number of Participants With With Grade 3 or Higher Laboratory Abnormalities | hyperkalemia | 0 Participants |
| Part A: Treatment 5 | Number of Participants With With Grade 3 or Higher Laboratory Abnormalities | hypocalcemia | 0 Participants |
| Part A: Treatment 5 | Number of Participants With With Grade 3 or Higher Laboratory Abnormalities | platelet count | 8 Participants |
| Part A: Treatment 5 | Number of Participants With With Grade 3 or Higher Laboratory Abnormalities | hypokalemia | 0 Participants |
| Part A: Treatment 5 | Number of Participants With With Grade 3 or Higher Laboratory Abnormalities | hyponatremia | 0 Participants |
| Part A: Treatment 5 | Number of Participants With With Grade 3 or Higher Laboratory Abnormalities | hemoglobin | 7 Participants |
| Part A: Treatment 5 | Number of Participants With With Grade 3 or Higher Laboratory Abnormalities | alkaline phosphatase | 0 Participants |
| Part A: Treatment 5 | Number of Participants With With Grade 3 or Higher Laboratory Abnormalities | Alanine aminotransferase | 0 Participants |
| Part A: Treatment 5 | Number of Participants With With Grade 3 or Higher Laboratory Abnormalities | asparatate aminotransferase | 0 Participants |
| Part A: Treatment 6 | Number of Participants With With Grade 3 or Higher Laboratory Abnormalities | creatinine | 0 Participants |
| Part A: Treatment 6 | Number of Participants With With Grade 3 or Higher Laboratory Abnormalities | potassium | 1 Participants |
| Part A: Treatment 6 | Number of Participants With With Grade 3 or Higher Laboratory Abnormalities | hyponatremia | 0 Participants |
| Part A: Treatment 6 | Number of Participants With With Grade 3 or Higher Laboratory Abnormalities | hypocalcemia | 0 Participants |
| Part A: Treatment 6 | Number of Participants With With Grade 3 or Higher Laboratory Abnormalities | hemoglobin | 10 Participants |
| Part A: Treatment 6 | Number of Participants With With Grade 3 or Higher Laboratory Abnormalities | neutrophils | 8 Participants |
| Part A: Treatment 6 | Number of Participants With With Grade 3 or Higher Laboratory Abnormalities | hypokalemia | 1 Participants |
| Part A: Treatment 6 | Number of Participants With With Grade 3 or Higher Laboratory Abnormalities | lymphocytes | 9 Participants |
| Part A: Treatment 6 | Number of Participants With With Grade 3 or Higher Laboratory Abnormalities | platelet count | 10 Participants |
| Part A: Treatment 6 | Number of Participants With With Grade 3 or Higher Laboratory Abnormalities | Alanine aminotransferase | 3 Participants |
| Part A: Treatment 6 | Number of Participants With With Grade 3 or Higher Laboratory Abnormalities | calcium, total | 0 Participants |
| Part A: Treatment 6 | Number of Participants With With Grade 3 or Higher Laboratory Abnormalities | alkaline phosphatase | 0 Participants |
| Part A: Treatment 6 | Number of Participants With With Grade 3 or Higher Laboratory Abnormalities | leukocytes | 9 Participants |
| Part A: Treatment 6 | Number of Participants With With Grade 3 or Higher Laboratory Abnormalities | sodium | 0 Participants |
| Part A: Treatment 6 | Number of Participants With With Grade 3 or Higher Laboratory Abnormalities | albumin | 1 Participants |
| Part A: Treatment 6 | Number of Participants With With Grade 3 or Higher Laboratory Abnormalities | asparatate aminotransferase | 1 Participants |
| Part A: Treatment 6 | Number of Participants With With Grade 3 or Higher Laboratory Abnormalities | bilirubin, total | 0 Participants |
| Part A: Treatment 6 | Number of Participants With With Grade 3 or Higher Laboratory Abnormalities | hyperkalemia | 0 Participants |
| Part A: Treatment 7 | Number of Participants With With Grade 3 or Higher Laboratory Abnormalities | bilirubin, total | 1 Participants |
| Part A: Treatment 7 | Number of Participants With With Grade 3 or Higher Laboratory Abnormalities | platelet count | 5 Participants |
| Part A: Treatment 7 | Number of Participants With With Grade 3 or Higher Laboratory Abnormalities | sodium | 0 Participants |
| Part A: Treatment 7 | Number of Participants With With Grade 3 or Higher Laboratory Abnormalities | creatinine | 0 Participants |
| Part A: Treatment 7 | Number of Participants With With Grade 3 or Higher Laboratory Abnormalities | neutrophils | 4 Participants |
| Part A: Treatment 7 | Number of Participants With With Grade 3 or Higher Laboratory Abnormalities | hypocalcemia | 0 Participants |
| Part A: Treatment 7 | Number of Participants With With Grade 3 or Higher Laboratory Abnormalities | alkaline phosphatase | 1 Participants |
| Part A: Treatment 7 | Number of Participants With With Grade 3 or Higher Laboratory Abnormalities | hypokalemia | 1 Participants |
| Part A: Treatment 7 | Number of Participants With With Grade 3 or Higher Laboratory Abnormalities | lymphocytes | 2 Participants |
| Part A: Treatment 7 | Number of Participants With With Grade 3 or Higher Laboratory Abnormalities | hemoglobin | 5 Participants |
| Part A: Treatment 7 | Number of Participants With With Grade 3 or Higher Laboratory Abnormalities | hyperkalemia | 0 Participants |
| Part A: Treatment 7 | Number of Participants With With Grade 3 or Higher Laboratory Abnormalities | asparatate aminotransferase | 1 Participants |
| Part A: Treatment 7 | Number of Participants With With Grade 3 or Higher Laboratory Abnormalities | hyponatremia | 0 Participants |
| Part A: Treatment 7 | Number of Participants With With Grade 3 or Higher Laboratory Abnormalities | Alanine aminotransferase | 1 Participants |
| Part A: Treatment 7 | Number of Participants With With Grade 3 or Higher Laboratory Abnormalities | leukocytes | 4 Participants |
| Part A: Treatment 7 | Number of Participants With With Grade 3 or Higher Laboratory Abnormalities | albumin | 0 Participants |
| Part A: Treatment 7 | Number of Participants With With Grade 3 or Higher Laboratory Abnormalities | calcium, total | 0 Participants |
| Part A: Treatment 7 | Number of Participants With With Grade 3 or Higher Laboratory Abnormalities | potassium | 1 Participants |
Secondary
AUC(0-T)
Area under the plasma concentration time-curve up to the last measurable concentration (AUC0-t)
Time frame: On Cycle 1 Day 1, C1D22 and C2D22.
Population: Pharmacokinetic Population
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: Treatment 1 | AUC(0-T) | Cycle 1 Day 1 | 27915.38 h*ug/mL | Geometric Coefficient of Variation 25.74 |
| Part A: Treatment 1 | AUC(0-T) | Cycle 1 Day 22 | 25766.21 h*ug/mL | Geometric Coefficient of Variation 366.57 |
| Part A: Treatment 1 | AUC(0-T) | Cycle 2 Day 22 | 42891.42 h*ug/mL | Geometric Coefficient of Variation 38.09 |
| Part A: Treatment 2 | AUC(0-T) | Cycle 1 Day 22 | 53952.86 h*ug/mL | Geometric Coefficient of Variation 105.79 |
| Part A: Treatment 2 | AUC(0-T) | Cycle 2 Day 22 | 54797.36 h*ug/mL | Geometric Coefficient of Variation 205.65 |
| Part A: Treatment 2 | AUC(0-T) | Cycle 1 Day 1 | 37242.17 h*ug/mL | Geometric Coefficient of Variation 41.18 |
| Part A: Treatment 3 | AUC(0-T) | Cycle 1 Day 22 | 38363.45 h*ug/mL | Geometric Coefficient of Variation 34.52 |
| Part A: Treatment 3 | AUC(0-T) | Cycle 1 Day 1 | 13125.85 h*ug/mL | Geometric Coefficient of Variation 48 |
| Part A: Treatment 3 | AUC(0-T) | Cycle 2 Day 22 | 37672.97 h*ug/mL | Geometric Coefficient of Variation 30.69 |
| Part A: Treatment 4 | AUC(0-T) | Cycle 1 Day 1 | 23850.09 h*ug/mL | Geometric Coefficient of Variation 50.97 |
| Part A: Treatment 4 | AUC(0-T) | Cycle 1 Day 22 | 46250.05 h*ug/mL | Geometric Coefficient of Variation 55.29 |
| Part A: Treatment 4 | AUC(0-T) | Cycle 2 Day 22 | 54425.19 h*ug/mL | Geometric Coefficient of Variation 131.05 |
| Part A: Treatment 5 | AUC(0-T) | Cycle 2 Day 22 | 116229.58 h*ug/mL | Geometric Coefficient of Variation 23.27 |
| Part A: Treatment 5 | AUC(0-T) | Cycle 1 Day 1 | 49377.47 h*ug/mL | Geometric Coefficient of Variation 10.9 |
| Part A: Treatment 5 | AUC(0-T) | Cycle 1 Day 22 | 84673.85 h*ug/mL | Geometric Coefficient of Variation 80.82 |
| Part A: Treatment 6 | AUC(0-T) | Cycle 1 Day 22 | 63857.81 h*ug/mL | Geometric Coefficient of Variation 83.67 |
| Part A: Treatment 6 | AUC(0-T) | Cycle 1 Day 1 | 28557.98 h*ug/mL | Geometric Coefficient of Variation 61.21 |
| Part A: Treatment 6 | AUC(0-T) | Cycle 2 Day 22 | 74865.57 h*ug/mL | Geometric Coefficient of Variation 104.46 |
| Part A: Treatment 7 | AUC(0-T) | Cycle 1 Day 22 | 186843.83 h*ug/mL | Geometric Coefficient of Variation 120.44 |
| Part A: Treatment 7 | AUC(0-T) | Cycle 2 Day 22 | 137581.5 h*ug/mL | — |
| Part A: Treatment 7 | AUC(0-T) | Cycle 1 Day 1 | 42273.81 h*ug/mL | Geometric Coefficient of Variation 28.09 |
Secondary
AUC(TAU)
Area under the plasma concentration time-curve during a dosing interval (AUCtau)
Time frame: On Cycle 1 Day 1, C1D22 and C2D22.
Population: Pharmacokinetic Population
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: Treatment 1 | AUC(TAU) | Cycle 1 Day 22 | 48306.42 h*ug/mL | Geometric Coefficient of Variation 48.94 |
| Part A: Treatment 1 | AUC(TAU) | Cycle 1 Day 1 | 27915.38 h*ug/mL | Geometric Coefficient of Variation 25.74 |
| Part A: Treatment 1 | AUC(TAU) | Cycle 2 Day 22 | 48436.92 h*ug/mL | Geometric Coefficient of Variation 44.72 |
| Part A: Treatment 2 | AUC(TAU) | Cycle 1 Day 22 | 87419.67 h*ug/mL | Geometric Coefficient of Variation 68.23 |
| Part A: Treatment 2 | AUC(TAU) | Cycle 2 Day 22 | 128864.45 h*ug/mL | Geometric Coefficient of Variation 8.24 |
| Part A: Treatment 2 | AUC(TAU) | Cycle 1 Day 1 | 39145.67 h*ug/mL | Geometric Coefficient of Variation 33.39 |
| Part A: Treatment 3 | AUC(TAU) | Cycle 1 Day 1 | 15987.61 h*ug/mL | Geometric Coefficient of Variation 16.16 |
| Part A: Treatment 3 | AUC(TAU) | Cycle 2 Day 22 | 37672.97 h*ug/mL | Geometric Coefficient of Variation 30.69 |
| Part A: Treatment 3 | AUC(TAU) | Cycle 1 Day 22 | 34295.76 h*ug/mL | Geometric Coefficient of Variation 16.51 |
| Part A: Treatment 4 | AUC(TAU) | Cycle 1 Day 1 | 28817.51 h*ug/mL | Geometric Coefficient of Variation 27.62 |
| Part A: Treatment 4 | AUC(TAU) | Cycle 2 Day 22 | 89459.57 h*ug/mL | Geometric Coefficient of Variation 19.99 |
| Part A: Treatment 4 | AUC(TAU) | Cycle 1 Day 22 | 64776.31 h*ug/mL | Geometric Coefficient of Variation 16.33 |
| Part A: Treatment 5 | AUC(TAU) | Cycle 2 Day 22 | 119737.08 h*ug/mL | Geometric Coefficient of Variation 25.79 |
| Part A: Treatment 5 | AUC(TAU) | Cycle 1 Day 1 | 49377.47 h*ug/mL | Geometric Coefficient of Variation 10.9 |
| Part A: Treatment 5 | AUC(TAU) | Cycle 1 Day 22 | 120818.65 h*ug/mL | Geometric Coefficient of Variation 32.18 |
| Part A: Treatment 6 | AUC(TAU) | Cycle 2 Day 22 | 114221.87 h*ug/mL | Geometric Coefficient of Variation 19.11 |
| Part A: Treatment 6 | AUC(TAU) | Cycle 1 Day 22 | 57119.56 h*ug/mL | Geometric Coefficient of Variation 67.28 |
| Part A: Treatment 6 | AUC(TAU) | Cycle 1 Day 1 | 29931.17 h*ug/mL | Geometric Coefficient of Variation 64.8 |
| Part A: Treatment 7 | AUC(TAU) | Cycle 2 Day 22 | 137581.85 h*ug/mL | — |
| Part A: Treatment 7 | AUC(TAU) | Cycle 1 Day 22 | 109428.93 h*ug/mL | Geometric Coefficient of Variation 41.91 |
| Part A: Treatment 7 | AUC(TAU) | Cycle 1 Day 1 | 46778.93 h*ug/mL | Geometric Coefficient of Variation 18.3 |
Secondary
Cmax
Maximum plasma concentration of drug
Time frame: On Cycle 1 Day 1, C1D22 and C2D22.
Population: Pharmacokinetic Population
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: Treatment 1 | Cmax | Cycle 2 Day 22 | 568.25 ug/mL | Geometric Coefficient of Variation 32.29 |
| Part A: Treatment 1 | Cmax | Cycle 1 Day 22 | 514.05 ug/mL | Geometric Coefficient of Variation 25.01 |
| Part A: Treatment 1 | Cmax | Cycle 1 Day 1 | 371.59 ug/mL | Geometric Coefficient of Variation 25.14 |
| Part A: Treatment 2 | Cmax | Cycle 1 Day 22 | 773.08 ug/mL | Geometric Coefficient of Variation 30.58 |
| Part A: Treatment 2 | Cmax | Cycle 1 Day 1 | 510.58 ug/mL | Geometric Coefficient of Variation 33.39 |
| Part A: Treatment 2 | Cmax | Cycle 2 Day 22 | 1217.78 ug/mL | Geometric Coefficient of Variation 19.11 |
| Part A: Treatment 3 | Cmax | Cycle 2 Day 22 | 318.09 ug/mL | Geometric Coefficient of Variation 21.12 |
| Part A: Treatment 3 | Cmax | Cycle 1 Day 1 | 209.40 ug/mL | Geometric Coefficient of Variation 14.13 |
| Part A: Treatment 3 | Cmax | Cycle 1 Day 22 | 314.49 ug/mL | Geometric Coefficient of Variation 16.76 |
| Part A: Treatment 4 | Cmax | Cycle 1 Day 22 | 641.78 ug/mL | Geometric Coefficient of Variation 21.6 |
| Part A: Treatment 4 | Cmax | Cycle 1 Day 1 | 428.72 ug/mL | Geometric Coefficient of Variation 22.78 |
| Part A: Treatment 4 | Cmax | Cycle 2 Day 22 | 637.76 ug/mL | Geometric Coefficient of Variation 21.01 |
| Part A: Treatment 5 | Cmax | Cycle 1 Day 22 | 1055.99 ug/mL | Geometric Coefficient of Variation 18.62 |
| Part A: Treatment 5 | Cmax | Cycle 1 Day 1 | 636.93 ug/mL | Geometric Coefficient of Variation 7.8 |
| Part A: Treatment 5 | Cmax | Cycle 2 Day 22 | 1468.00 ug/mL | Geometric Coefficient of Variation 18.85 |
| Part A: Treatment 6 | Cmax | Cycle 1 Day 1 | 418.39 ug/mL | Geometric Coefficient of Variation 42.61 |
| Part A: Treatment 6 | Cmax | Cycle 2 Day 22 | 833.06 ug/mL | Geometric Coefficient of Variation 38.61 |
| Part A: Treatment 6 | Cmax | Cycle 1 Day 22 | 592.41 ug/mL | Geometric Coefficient of Variation 50.25 |
| Part A: Treatment 7 | Cmax | Cycle 2 Day 22 | 1470.00 ug/mL | — |
| Part A: Treatment 7 | Cmax | Cycle 1 Day 22 | 1036.14 ug/mL | Geometric Coefficient of Variation 28.08 |
| Part A: Treatment 7 | Cmax | Cycle 1 Day 1 | 653.88 ug/mL | Geometric Coefficient of Variation 10.36 |
Secondary
Cmin
Minimum serum concentration
Time frame: On Cycle 1 Day 1, C1D22 and C2D22.
Population: Pharmacokinetic Population
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: Treatment 1 | Cmin | Cycle 2 Day 22 | 171.28 ug/mL | Geometric Coefficient of Variation 48.96 |
| Part A: Treatment 1 | Cmin | Cycle 1 Day 22 | 149.97 ug/mL | Geometric Coefficient of Variation 50.58 |
| Part A: Treatment 1 | Cmin | Cycle 1 Day 1 | NA ug/mL | — |
| Part A: Treatment 2 | Cmin | Cycle 2 Day 22 | 588.04 ug/mL | Geometric Coefficient of Variation 36.19 |
| Part A: Treatment 2 | Cmin | Cycle 1 Day 22 | 213.59 ug/mL | Geometric Coefficient of Variation 104.9 |
| Part A: Treatment 2 | Cmin | Cycle 1 Day 1 | 1.96 ug/mL | — |
| Part A: Treatment 3 | Cmin | Cycle 2 Day 22 | 135.10 ug/mL | Geometric Coefficient of Variation 44.61 |
| Part A: Treatment 3 | Cmin | Cycle 1 Day 22 | 109.90 ug/mL | Geometric Coefficient of Variation 40.52 |
| Part A: Treatment 3 | Cmin | Cycle 1 Day 1 | NA ug/mL | — |
| Part A: Treatment 4 | Cmin | Cycle 2 Day 22 | 225.45 ug/mL | Geometric Coefficient of Variation 37.09 |
| Part A: Treatment 4 | Cmin | Cycle 1 Day 1 | 140.00 ug/mL | — |
| Part A: Treatment 4 | Cmin | Cycle 1 Day 22 | 153.17 ug/mL | Geometric Coefficient of Variation 97.33 |
| Part A: Treatment 5 | Cmin | Cycle 1 Day 22 | 342.42 ug/mL | Geometric Coefficient of Variation 39.35 |
| Part A: Treatment 5 | Cmin | Cycle 2 Day 22 | 573.75 ug/mL | Geometric Coefficient of Variation 46.78 |
| Part A: Treatment 5 | Cmin | Cycle 1 Day 1 | NA ug/mL | — |
| Part A: Treatment 6 | Cmin | Cycle 2 Day 22 | 291.15 ug/mL | Geometric Coefficient of Variation 94.88 |
| Part A: Treatment 6 | Cmin | Cycle 1 Day 1 | NA ug/mL | — |
| Part A: Treatment 6 | Cmin | Cycle 1 Day 22 | 167.12 ug/mL | Geometric Coefficient of Variation 89.5 |
| Part A: Treatment 7 | Cmin | Cycle 1 Day 22 | 336.79 ug/mL | Geometric Coefficient of Variation 54.07 |
| Part A: Treatment 7 | Cmin | Cycle 1 Day 1 | 0.47 ug/mL | — |
| Part A: Treatment 7 | Cmin | Cycle 2 Day 22 | 545.00 ug/mL | — |
Secondary
Tmax
Time to maximum plasma concentration (Tmax)
Time frame: On Cycle 1 Day 1, C1D22 and C2D22.
Population: Pharmacokinetic Population
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Part A: Treatment 1 | Tmax | Cycle 2 Day 22 | 3.78 hours |
| Part A: Treatment 1 | Tmax | Cycle 1 Day 1 | 2.33 hours |
| Part A: Treatment 1 | Tmax | Cycle 1 Day 22 | 1.93 hours |
| Part A: Treatment 2 | Tmax | Cycle 1 Day 22 | 6.80 hours |
| Part A: Treatment 2 | Tmax | Cycle 2 Day 22 | 5.02 hours |
| Part A: Treatment 2 | Tmax | Cycle 1 Day 1 | 4.87 hours |
| Part A: Treatment 3 | Tmax | Cycle 1 Day 1 | 1.80 hours |
| Part A: Treatment 3 | Tmax | Cycle 2 Day 22 | 3.51 hours |
| Part A: Treatment 3 | Tmax | Cycle 1 Day 22 | 3.17 hours |
| Part A: Treatment 4 | Tmax | Cycle 2 Day 22 | 12.27 hours |
| Part A: Treatment 4 | Tmax | Cycle 1 Day 1 | 4.02 hours |
| Part A: Treatment 4 | Tmax | Cycle 1 Day 22 | 3.87 hours |
| Part A: Treatment 5 | Tmax | Cycle 1 Day 22 | 5.88 hours |
| Part A: Treatment 5 | Tmax | Cycle 1 Day 1 | 5.47 hours |
| Part A: Treatment 5 | Tmax | Cycle 2 Day 22 | 3.28 hours |
| Part A: Treatment 6 | Tmax | Cycle 1 Day 1 | 4.61 hours |
| Part A: Treatment 6 | Tmax | Cycle 1 Day 22 | 3.42 hours |
| Part A: Treatment 6 | Tmax | Cycle 2 Day 22 | 2.14 hours |
| Part A: Treatment 7 | Tmax | Cycle 2 Day 22 | 3.37 hours |
| Part A: Treatment 7 | Tmax | Cycle 1 Day 1 | 4.78 hours |
| Part A: Treatment 7 | Tmax | Cycle 1 Day 22 | 6.75 hours |