Relapsed or Refractory Acute Myeloid Leukemia, Relapsed or Refractory Chronic Myelomonocytic Leukemia
Conditions
Brief summary
The purpose of this study is to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and recommended Phase 2 dose (RP2D) of MK-0482. There are 2 parts of this study. Part 1 is a dose escalation which will follow an accelerated titration design (ATD) for participants with relapsed/refractory (R/R) AML or CMML. Part 2 is a dose expansion for participants with R/R AML.
Detailed description
In Part 1, single participants will be enrolled sequentially into escalating dose levels. Progression from one dose level to the next higher dose level will be based on the evaluation of dose-limiting toxicity (DLT). Once a preliminary RP2D is identified in Part 1, approximately 10 to 15 additional participants with R/R AML will be enrolled at the RP2D for Part 2.
Interventions
BIOLOGICALMK-0482
IV infusion
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
-Has confirmed diagnosis of AML with myelomonocytic or monoblastic/monocytic differentiation per World Health Organization (WHO) 2016 criteria and with confirmed refractory or relapsed disease (i.e., ≥5% blast in bone marrow or in peripheral blood) after treatment with available therapies known to benefit participant's AML subtypes or has a known diagnosis of CMML per WHO criteria \[2017\] with confirmed refractory or released disease after treatment with available therapies known to be active for CMML.
Exclusion criteria
* Has active central nervous system (CNS) leukemia. * Has isolated extramedullary disease, i.e., no leukemic involvement in bone marrow or peripheral blood. * Has diagnosis of acute promyelocytic leukemia or participants with known Philadelphia chromosome positive (Ph+) AML. * Has received previous allogeneic stem cell transplant or organ transplant within 60 days of the start of study treatment. * Has a history of a second malignancy, unless potentially curative treatment has been completed with no evidence of malignancy for 1 year. * Has a history of any of the following cardiovascular conditions within 6 months of screening: myocardial infarction, unstable angina, cerebrovascular accident, transient ischemic attack, coronary artery bypass graft, or pulmonary embolism; has New York Heart Association (NYHA) Class III or IV congestive heart failure. * Has had a severe hypersensitivity reaction to treatment with a monoclonal antibody (mAB) and or any components of the study intervention, MK-0482. * Has an active uncontrolled infection requiring directed therapy. * Has immediately life-threatening, severe complications of leukemia such as uncontrolled bleeding, pneumonia with hypoxia or shock, or disseminated intravascular coagulation. * Has known human immunodeficiency virus (HIV) and/or hepatitis B or C infections, or is known to be positive for HBsAg/ Hepatitis B virus (HBV) Deoxyribonucleic acid (DNA) or hepatitis C antibody or Ribonucleic acid (RNA). * Has known psychiatric or substance abuse disorders (verbally reported) that would interfere with the participant's ability to cooperate with the requirements of the study. * Is pregnant or breast feeding or expecting to conceive or father children within the projected duration of the study, starting with the Screening Visit through 120 days after the last dose of study intervention. * Has received systemic anticancer therapy, radiotherapy, or surgery within 2 weeks before the start of study treatment. * Has received hematopoietic cytokines (Granulocyte Colony Stimulating Factor (G-CSF), Granulocyte Macrophage (GM)-CSF, or erythropoietin) within 2 weeks prior to start of study treatment. * Has received a live or live attenuated vaccine within 30 days before the first dose of study medication. * Is currently participating and receiving study intervention in a study of an investigational agent or has participated and received study intervention in a study of an investigational agent or has used an investigational device within 14 days of administration of MK-0482. * Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior the first dose of study medication.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Who Experienced a Dose-Limiting Toxicity (DLT) | Cycle 1 (up to 21 days) | DLTs were defined as any of the following assessed as treatment-related by investigator (with pre-specified exceptions): Grade (Gr) 4 non-hematologic toxicity; Gr 3 non-hematologic toxicity; Gr 3 or Gr 4 non-hematologic laboratory value if: clinically significant medical intervention was required to treat the participant, the abnormality led to hospitalization, the abnormality persisted for \>1 week, electrolyte imbalances that lasted \>48 hours despite optimal therapy, or the abnormality resulted in a drug-induced liver injury; Gr 4 neutropenia and/or thrombocytopenia lasting \>14 days; \>2 week-delay in starting Cycle 2 due to treatment-related toxicity; treatment-related toxicity resulting in treatment discontinuation during DLT evaluation period; missing \>25% of MK-0482 dose during DLT evaluation period resulting from treatment-related adverse event (AE); or Gr 5 toxicity. The percentage of participants that experienced a DLT was reported for each arm. |
| Number of Participants Who Experience at Least One Adverse Event (AE) | Up to approximately 10 months | An AE was defined as any untoward medical occurrence in a participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. The number of participants who experienced at least one AE was reported for each arm. |
| Number of Participants Who Discontinued Study Treatment Due to an AE | Up to approximately 4 months | An AE was defined as any untoward medical occurrence in a participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. The number of participants who discontinued study treatment due to an AE was reported for each arm. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Maximum Concentration (Tmax) of MK-0482 | Cycle 1: Pre-dose and Days 1, 2, 4, 8, and 15 post-dose. Cycle=21 days. | Tmax was defined as the time to maximum concentration of MK-0482 observed in plasma. Blood samples were collected pre-dose and post-dose at designated timepoints to determine Tmax of MK-0482. |
| Plasma Elimination Terminal Half-life (t½) of MK-0482 | Cycle 1: Pre-dose and Days 1, 2, 4, 8, and 15 post-dose. Cycle=21 days. | t½ was defined as the time required to divide the MK-0482 plasma concentration by two after reaching pseudo-equilibrium. Blood samples were collected pre-dose and post-dose at designated timepoints to determine t½ of MK-0482. |
| Maximum Concentration (Cmax) of MK-0482 | Cycle 1: Pre-dose and Days 1, 2, 4, 8, and 15 post-dose. Cycle=21 days. | Cmax was defined as the maximum concentration of MK-0482 observed in plasma. Blood samples were collected pre-dose and post-dose at designated timepoints to determine Cmax of MK-0482. |
| Composite CR Rate | Up to approximately 10 months | Composite CR rate was assessed by the investigator per 2017 ELN Response Criteria for AML and was defined as CR plus CR with incomplete recovery (CRi). CR was defined as bone marrow blasts \<5%; absence of circulating blasts and blasts with Auer rods; absence of extramedullary disease; ANC ≥1.0 × 10\^9/L (1000/µL); and platelet count ≥100 × 10\^9/L (100,000/µL). CRi was defined as all CR criteria except for residual neutropenia (\<1.0 × 10\^9/L \[1000/µL\]) or thrombocytopenia (\<100 × 10\^9/L \[100,000/µL\]). The percentage of participants with Composite CR (Composite CR Rate) was reported for each arm. |
| Objective Response Rate (ORR) | Up to approximately 10 months | ORR was assessed by the investigator per 2017 ELN Response Criteria for AML and was defined as the combined percentage of participants with CR, CRi, and partial remission (PR). CR was defined as bone marrow blasts \<5%; absence of circulating blasts and blasts with Auer rods; absence of extramedullary disease; ANC ≥1.0 × 10\^9/L (1000/µL); platelet count ≥100 × 10\^9/L (100,000/µL)\]. CRi was defined as all CR criteria except for residual neutropenia (\<1.0 × 10\^9/L \[1000/µL\]) or thrombocytopenia (\<100 × 10\^9/L \[100,000/µL\]). PR was defined as all hematologic criteria of CR; decrease of bone marrow blast percentage to 5% to 25%; and decrease of pre-treatment bone marrow blast percentage by at least 50%). ORR was reported for each arm. |
| Complete Remission (CR) Rate | Up to approximately 10 months | CR Rate was assessed by the investigator per 2017 European Leukemia Net (ELN) Response Criteria for Acute Myeloid Leukemia (AML) and was defined as bone marrow blasts \<5%; absence of circulating blasts and blasts with Auer rods; absence of extramedullary disease; absolute neutrophil count (ANC) ≥1.0 × 10\^9/L (1000/µL); and platelet count ≥100 × 10\^9/L (100,000/µL). The percentage of participants with CR (CR Rate) was reported for each arm. |
| Minimum Concentration (Cmin) of MK-0482 | Cycle 1: Pre-dose and Days 1, 2, 4, 8, and 15 post-dose. Cycle=21 days. | Cmin (or Ctrough) was defined as the lowest concentration of MK-0482 reached during a dosing interval (time interval between administration of two doses). Blood samples were collected pre-dose and post-dose at designated timepoints to determine Cmin of MK-0482. |
| Area Under the Plasma Concentration-Time Curve From Time Zero to 21 Days (AUC0-21) of MK-0482 | Cycle 1: Pre-dose and Days 1, 2, 4, 8, and 15 post-dose. Cycle=21 days. | AUC0-21 was defined as the area under the plasma concentration-time curve from time zero to 21 days. Blood samples were collected pre-dose and post-dose at designated timepoints to determine AUC0-21 of MK-0482. |
Countries
Israel, Spain, United States
Participant flow
Pre-assignment details
Thirteen participants enrolled, of which 12 received study treatment in Part 1 of the study (dose-escalation). Part 2 of the study (dose expansion) was not conducted due to early termination of the study.
Participants by arm
| Arm | Count |
|---|---|
| MK-0482 7.5 mg Q3W Participants were to receive 7.5 mg of MK-0482 via intravenous (IV) infusion on Day 1 of each 21-day cycle (every 3 weeks \[Q3W\]) for up to 35 cycles (approximately 24 months). | 1 |
| MK-0482 25 mg Q3W Participants were to receive 25 mg of MK-0482 via IV infusion on Day 1 of each 21-day cycle (Q3W) for up to 35 cycles (approximately 24 months). | 1 |
| MK-0482 75 mg Q3W Participants were to receive 75 mg of MK-0482 via IV infusion on Day 1 of each 21-day cycle (Q3W) for up to 35 cycles (approximately 24 months). | 5 |
| MK-0482 225 mg Q3W Participants were to receive 225 mg of MK-0482 via IV infusion on Day 1 of each 21-day cycle (Q3W) for up to 35 cycles (approximately 24 months). | 3 |
| MK-0482 750 mg Q3W Participants were to receive 750 mg of MK-0482 via IV infusion on Day 1 of each 21-day cycle (Q3W) for up to 35 cycles (approximately 24 months). | 3 |
| Total | 13 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Death | 1 | 1 | 5 | 3 | 1 |
| Overall Study | Lack of Efficacy | 0 | 0 | 0 | 0 | 1 |
| Overall Study | Randomized By Mistake Without Study Treatment | 0 | 0 | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | MK-0482 7.5 mg Q3W | MK-0482 25 mg Q3W | MK-0482 75 mg Q3W | MK-0482 225 mg Q3W | MK-0482 750 mg Q3W | Total |
|---|---|---|---|---|---|---|
| Age, Customized 0 to 17 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Customized 18 to 64 years | 0 Participants | 0 Participants | 2 Participants | 1 Participants | 0 Participants | 3 Participants |
| Age, Customized 65 to 84 years | 1 Participants | 1 Participants | 3 Participants | 2 Participants | 3 Participants | 10 Participants |
| Age, Customized 85 years and over | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 0 Participants | 0 Participants | 5 Participants | 3 Participants | 2 Participants | 10 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 3 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 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 |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 4 Participants | 3 Participants | 2 Participants | 9 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 2 Participants | 1 Participants | 1 Participants | 4 Participants |
| Sex: Female, Male Male | 1 Participants | 1 Participants | 3 Participants | 2 Participants | 2 Participants | 9 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 |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 1 | 1 / 1 | 5 / 5 | 3 / 3 | 1 / 3 |
| other Total, other adverse events | 1 / 1 | 0 / 1 | 4 / 5 | 3 / 3 | 2 / 2 |
| serious Total, serious adverse events | 1 / 1 | 1 / 1 | 3 / 5 | 2 / 3 | 2 / 2 |
Outcome results
Primary
Number of Participants Who Discontinued Study Treatment Due to an AE
An AE was defined as any untoward medical occurrence in a participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. The number of participants who discontinued study treatment due to an AE was reported for each arm.
Time frame: Up to approximately 4 months
Population: All allocated participants who received at least 1 dose of study intervention were analyzed.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| MK-0482 7.5 mg Q3W | Number of Participants Who Discontinued Study Treatment Due to an AE | 0 Participants |
| MK-0482 25 mg Q3W | Number of Participants Who Discontinued Study Treatment Due to an AE | 0 Participants |
| MK-0482 75 mg Q3W | Number of Participants Who Discontinued Study Treatment Due to an AE | 1 Participants |
| MK-0482 225 mg Q3W | Number of Participants Who Discontinued Study Treatment Due to an AE | 0 Participants |
| MK-0482 750 mg Q3W | Number of Participants Who Discontinued Study Treatment Due to an AE | 0 Participants |
Primary
Number of Participants Who Experience at Least One Adverse Event (AE)
An AE was defined as any untoward medical occurrence in a participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. The number of participants who experienced at least one AE was reported for each arm.
Time frame: Up to approximately 10 months
Population: All allocated participants who received at least 1 dose of study intervention were analyzed.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| MK-0482 7.5 mg Q3W | Number of Participants Who Experience at Least One Adverse Event (AE) | 1 Participants |
| MK-0482 25 mg Q3W | Number of Participants Who Experience at Least One Adverse Event (AE) | 1 Participants |
| MK-0482 75 mg Q3W | Number of Participants Who Experience at Least One Adverse Event (AE) | 5 Participants |
| MK-0482 225 mg Q3W | Number of Participants Who Experience at Least One Adverse Event (AE) | 3 Participants |
| MK-0482 750 mg Q3W | Number of Participants Who Experience at Least One Adverse Event (AE) | 2 Participants |
Primary
Percentage of Participants Who Experienced a Dose-Limiting Toxicity (DLT)
DLTs were defined as any of the following assessed as treatment-related by investigator (with pre-specified exceptions): Grade (Gr) 4 non-hematologic toxicity; Gr 3 non-hematologic toxicity; Gr 3 or Gr 4 non-hematologic laboratory value if: clinically significant medical intervention was required to treat the participant, the abnormality led to hospitalization, the abnormality persisted for \>1 week, electrolyte imbalances that lasted \>48 hours despite optimal therapy, or the abnormality resulted in a drug-induced liver injury; Gr 4 neutropenia and/or thrombocytopenia lasting \>14 days; \>2 week-delay in starting Cycle 2 due to treatment-related toxicity; treatment-related toxicity resulting in treatment discontinuation during DLT evaluation period; missing \>25% of MK-0482 dose during DLT evaluation period resulting from treatment-related adverse event (AE); or Gr 5 toxicity. The percentage of participants that experienced a DLT was reported for each arm.
Time frame: Cycle 1 (up to 21 days)
Population: The DLT evaluable population included all allocated participants in Part 1 (dose escalation) who received at least 1 dose of study intervention and met the criteria for DLT evaluability (i.e finished Cycle 1 without a DLT, or experienced a DLT in Cycle 1).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MK-0482 7.5 mg Q3W | Percentage of Participants Who Experienced a Dose-Limiting Toxicity (DLT) | 0.0 Percentage of Participants |
| MK-0482 25 mg Q3W | Percentage of Participants Who Experienced a Dose-Limiting Toxicity (DLT) | 0.0 Percentage of Participants |
| MK-0482 75 mg Q3W | Percentage of Participants Who Experienced a Dose-Limiting Toxicity (DLT) | 0.0 Percentage of Participants |
| MK-0482 225 mg Q3W | Percentage of Participants Who Experienced a Dose-Limiting Toxicity (DLT) | 0.0 Percentage of Participants |
| MK-0482 750 mg Q3W | Percentage of Participants Who Experienced a Dose-Limiting Toxicity (DLT) | 0.0 Percentage of Participants |
Secondary
Area Under the Plasma Concentration-Time Curve From Time Zero to 21 Days (AUC0-21) of MK-0482
AUC0-21 was defined as the area under the plasma concentration-time curve from time zero to 21 days. Blood samples were collected pre-dose and post-dose at designated timepoints to determine AUC0-21 of MK-0482.
Time frame: Cycle 1: Pre-dose and Days 1, 2, 4, 8, and 15 post-dose. Cycle=21 days.
Population: All allocated participants who received at least 1 dose of study intervention, were compliant with the study procedures, and had available data from at least 1 treatment dose were analyzed.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| MK-0482 7.5 mg Q3W | Area Under the Plasma Concentration-Time Curve From Time Zero to 21 Days (AUC0-21) of MK-0482 | 3110 day*ng/mL | — |
| MK-0482 25 mg Q3W | Area Under the Plasma Concentration-Time Curve From Time Zero to 21 Days (AUC0-21) of MK-0482 | 17200 day*ng/mL | — |
| MK-0482 75 mg Q3W | Area Under the Plasma Concentration-Time Curve From Time Zero to 21 Days (AUC0-21) of MK-0482 | 105000 day*ng/mL | Geometric Coefficient of Variation 64.5 |
| MK-0482 225 mg Q3W | Area Under the Plasma Concentration-Time Curve From Time Zero to 21 Days (AUC0-21) of MK-0482 | 521000 day*ng/mL | Geometric Coefficient of Variation 22.9 |
| MK-0482 750 mg Q3W | Area Under the Plasma Concentration-Time Curve From Time Zero to 21 Days (AUC0-21) of MK-0482 | 885000 day*ng/mL | Geometric Coefficient of Variation 12.4 |
Secondary
Complete Remission (CR) Rate
CR Rate was assessed by the investigator per 2017 European Leukemia Net (ELN) Response Criteria for Acute Myeloid Leukemia (AML) and was defined as bone marrow blasts \<5%; absence of circulating blasts and blasts with Auer rods; absence of extramedullary disease; absolute neutrophil count (ANC) ≥1.0 × 10\^9/L (1000/µL); and platelet count ≥100 × 10\^9/L (100,000/µL). The percentage of participants with CR (CR Rate) was reported for each arm.
Time frame: Up to approximately 10 months
Population: All allocated participants who received at least 1 dose of study intervention and had a baseline assessment were analyzed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MK-0482 7.5 mg Q3W | Complete Remission (CR) Rate | 0.0 Percentage of Participants |
| MK-0482 25 mg Q3W | Complete Remission (CR) Rate | 0.0 Percentage of Participants |
| MK-0482 75 mg Q3W | Complete Remission (CR) Rate | 0.0 Percentage of Participants |
| MK-0482 225 mg Q3W | Complete Remission (CR) Rate | 0.0 Percentage of Participants |
| MK-0482 750 mg Q3W | Complete Remission (CR) Rate | 0.0 Percentage of Participants |
Secondary
Composite CR Rate
Composite CR rate was assessed by the investigator per 2017 ELN Response Criteria for AML and was defined as CR plus CR with incomplete recovery (CRi). CR was defined as bone marrow blasts \<5%; absence of circulating blasts and blasts with Auer rods; absence of extramedullary disease; ANC ≥1.0 × 10\^9/L (1000/µL); and platelet count ≥100 × 10\^9/L (100,000/µL). CRi was defined as all CR criteria except for residual neutropenia (\<1.0 × 10\^9/L \[1000/µL\]) or thrombocytopenia (\<100 × 10\^9/L \[100,000/µL\]). The percentage of participants with Composite CR (Composite CR Rate) was reported for each arm.
Time frame: Up to approximately 10 months
Population: All allocated participants who received at least 1 dose of study intervention and had a baseline assessment were analyzed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MK-0482 7.5 mg Q3W | Composite CR Rate | 0.0 Percentage of Participants |
| MK-0482 25 mg Q3W | Composite CR Rate | 0.0 Percentage of Participants |
| MK-0482 75 mg Q3W | Composite CR Rate | 0.0 Percentage of Participants |
| MK-0482 225 mg Q3W | Composite CR Rate | 0.0 Percentage of Participants |
| MK-0482 750 mg Q3W | Composite CR Rate | 0.0 Percentage of Participants |
Secondary
Maximum Concentration (Cmax) of MK-0482
Cmax was defined as the maximum concentration of MK-0482 observed in plasma. Blood samples were collected pre-dose and post-dose at designated timepoints to determine Cmax of MK-0482.
Time frame: Cycle 1: Pre-dose and Days 1, 2, 4, 8, and 15 post-dose. Cycle=21 days.
Population: All allocated participants who received at least 1 dose of study intervention, were compliant with the study procedures, and had available data from at least 1 treatment dose were analyzed.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| MK-0482 7.5 mg Q3W | Maximum Concentration (Cmax) of MK-0482 | 1490 ng/mL | — |
| MK-0482 25 mg Q3W | Maximum Concentration (Cmax) of MK-0482 | 5610 ng/mL | — |
| MK-0482 75 mg Q3W | Maximum Concentration (Cmax) of MK-0482 | 22000 ng/mL | Geometric Coefficient of Variation 28.1 |
| MK-0482 225 mg Q3W | Maximum Concentration (Cmax) of MK-0482 | 53400 ng/mL | Geometric Coefficient of Variation 31 |
| MK-0482 750 mg Q3W | Maximum Concentration (Cmax) of MK-0482 | 125000 ng/mL | Geometric Coefficient of Variation 24.6 |
Secondary
Minimum Concentration (Cmin) of MK-0482
Cmin (or Ctrough) was defined as the lowest concentration of MK-0482 reached during a dosing interval (time interval between administration of two doses). Blood samples were collected pre-dose and post-dose at designated timepoints to determine Cmin of MK-0482.
Time frame: Cycle 1: Pre-dose and Days 1, 2, 4, 8, and 15 post-dose. Cycle=21 days.
Population: All allocated participants who received at least 1 dose of study intervention, were compliant with the study procedures, and had available data from at least 1 treatment dose were analyzed.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| MK-0482 7.5 mg Q3W | Minimum Concentration (Cmin) of MK-0482 | 0.00 ng/mL | — |
| MK-0482 25 mg Q3W | Minimum Concentration (Cmin) of MK-0482 | 0.00 ng/mL | — |
| MK-0482 75 mg Q3W | Minimum Concentration (Cmin) of MK-0482 | 415 ng/mL | Geometric Coefficient of Variation 2077.3 |
| MK-0482 225 mg Q3W | Minimum Concentration (Cmin) of MK-0482 | 11200 ng/mL | Geometric Coefficient of Variation 34.6 |
| MK-0482 750 mg Q3W | Minimum Concentration (Cmin) of MK-0482 | 24500 ng/mL | Geometric Coefficient of Variation 61.9 |
Secondary
Objective Response Rate (ORR)
ORR was assessed by the investigator per 2017 ELN Response Criteria for AML and was defined as the combined percentage of participants with CR, CRi, and partial remission (PR). CR was defined as bone marrow blasts \<5%; absence of circulating blasts and blasts with Auer rods; absence of extramedullary disease; ANC ≥1.0 × 10\^9/L (1000/µL); platelet count ≥100 × 10\^9/L (100,000/µL)\]. CRi was defined as all CR criteria except for residual neutropenia (\<1.0 × 10\^9/L \[1000/µL\]) or thrombocytopenia (\<100 × 10\^9/L \[100,000/µL\]). PR was defined as all hematologic criteria of CR; decrease of bone marrow blast percentage to 5% to 25%; and decrease of pre-treatment bone marrow blast percentage by at least 50%). ORR was reported for each arm.
Time frame: Up to approximately 10 months
Population: All allocated participants who received at least 1 dose of study intervention and had a baseline assessment were analyzed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MK-0482 7.5 mg Q3W | Objective Response Rate (ORR) | 0.0 Percentage of Participants |
| MK-0482 25 mg Q3W | Objective Response Rate (ORR) | 0.0 Percentage of Participants |
| MK-0482 75 mg Q3W | Objective Response Rate (ORR) | 0.0 Percentage of Participants |
| MK-0482 225 mg Q3W | Objective Response Rate (ORR) | 0.0 Percentage of Participants |
| MK-0482 750 mg Q3W | Objective Response Rate (ORR) | 0.0 Percentage of Participants |
Secondary
Plasma Elimination Terminal Half-life (t½) of MK-0482
t½ was defined as the time required to divide the MK-0482 plasma concentration by two after reaching pseudo-equilibrium. Blood samples were collected pre-dose and post-dose at designated timepoints to determine t½ of MK-0482.
Time frame: Cycle 1: Pre-dose and Days 1, 2, 4, 8, and 15 post-dose. Cycle=21 days.
Population: All allocated participants who received at least 1 dose of study intervention, were compliant with the study procedures, and had available data from at least 1 treatment dose were analyzed.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| MK-0482 7.5 mg Q3W | Plasma Elimination Terminal Half-life (t½) of MK-0482 | NA Days | — |
| MK-0482 25 mg Q3W | Plasma Elimination Terminal Half-life (t½) of MK-0482 | 2.46 Days | — |
| MK-0482 75 mg Q3W | Plasma Elimination Terminal Half-life (t½) of MK-0482 | 3.69 Days | Geometric Coefficient of Variation 73.9 |
| MK-0482 225 mg Q3W | Plasma Elimination Terminal Half-life (t½) of MK-0482 | 11.2 Days | Geometric Coefficient of Variation 34.7 |
| MK-0482 750 mg Q3W | Plasma Elimination Terminal Half-life (t½) of MK-0482 | 11.2 Days | Geometric Coefficient of Variation 23.6 |
Secondary
Time to Maximum Concentration (Tmax) of MK-0482
Tmax was defined as the time to maximum concentration of MK-0482 observed in plasma. Blood samples were collected pre-dose and post-dose at designated timepoints to determine Tmax of MK-0482.
Time frame: Cycle 1: Pre-dose and Days 1, 2, 4, 8, and 15 post-dose. Cycle=21 days.
Population: All allocated participants who received at least 1 dose of study intervention, were compliant with the study procedures, and had available data from at least 1 treatment dose were analyzed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| MK-0482 7.5 mg Q3W | Time to Maximum Concentration (Tmax) of MK-0482 | 0.04 Days |
| MK-0482 25 mg Q3W | Time to Maximum Concentration (Tmax) of MK-0482 | 0.04 Days |
| MK-0482 75 mg Q3W | Time to Maximum Concentration (Tmax) of MK-0482 | 0.04 Days |
| MK-0482 225 mg Q3W | Time to Maximum Concentration (Tmax) of MK-0482 | 0.02 Days |
| MK-0482 750 mg Q3W | Time to Maximum Concentration (Tmax) of MK-0482 | 0.03 Days |