Acute Myelogenous Leukemia (AML)
Conditions
Brief summary
This is a study of MK-8242 alone and in combination with cytarabine in adult participants with refractory or recurrent acute myelogenous leukemia (AML). The study will have 2 Arms. Arm A is for participants with refractory or recurrent AML who are considered ineligible for standard chemotherapy. In Part 1 of Arm A, participants will receive MK-8242 monotherapy in escalating doses to determine the recommended phase 2 dose \[RP2D\]. In Part 2, participants will receive monotherapy with MK-8242 to confirm the RP2D and assess preliminary efficacy. Arm B is for participants with recurrent AML following an initial complete remission (CR) or CR with incomplete marrow recovery (CRi) of 6 to 12 months duration. In Part 1 of Arm B, participants will receive MK-8242 in escalating doses + cytarabine to determine the RP2D in combination with cytarabine. In Part 2, participants will receive MK-8242 + cytarabine to confirm the RP2D and assess preliminary efficacy. The pharmacokinetics of MK-8242 will be studied in both arms. With Amendment 4 (22 August 2013) a 21-day dosing cycle is added, with MK-8242 being given on Days 1-7 of each 21-day cycle in both the monotherapy and combination therapy arms; data from Arm A will be used to determine whether a participant receives 21-day or 28-day therapy in Arm B.
Interventions
DRUGMK-8242
MK-8242 capsules, orally, once per day on Days 1-7 and Days 15-21 of each 28-day cycle (except Cycle 1 Day 7) up to a maximum of 12 cycles. Starting dose will be 30 mg and will be escalated in successive cohorts until maximum tolerated dose (MTD) is established. Beginning at a dose level of ≥120 mg total daily dose (TDD), the dosing regimen will switch to twice daily (BID). Amendment 4 added a 21-day dosing cycle in which MK-8242 would be given BID on Days 1-7 of each cycle, at the assigned dose level.
Sponsors
Merck Sharp & Dohme LLC
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
* For Arm A Part 1 (monotherapy/dose escalation): refractory or recurrent AML, not an appropriate candidate for standard therapy * For Arm A Part 2 (monotherapy/dose confirmation/cohort expansion): refractory or recurrent AML, not an appropriate candidate for standard therapy, and have wild type p53 gene mutation analysis * For Arm B Part 1 (combination therapy/dose escalation): recurrent AML having achieved an initial CR or CRi of 6-12 months duration and age ≥18 years old and \<70 years old * For Arm B Part 2 (combination therapy/dose confirmation/cohort expansion): recurrent AML having achieved an initial CR or CRi of 6-12 months duration, age ≥18 years old and \<70 years old, and have wild type P53 gene mutation analysis * Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 for all Arm A, or 0 or 1 for all Arm B * Negative pregnancy test within 72 hours of the first dose of study medication * Female participants and male participants and their partners who are of childbearing potential must agree to abstain from sexual intercourse or to use an acceptable method of contraception during the study and for 90 days following the last dose of study therapy * Adequate organ function * Recovered from the effects of any prior surgery, radiotherapy or anti-neoplastic treatment, with the exception of alopecia * Must be able to swallow, retain, and absorb oral medications and oral nutrition * Must follow the appropriate washout period for prohibited treatments
Exclusion criteria
* Active malignancy other than AML * Leptomeningeal leukemia requiring intrathecal therapy * For Arm A and B, Part 1 only: history of myelodysplastic syndrome (MDS) * For Arm A and B, Part 2: AML in the background of MDS may be included * Isolated extramedullary leukemia without also meeting bone marrow criteria for acute leukemia * AML blast crisis of chronic myelogenous leukemia (CML) * Bone marrow transplant with active graft-versus host disease (GVHD) or who receives immunosuppressive therapy * Uncontrolled active infection that requires systemic treatment * Clinically significant hepatitis at Screening, or hepatitis C antibody positive, hepatitis B surface antigen positive, or human immunodeficiency virus (HIV) seropositive * Persistent, unresolved, drug-related toxicity * Breast-feeding, pregnant, intends to become pregnant or intends to breast feed during the study or has a positive pregnancy test at Screening * A person participating in any other clinical study with a potentially therapeutic agent or who has received another investigational product within 5 half-lives (if the half-life is known) or 28 days (if the half-life is unknown) prior to Day 1 of cycle 1 * A participant who, within the past 6 months, has had any of the following: myocardial infarction, coronary/peripheral artery bypass graft, cerebrovascular accident, transient ischemic attack, or uncontrolled seizure disorder (i.e., seizures within the past 6 months) * A participant who, at the time of Screening, presents with: unstable or uncontrolled angina, New York Heart Association (NYHA) class III or IV congestive heart failure, uncontrolled hypertension, clinically significant cardiac dysrhythmia or clinically significant electrocardiogram (ECG) abnormality * Known bleeding disorder, e.g. hemophilia or disseminated intravascular coagulopathy or on anti-coagulation therapy * For Arm B only: Known hypersensitivity to cytarabine
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Dose Limiting Toxicities (DLTs) | Up to 28 days (Cycle 1) for non-hematologic toxicities and 42 days (Cycle 1) for hematologic toxicities | DLTs were identified using Common Terminology Criteria for Adverse Events (CTCAE) v. 4.0 for toxicities attributable to the study drug. Hematologic DLTs were defined in the absence of morphological evidence of acute leukemia in the marrow if 1) bone marrow: aplastic marrow with \<5% cellularity without erythroid, myeloid, or megakaryocytic precursors and 2) peripheral blood: absolute neutrophil count (ANC) \<100/µL, platelet count \<10,000/µL, and transfusion-dependent anemia. Non-hematologic DLTs were defined as any ≥Grade 3 toxicity with the following exceptions/clarifications: 1) infection, fatigue, anorexia, or alopecia are not included in determination of the DLT 2) Grade 3 nausea, vomiting, diarrhea, or dehydration occurring in a setting of inadequate treatment 3) any abnormal non-hematological laboratory value ≥Grade 3 will be considered a DLT after 72 hours of appropriate medical intervention if not related to an underlying disease or not attributable to another event. |
| Number of Participants With Complete Remission (CR) at RP2D | End of Treatment (up to 198 days) | Clinical activity of MK-8242 given as monotherapy in participants with refractory or recurrent AML measured as participants who achieved CR according to Cheson (2003) criteria at the RP2D. The outcome analysis was not performed since the RP2D for MK-8242 monotherapy could not be established due to early termination of the study. |
| Number of Participants With Complete Remission With Incomplete Marrow Recovery (CRi) at RP2D | End of Treatment (up to 198 days) | Clinical activity of MK-8242 given as monotherapy in participants with refractory or recurrent AML measured as participants who achieved CRi according to Cheson (2003) criteria at the RP2D. The outcome analysis was not performed since the RP2D for MK-8242 monotherapy could not be established due to early termination of the study. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Concentration-time Curve From Time 0 to Last (AUC0-last) for MK-8242 Alone and in Combination With Cytarabine | Cycle 1, Day 1 and Day 7 (QD arms: predose and 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 10, 24, and 48 [Day 7 only] hrs postdose; BID arms: predose and 0.5, 1, 2, 4, 6, 8, 12 [optional], 24 [Day 7 only], 48 [Day 7 only] hrs postdose) | AUC(0-last) defined as AUC from time zero to the time of last quantifiable sample was determined for Cycle 1 Days 1 and 7 of MK-8242 QD and BID dosing using the trapezoidal up/log trapezoidal down method. Analysis for the combination therapy was not performed due to early termination of the study (Study Arm B was not performed). |
| Area Under the Concentration-time Curve From Time 0 to Infinity (AUC0-∞) for MK-8242 Alone and in Combination With Cytarabine | Cycle 1 Day 7 (QD arms: predose and 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 10, 24, and 48 hrs postdose; BID arms: predose and 0.5, 1, 2, 4, 6, 8, 12 [optional], 24, 48 hrs postdose) | AUC0-∞ defined as AUC from time zero to infinity was determined for Cycle 1 Day 7 of MK-8242 QD and BID dosing using the trapezoidal up/log trapezoidal down method. Projection beyond the last sampled time was made if a linear terminal elimination phase half-life was identified with three time-points after Tmax (condition not met for 60 QD and 120 BID dose groups). Analysis for the combination therapy was not performed due to early termination of the study (Study Arm B was not performed). |
| Maximum Plasma Concentration (Cmax) of MK-8242 Alone and in Combination With Cytarabine | Cycle 1, Day 1 and Day 7 (QD arms: predose and 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 10, 24, and 48 [Day 7 only] hrs postdose; BID arms: predose and 0.5, 1, 2, 4, 6, 8, 12 [optional], 24 [Day 7 only], 48 [Day 7 only] hrs postdose) | Cmax was determined for Cycle 1 Days 1 and 7 of MK-8226 QD and BID dosing. Analysis for the combination therapy was not performed due to early termination of the study (Study Arm B was not performed). |
| Number of Participants With CR at Dose Levels Other Than RP2D | End of Treatment (up to 198 days) | Clinical activity of MK-8242 given as monotherapy in participants with refractory or recurrent AML measured as participants who achieved CR according to Cheson (2003) criteria at dose levels other than RP2D. CR is defined as a morphologic leukemia-free state with a neutrophil count ≥1,000/µL, a platelet count ≥100,000/µL, no extramedullary disease, and RBC transfusion independence. Presented outcome values are not stratified for dose levels other than RP2D; the RP2D for MK-8242 monotherapy could not be established due to early termination of the study. |
| Apparent Terminal Half-life (t1/2) for MK-8242 Alone and in Combination With Cytarabine | Cycle 1 Day 7 (QD arms: predose and 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 10, 24, and 48 hrs postdose; BID arms: predose and 0.5, 1, 2, 4, 6, 8, 12 [optional], 24, 48 hrs postdose) | Elimination phase t1/2 was determined for Cycle 1 Day 7 of MK-8242 QD and BID dosing. Analysis for the combination therapy was not performed due to early termination of the study (Study Arm B was not performed). |
| Accumulation Ratio (R) of MK-8242 Alone and in Combination With Cytarabine | Cycle 1 Day 7 (QD arms: predose and 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 10, 24, and 48 hrs postdose; BID arms: predose and 0.5, 1, 2, 4, 6, 8, 12 [optional], 24 [Day 7 only], 48 [Day 7 only] hrs postdose) | The accumulation ratio (R) at steady state (based on dosing interval and apparent terminal half-life (t1/2)) for MK-8242 alone was not determined due to confounding of results by significant concentrations of a drug metabolite (M16). Analysis for the combination therapy was not performed due to early termination of the study (Study Arm B was not performed). |
| Urine Concentration of MK-8242 (Part 2 Arm A Only) | Day 1 (predose and postdose) and Day 7 (postdose) | The urine concentration of MK-8242 assessed as a measure of drug bioavailability was not determined due to early termination of the study (Study Part 2 was not performed). |
| Time to Maximum Concentration (Tmax) of MK-8242 Alone and in Combination With Cytarabine | Cycle 1, Day 1 and Day 7 (QD arms: predose and 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 10, 24, and 48 [Day 7 only] hrs postdose; BID arms: predose and 0.5, 1, 2, 4, 6, 8, 12 [optional], 24 [Day 7 only], 48 [Day 7 only] hrs postdose) | Tmax was determined for Cycle 1 Days 1 and 7 of MK-8226 QD and BID dosing. Analysis for the combination therapy was not performed due to early termination of the study (Study Arm B was not performed). |
| Number of Participants With CRi at Dose Levels Other Than RP2D | End of Treatment (up to 198 days) | Clinical activity of MK-8242 given as monotherapy in participants with refractory or recurrent AML measured as participants who achieved CRi according to Cheson (2003) criteria at dose levels other than RP2D. CRi is defined as fulfillment of all CR criteria with exceptions for residual neutropenia (\<1,000/µL), thrombocytopenia (\<100,000/µL), and RBC transfusion dependence. Presented outcome values are not stratified for dose levels other than RP2D; the RP2D for MK-8242 monotherapy could not be established due to early termination of the study. |
| Area Under the Concentration-time Curve From Time 0 to 24 Hours (AUC0-24hr) for MK-8242 Alone and in Combination With Cytarabine | Cycle 1, Day 1 and Day 7 (QD arms: predose and 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 10, and 24 hrs postdose; BID arms: predose and 0.5, 1, 2, 4, 6, 8, 12 [optional], and 24 [Day 7 only] hrs postdose) | AUC(0-24hr) defined as AUC from time zero to 24 hours was determined for Cycle 1 Days 1 and 7 of MK-8242 QD and BID dosing using the trapezoidal up/log trapezoidal down method. For the BID arms, a projection beyond the last sampled time was made if a linear terminal elimination phase half-life was identified with three time-points after Tmax. Analysis for the combination therapy was not performed due to early termination of the study (Study Arm B was not performed). |
Participant flow
Pre-assignment details
No participant in Part 1 received combination therapy (MK-8242 + cytarabine). Study Part 2 was not performed due to early termination of the study.
Participants by arm
| Arm | Count |
|---|---|
| Pt 1 Arm A: MK-8242 30 mg QD Participants received MK-8242 30 mg QD monotherapy on Days 1-7 and Days 15-21 of each 28-day cycle in Part 1 Arm A. | 1 |
| Pt 1 Arm A: MK-8242 60 mg QD Participants received MK-8242 60 mg QD monotherapy on Days 1-7 and Days 15-21 of each 28-day cycle in Part 1 Arm A. | 1 |
| Pt 1 Arm A: MK-8242 120 mg QD Participants received MK-8242 120 mg QD monotherapy on Days 1-7 and Days 15-21 of each 28-day cycle in Part 1 Arm A. | 3 |
| Pt 1 Arm A: MK-8242 250 mg QD Participants received MK-8242 250 mg QD monotherapy on Days 1-7 and Days 15-21 of each 28-day cycle in Part 1 Arm A. | 1 |
| Pt 1 Arm A: MK-8242 120 mg BID Participants received MK-8242 120 mg BID monotherapy on Days 1-7 and Days 15-21 of each 28-day cycle (except Cycle 1 Day 7 on which MK-8242 120 mg was administered QD in the morning) in Part 1 Arm A. | 4 |
| Pt 1 Arm A: MK-8242 170 mg BID Participants received MK-8242 170 mg BID monotherapy on Days 1-7 and Days 15-21 of each 28-day cycle (except Cycle 1 Day 7 on which MK-8242 170 mg was administered QD in the morning) in Part 1 Arm A. | 3 |
| Pt 1 Arm A: MK-8242 210 mg BID Participants received MK-8242 210 mg BID monotherapy on Days 1-7 of each 21-day cycle (except Cycle 1 Day 7 on which MK-8242 210 mg was administered QD in the morning) in Part 1 Arm A. | 6 |
| Pt 1 Arm A: MK-8242 250 mg BID Participants received MK-8242 250 mg BID monotherapy on Days 1-7 and Days 15-21 of each 28-day cycle (except Cycle 1 Day 7 on which MK-8242 250 mg was administered QD in the morning) in Part 1 Arm A. | 3 |
| Pt 1 Arm A: MK-8242 300 mg BID Participants received MK-8242 300 mg BID monotherapy on Days 1-7 of each 21-day cycle (except Cycle 1 Day 7 on which MK-8242 300 mg was administered QD in the morning) in Part 1 Arm A. | 4 |
| Total | 26 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 |
|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 0 | 0 | 0 | 1 | 1 | 2 | 1 |
| Overall Study | Disease Progression | 0 | 0 | 1 | 1 | 3 | 2 | 3 | 1 | 3 |
| Overall Study | Physician Decision | 1 | 1 | 2 | 0 | 0 | 0 | 0 | 0 | 0 |
| Overall Study | Protocol Violation | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 0 | 0 | 1 | 0 | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Pt 1 Arm A: MK-8242 30 mg QD | Pt 1 Arm A: MK-8242 60 mg QD | Pt 1 Arm A: MK-8242 120 mg QD | Pt 1 Arm A: MK-8242 250 mg QD | Pt 1 Arm A: MK-8242 120 mg BID | Pt 1 Arm A: MK-8242 170 mg BID | Pt 1 Arm A: MK-8242 210 mg BID | Pt 1 Arm A: MK-8242 250 mg BID | Pt 1 Arm A: MK-8242 300 mg BID | Total |
|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 63.0 Years | 74.0 Years | 72.3 Years STANDARD_DEVIATION 6.7 | 77.0 Years | 58.8 Years STANDARD_DEVIATION 18.5 | 63.3 Years STANDARD_DEVIATION 14.6 | 63.5 Years STANDARD_DEVIATION 11.5 | 72.3 Years STANDARD_DEVIATION 12.5 | 41.0 Years STANDARD_DEVIATION 14.3 | 62.2 Years STANDARD_DEVIATION 15.5 |
| Age, Customized Adults between 18 and 64 years | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 1 Participants | 3 Participants | 1 Participants | 4 Participants | 12 Participants |
| Age, Customized From 65 to 84 years | 0 Participants | 1 Participants | 3 Participants | 1 Participants | 2 Participants | 2 Participants | 3 Participants | 2 Participants | 0 Participants | 14 Participants |
| Race/Ethnicity, Customized Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Hispanic Or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Not Hispanic Or Latino | 1 Participants | 1 Participants | 3 Participants | 1 Participants | 3 Participants | 2 Participants | 5 Participants | 3 Participants | 3 Participants | 22 Participants |
| Race/Ethnicity, Customized Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Unknown | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 2 Participants |
| Race/Ethnicity, Customized White | 1 Participants | 1 Participants | 3 Participants | 1 Participants | 4 Participants | 3 Participants | 5 Participants | 3 Participants | 3 Participants | 24 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 3 Participants | 0 Participants | 1 Participants | 6 Participants |
| Sex: Female, Male Male | 1 Participants | 1 Participants | 2 Participants | 1 Participants | 4 Participants | 2 Participants | 3 Participants | 3 Participants | 3 Participants | 20 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 1 / 1 | 1 / 1 | 3 / 3 | 1 / 1 | 4 / 4 | 3 / 3 | 6 / 6 | 3 / 3 | 3 / 4 |
| serious Total, serious adverse events | 1 / 1 | 0 / 1 | 2 / 3 | 1 / 1 | 1 / 4 | 1 / 3 | 5 / 6 | 3 / 3 | 2 / 4 |
Outcome results
Primary
Number of Participants With Complete Remission (CR) at RP2D
Clinical activity of MK-8242 given as monotherapy in participants with refractory or recurrent AML measured as participants who achieved CR according to Cheson (2003) criteria at the RP2D. The outcome analysis was not performed since the RP2D for MK-8242 monotherapy could not be established due to early termination of the study.
Time frame: End of Treatment (up to 198 days)
Population: Full Analysis Set for Efficacy: all participants with confirmed p53 wild type (WT) status who received at least one dose of MK-8242 and have at least one baseline and one post-baseline efficacy assessment.
Primary
Number of Participants With Complete Remission With Incomplete Marrow Recovery (CRi) at RP2D
Clinical activity of MK-8242 given as monotherapy in participants with refractory or recurrent AML measured as participants who achieved CRi according to Cheson (2003) criteria at the RP2D. The outcome analysis was not performed since the RP2D for MK-8242 monotherapy could not be established due to early termination of the study.
Time frame: End of Treatment (up to 198 days)
Population: Full Analysis Set for Efficacy: all participants with confirmed p53 WT status who received at least one dose of MK-8242 and have at least one baseline and one post-baseline efficacy assessment.
Primary
Number of Participants With Dose Limiting Toxicities (DLTs)
DLTs were identified using Common Terminology Criteria for Adverse Events (CTCAE) v. 4.0 for toxicities attributable to the study drug. Hematologic DLTs were defined in the absence of morphological evidence of acute leukemia in the marrow if 1) bone marrow: aplastic marrow with \<5% cellularity without erythroid, myeloid, or megakaryocytic precursors and 2) peripheral blood: absolute neutrophil count (ANC) \<100/µL, platelet count \<10,000/µL, and transfusion-dependent anemia. Non-hematologic DLTs were defined as any ≥Grade 3 toxicity with the following exceptions/clarifications: 1) infection, fatigue, anorexia, or alopecia are not included in determination of the DLT 2) Grade 3 nausea, vomiting, diarrhea, or dehydration occurring in a setting of inadequate treatment 3) any abnormal non-hematological laboratory value ≥Grade 3 will be considered a DLT after 72 hours of appropriate medical intervention if not related to an underlying disease or not attributable to another event.
Time frame: Up to 28 days (Cycle 1) for non-hematologic toxicities and 42 days (Cycle 1) for hematologic toxicities
Population: DLT-evaluable Population: participants who received at least one dose of MK-8242 and completed Cycle 1 of Part 1 or discontinued due to reason of toxicity.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pt 1 Arm A: MK-8242 30 mg QD | Number of Participants With Dose Limiting Toxicities (DLTs) | 0 Participants |
| Pt 1 Arm A: MK-8242 60 mg QD | Number of Participants With Dose Limiting Toxicities (DLTs) | 0 Participants |
| Pt 1 Arm A: MK-8242 120 mg QD | Number of Participants With Dose Limiting Toxicities (DLTs) | 0 Participants |
| Pt 1 Arm A: MK-8242 250 mg QD | Number of Participants With Dose Limiting Toxicities (DLTs) | 0 Participants |
| Pt 1 Arm A: MK-8242 120 mg BID | Number of Participants With Dose Limiting Toxicities (DLTs) | 0 Participants |
| Pt 1 Arm A: MK-8242 170 mg BID | Number of Participants With Dose Limiting Toxicities (DLTs) | 0 Participants |
| Pt 1 Arm A: MK-8242 210 mg BID | Number of Participants With Dose Limiting Toxicities (DLTs) | 0 Participants |
| Pt 1 Arm A: MK-8242 250 mg BID | Number of Participants With Dose Limiting Toxicities (DLTs) | 2 Participants |
| Pt 1 Arm A: MK-8242 300 mg BID | Number of Participants With Dose Limiting Toxicities (DLTs) | 0 Participants |
Secondary
Accumulation Ratio (R) of MK-8242 Alone and in Combination With Cytarabine
The accumulation ratio (R) at steady state (based on dosing interval and apparent terminal half-life (t1/2)) for MK-8242 alone was not determined due to confounding of results by significant concentrations of a drug metabolite (M16). Analysis for the combination therapy was not performed due to early termination of the study (Study Arm B was not performed).
Time frame: Cycle 1 Day 7 (QD arms: predose and 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 10, 24, and 48 hrs postdose; BID arms: predose and 0.5, 1, 2, 4, 6, 8, 12 [optional], 24 [Day 7 only], 48 [Day 7 only] hrs postdose)
Population: Participants who received at least one dose of MK-8242, were compliant with study procedures, and had available pharmacokinetic data (R) at the time of assessment.
Secondary
Apparent Terminal Half-life (t1/2) for MK-8242 Alone and in Combination With Cytarabine
Elimination phase t1/2 was determined for Cycle 1 Day 7 of MK-8242 QD and BID dosing. Analysis for the combination therapy was not performed due to early termination of the study (Study Arm B was not performed).
Time frame: Cycle 1 Day 7 (QD arms: predose and 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 10, 24, and 48 hrs postdose; BID arms: predose and 0.5, 1, 2, 4, 6, 8, 12 [optional], 24, 48 hrs postdose)
Population: Participants who received at least one dose of MK-8242, were compliant with study procedures, and had available pharmacokinetic data (at least three time-points after Tmax).
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Pt 1 Arm A: MK-8242 30 mg QD | Apparent Terminal Half-life (t1/2) for MK-8242 Alone and in Combination With Cytarabine | 4.7 hr | — |
| Pt 1 Arm A: MK-8242 120 mg QD | Apparent Terminal Half-life (t1/2) for MK-8242 Alone and in Combination With Cytarabine | 5.33 hr | Geometric Coefficient of Variation 23.5 |
| Pt 1 Arm A: MK-8242 250 mg QD | Apparent Terminal Half-life (t1/2) for MK-8242 Alone and in Combination With Cytarabine | 4.57 hr | — |
| Pt 1 Arm A: MK-8242 170 mg BID | Apparent Terminal Half-life (t1/2) for MK-8242 Alone and in Combination With Cytarabine | 10.30 hr | — |
| Pt 1 Arm A: MK-8242 210 mg BID | Apparent Terminal Half-life (t1/2) for MK-8242 Alone and in Combination With Cytarabine | 7.92 hr | Geometric Coefficient of Variation 31.6 |
| Pt 1 Arm A: MK-8242 250 mg BID | Apparent Terminal Half-life (t1/2) for MK-8242 Alone and in Combination With Cytarabine | 5.21 hr | Geometric Coefficient of Variation 17.9 |
| Pt 1 Arm A: MK-8242 300 mg BID | Apparent Terminal Half-life (t1/2) for MK-8242 Alone and in Combination With Cytarabine | 7.06 hr | Geometric Coefficient of Variation 36.6 |
Secondary
Area Under the Concentration-time Curve From Time 0 to 24 Hours (AUC0-24hr) for MK-8242 Alone and in Combination With Cytarabine
AUC(0-24hr) defined as AUC from time zero to 24 hours was determined for Cycle 1 Days 1 and 7 of MK-8242 QD and BID dosing using the trapezoidal up/log trapezoidal down method. For the BID arms, a projection beyond the last sampled time was made if a linear terminal elimination phase half-life was identified with three time-points after Tmax. Analysis for the combination therapy was not performed due to early termination of the study (Study Arm B was not performed).
Time frame: Cycle 1, Day 1 and Day 7 (QD arms: predose and 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 10, and 24 hrs postdose; BID arms: predose and 0.5, 1, 2, 4, 6, 8, 12 [optional], and 24 [Day 7 only] hrs postdose)
Population: Participants who received at least one dose of MK-8242, were compliant with study procedures, and had available pharmacokinetic data (AUC0-24hr) at the time of assessment.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Pt 1 Arm A: MK-8242 30 mg QD | Area Under the Concentration-time Curve From Time 0 to 24 Hours (AUC0-24hr) for MK-8242 Alone and in Combination With Cytarabine | Day 1 (n=1,1,3,1,3,2,4,3,1) | 604 hr*nM | — |
| Pt 1 Arm A: MK-8242 30 mg QD | Area Under the Concentration-time Curve From Time 0 to 24 Hours (AUC0-24hr) for MK-8242 Alone and in Combination With Cytarabine | Day 7 (n=1,1,3,1,3,3,5,3,3) | 665 hr*nM | — |
| Pt 1 Arm A: MK-8242 60 mg QD | Area Under the Concentration-time Curve From Time 0 to 24 Hours (AUC0-24hr) for MK-8242 Alone and in Combination With Cytarabine | Day 1 (n=1,1,3,1,3,2,4,3,1) | 510 hr*nM | — |
| Pt 1 Arm A: MK-8242 60 mg QD | Area Under the Concentration-time Curve From Time 0 to 24 Hours (AUC0-24hr) for MK-8242 Alone and in Combination With Cytarabine | Day 7 (n=1,1,3,1,3,3,5,3,3) | 515 hr*nM | — |
| Pt 1 Arm A: MK-8242 120 mg QD | Area Under the Concentration-time Curve From Time 0 to 24 Hours (AUC0-24hr) for MK-8242 Alone and in Combination With Cytarabine | Day 1 (n=1,1,3,1,3,2,4,3,1) | 3710 hr*nM | Geometric Coefficient of Variation 126 |
| Pt 1 Arm A: MK-8242 120 mg QD | Area Under the Concentration-time Curve From Time 0 to 24 Hours (AUC0-24hr) for MK-8242 Alone and in Combination With Cytarabine | Day 7 (n=1,1,3,1,3,3,5,3,3) | 3460 hr*nM | Geometric Coefficient of Variation 54.6 |
| Pt 1 Arm A: MK-8242 250 mg QD | Area Under the Concentration-time Curve From Time 0 to 24 Hours (AUC0-24hr) for MK-8242 Alone and in Combination With Cytarabine | Day 1 (n=1,1,3,1,3,2,4,3,1) | 10900 hr*nM | — |
| Pt 1 Arm A: MK-8242 250 mg QD | Area Under the Concentration-time Curve From Time 0 to 24 Hours (AUC0-24hr) for MK-8242 Alone and in Combination With Cytarabine | Day 7 (n=1,1,3,1,3,3,5,3,3) | 6840 hr*nM | — |
| Pt 1 Arm A: MK-8242 120 mg BID | Area Under the Concentration-time Curve From Time 0 to 24 Hours (AUC0-24hr) for MK-8242 Alone and in Combination With Cytarabine | Day 1 (n=1,1,3,1,3,2,4,3,1) | 3230 hr*nM | Geometric Coefficient of Variation 101 |
| Pt 1 Arm A: MK-8242 120 mg BID | Area Under the Concentration-time Curve From Time 0 to 24 Hours (AUC0-24hr) for MK-8242 Alone and in Combination With Cytarabine | Day 7 (n=1,1,3,1,3,3,5,3,3) | 4180 hr*nM | Geometric Coefficient of Variation 41.2 |
| Pt 1 Arm A: MK-8242 170 mg BID | Area Under the Concentration-time Curve From Time 0 to 24 Hours (AUC0-24hr) for MK-8242 Alone and in Combination With Cytarabine | Day 7 (n=1,1,3,1,3,3,5,3,3) | 8440 hr*nM | Geometric Coefficient of Variation 105 |
| Pt 1 Arm A: MK-8242 170 mg BID | Area Under the Concentration-time Curve From Time 0 to 24 Hours (AUC0-24hr) for MK-8242 Alone and in Combination With Cytarabine | Day 1 (n=1,1,3,1,3,2,4,3,1) | 6940 hr*nM | Geometric Coefficient of Variation 127 |
| Pt 1 Arm A: MK-8242 210 mg BID | Area Under the Concentration-time Curve From Time 0 to 24 Hours (AUC0-24hr) for MK-8242 Alone and in Combination With Cytarabine | Day 7 (n=1,1,3,1,3,3,5,3,3) | 11200 hr*nM | Geometric Coefficient of Variation 53 |
| Pt 1 Arm A: MK-8242 210 mg BID | Area Under the Concentration-time Curve From Time 0 to 24 Hours (AUC0-24hr) for MK-8242 Alone and in Combination With Cytarabine | Day 1 (n=1,1,3,1,3,2,4,3,1) | 6400 hr*nM | Geometric Coefficient of Variation 76.4 |
| Pt 1 Arm A: MK-8242 250 mg BID | Area Under the Concentration-time Curve From Time 0 to 24 Hours (AUC0-24hr) for MK-8242 Alone and in Combination With Cytarabine | Day 1 (n=1,1,3,1,3,2,4,3,1) | 7910 hr*nM | Geometric Coefficient of Variation 81.5 |
| Pt 1 Arm A: MK-8242 250 mg BID | Area Under the Concentration-time Curve From Time 0 to 24 Hours (AUC0-24hr) for MK-8242 Alone and in Combination With Cytarabine | Day 7 (n=1,1,3,1,3,3,5,3,3) | 8800 hr*nM | Geometric Coefficient of Variation 56.9 |
| Pt 1 Arm A: MK-8242 300 mg BID | Area Under the Concentration-time Curve From Time 0 to 24 Hours (AUC0-24hr) for MK-8242 Alone and in Combination With Cytarabine | Day 1 (n=1,1,3,1,3,2,4,3,1) | 9480 hr*nM | — |
| Pt 1 Arm A: MK-8242 300 mg BID | Area Under the Concentration-time Curve From Time 0 to 24 Hours (AUC0-24hr) for MK-8242 Alone and in Combination With Cytarabine | Day 7 (n=1,1,3,1,3,3,5,3,3) | 14200 hr*nM | Geometric Coefficient of Variation 62.5 |
Secondary
Area Under the Concentration-time Curve From Time 0 to Infinity (AUC0-∞) for MK-8242 Alone and in Combination With Cytarabine
AUC0-∞ defined as AUC from time zero to infinity was determined for Cycle 1 Day 7 of MK-8242 QD and BID dosing using the trapezoidal up/log trapezoidal down method. Projection beyond the last sampled time was made if a linear terminal elimination phase half-life was identified with three time-points after Tmax (condition not met for 60 QD and 120 BID dose groups). Analysis for the combination therapy was not performed due to early termination of the study (Study Arm B was not performed).
Time frame: Cycle 1 Day 7 (QD arms: predose and 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 10, 24, and 48 hrs postdose; BID arms: predose and 0.5, 1, 2, 4, 6, 8, 12 [optional], 24, 48 hrs postdose)
Population: Participants who received at least one dose of MK-8242, were compliant with study procedures, and had available pharmacokinetic data (AUC0-∞) at the time of assessment.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Pt 1 Arm A: MK-8242 30 mg QD | Area Under the Concentration-time Curve From Time 0 to Infinity (AUC0-∞) for MK-8242 Alone and in Combination With Cytarabine | 650 hr*nM | — |
| Pt 1 Arm A: MK-8242 120 mg QD | Area Under the Concentration-time Curve From Time 0 to Infinity (AUC0-∞) for MK-8242 Alone and in Combination With Cytarabine | 3570 hr*nM | Geometric Coefficient of Variation 61.6 |
| Pt 1 Arm A: MK-8242 250 mg QD | Area Under the Concentration-time Curve From Time 0 to Infinity (AUC0-∞) for MK-8242 Alone and in Combination With Cytarabine | 6990 hr*nM | — |
| Pt 1 Arm A: MK-8242 170 mg BID | Area Under the Concentration-time Curve From Time 0 to Infinity (AUC0-∞) for MK-8242 Alone and in Combination With Cytarabine | 6480 hr*nM | — |
| Pt 1 Arm A: MK-8242 210 mg BID | Area Under the Concentration-time Curve From Time 0 to Infinity (AUC0-∞) for MK-8242 Alone and in Combination With Cytarabine | 13300 hr*nM | Geometric Coefficient of Variation 84.2 |
| Pt 1 Arm A: MK-8242 250 mg BID | Area Under the Concentration-time Curve From Time 0 to Infinity (AUC0-∞) for MK-8242 Alone and in Combination With Cytarabine | 11700 hr*nM | Geometric Coefficient of Variation 40.3 |
| Pt 1 Arm A: MK-8242 300 mg BID | Area Under the Concentration-time Curve From Time 0 to Infinity (AUC0-∞) for MK-8242 Alone and in Combination With Cytarabine | 15100 hr*nM | Geometric Coefficient of Variation 112 |
Secondary
Area Under the Concentration-time Curve From Time 0 to Last (AUC0-last) for MK-8242 Alone and in Combination With Cytarabine
AUC(0-last) defined as AUC from time zero to the time of last quantifiable sample was determined for Cycle 1 Days 1 and 7 of MK-8242 QD and BID dosing using the trapezoidal up/log trapezoidal down method. Analysis for the combination therapy was not performed due to early termination of the study (Study Arm B was not performed).
Time frame: Cycle 1, Day 1 and Day 7 (QD arms: predose and 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 10, 24, and 48 [Day 7 only] hrs postdose; BID arms: predose and 0.5, 1, 2, 4, 6, 8, 12 [optional], 24 [Day 7 only], 48 [Day 7 only] hrs postdose)
Population: Participants who received at least one dose of MK-8242, were compliant with study procedures, and had available pharmacokinetic data (AUC0-last) at the time of assessment.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Pt 1 Arm A: MK-8242 30 mg QD | Area Under the Concentration-time Curve From Time 0 to Last (AUC0-last) for MK-8242 Alone and in Combination With Cytarabine | Day 1 | 323 hr*nM | — |
| Pt 1 Arm A: MK-8242 30 mg QD | Area Under the Concentration-time Curve From Time 0 to Last (AUC0-last) for MK-8242 Alone and in Combination With Cytarabine | Day 7 | 470 hr*nM | — |
| Pt 1 Arm A: MK-8242 60 mg QD | Area Under the Concentration-time Curve From Time 0 to Last (AUC0-last) for MK-8242 Alone and in Combination With Cytarabine | Day 7 | 482 hr*nM | — |
| Pt 1 Arm A: MK-8242 60 mg QD | Area Under the Concentration-time Curve From Time 0 to Last (AUC0-last) for MK-8242 Alone and in Combination With Cytarabine | Day 1 | 482 hr*nM | — |
| Pt 1 Arm A: MK-8242 120 mg QD | Area Under the Concentration-time Curve From Time 0 to Last (AUC0-last) for MK-8242 Alone and in Combination With Cytarabine | Day 7 | 3180 hr*nM | Geometric Coefficient of Variation 73.5 |
| Pt 1 Arm A: MK-8242 120 mg QD | Area Under the Concentration-time Curve From Time 0 to Last (AUC0-last) for MK-8242 Alone and in Combination With Cytarabine | Day 1 | 3420 hr*nM | Geometric Coefficient of Variation 156 |
| Pt 1 Arm A: MK-8242 250 mg QD | Area Under the Concentration-time Curve From Time 0 to Last (AUC0-last) for MK-8242 Alone and in Combination With Cytarabine | Day 1 | 10900 hr*nM | — |
| Pt 1 Arm A: MK-8242 250 mg QD | Area Under the Concentration-time Curve From Time 0 to Last (AUC0-last) for MK-8242 Alone and in Combination With Cytarabine | Day 7 | 6830 hr*nM | — |
| Pt 1 Arm A: MK-8242 120 mg BID | Area Under the Concentration-time Curve From Time 0 to Last (AUC0-last) for MK-8242 Alone and in Combination With Cytarabine | Day 7 | 3100 hr*nM | Geometric Coefficient of Variation 73.1 |
| Pt 1 Arm A: MK-8242 120 mg BID | Area Under the Concentration-time Curve From Time 0 to Last (AUC0-last) for MK-8242 Alone and in Combination With Cytarabine | Day 1 | 2710 hr*nM | Geometric Coefficient of Variation 58.3 |
| Pt 1 Arm A: MK-8242 170 mg BID | Area Under the Concentration-time Curve From Time 0 to Last (AUC0-last) for MK-8242 Alone and in Combination With Cytarabine | Day 1 | 4370 hr*nM | Geometric Coefficient of Variation 111 |
| Pt 1 Arm A: MK-8242 170 mg BID | Area Under the Concentration-time Curve From Time 0 to Last (AUC0-last) for MK-8242 Alone and in Combination With Cytarabine | Day 7 | 9560 hr*nM | Geometric Coefficient of Variation 183 |
| Pt 1 Arm A: MK-8242 210 mg BID | Area Under the Concentration-time Curve From Time 0 to Last (AUC0-last) for MK-8242 Alone and in Combination With Cytarabine | Day 1 | 5310 hr*nM | Geometric Coefficient of Variation 56.1 |
| Pt 1 Arm A: MK-8242 210 mg BID | Area Under the Concentration-time Curve From Time 0 to Last (AUC0-last) for MK-8242 Alone and in Combination With Cytarabine | Day 7 | 11900 hr*nM | Geometric Coefficient of Variation 59.8 |
| Pt 1 Arm A: MK-8242 250 mg BID | Area Under the Concentration-time Curve From Time 0 to Last (AUC0-last) for MK-8242 Alone and in Combination With Cytarabine | Day 1 | 6710 hr*nM | Geometric Coefficient of Variation 76.3 |
| Pt 1 Arm A: MK-8242 250 mg BID | Area Under the Concentration-time Curve From Time 0 to Last (AUC0-last) for MK-8242 Alone and in Combination With Cytarabine | Day 7 | 9080 hr*nM | Geometric Coefficient of Variation 51.4 |
| Pt 1 Arm A: MK-8242 300 mg BID | Area Under the Concentration-time Curve From Time 0 to Last (AUC0-last) for MK-8242 Alone and in Combination With Cytarabine | Day 7 | 15200 hr*nM | Geometric Coefficient of Variation 74.1 |
| Pt 1 Arm A: MK-8242 300 mg BID | Area Under the Concentration-time Curve From Time 0 to Last (AUC0-last) for MK-8242 Alone and in Combination With Cytarabine | Day 1 | 7200 hr*nM | Geometric Coefficient of Variation 15.1 |
Secondary
Maximum Plasma Concentration (Cmax) of MK-8242 Alone and in Combination With Cytarabine
Cmax was determined for Cycle 1 Days 1 and 7 of MK-8226 QD and BID dosing. Analysis for the combination therapy was not performed due to early termination of the study (Study Arm B was not performed).
Time frame: Cycle 1, Day 1 and Day 7 (QD arms: predose and 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 10, 24, and 48 [Day 7 only] hrs postdose; BID arms: predose and 0.5, 1, 2, 4, 6, 8, 12 [optional], 24 [Day 7 only], 48 [Day 7 only] hrs postdose)
Population: Participants who received at least one dose of MK-8242, were compliant with study procedures, and had available pharmacokinetic data (Cmax) at the time of assessment.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Pt 1 Arm A: MK-8242 30 mg QD | Maximum Plasma Concentration (Cmax) of MK-8242 Alone and in Combination With Cytarabine | Day 1 (n=1,1,3,1,4,3,5,3,3) | 56.7 nM | — |
| Pt 1 Arm A: MK-8242 30 mg QD | Maximum Plasma Concentration (Cmax) of MK-8242 Alone and in Combination With Cytarabine | Day 7 (n=1,1,3,1,3,3,5,3,3) | 88.8 nM | — |
| Pt 1 Arm A: MK-8242 60 mg QD | Maximum Plasma Concentration (Cmax) of MK-8242 Alone and in Combination With Cytarabine | Day 1 (n=1,1,3,1,4,3,5,3,3) | 109 nM | — |
| Pt 1 Arm A: MK-8242 60 mg QD | Maximum Plasma Concentration (Cmax) of MK-8242 Alone and in Combination With Cytarabine | Day 7 (n=1,1,3,1,3,3,5,3,3) | 178 nM | — |
| Pt 1 Arm A: MK-8242 120 mg QD | Maximum Plasma Concentration (Cmax) of MK-8242 Alone and in Combination With Cytarabine | Day 1 (n=1,1,3,1,4,3,5,3,3) | 416 nM | Geometric Coefficient of Variation 81.4 |
| Pt 1 Arm A: MK-8242 120 mg QD | Maximum Plasma Concentration (Cmax) of MK-8242 Alone and in Combination With Cytarabine | Day 7 (n=1,1,3,1,3,3,5,3,3) | 530 nM | Geometric Coefficient of Variation 55.9 |
| Pt 1 Arm A: MK-8242 250 mg QD | Maximum Plasma Concentration (Cmax) of MK-8242 Alone and in Combination With Cytarabine | Day 1 (n=1,1,3,1,4,3,5,3,3) | 1270 nM | — |
| Pt 1 Arm A: MK-8242 250 mg QD | Maximum Plasma Concentration (Cmax) of MK-8242 Alone and in Combination With Cytarabine | Day 7 (n=1,1,3,1,3,3,5,3,3) | 1320 nM | — |
| Pt 1 Arm A: MK-8242 120 mg BID | Maximum Plasma Concentration (Cmax) of MK-8242 Alone and in Combination With Cytarabine | Day 1 (n=1,1,3,1,4,3,5,3,3) | 561 nM | Geometric Coefficient of Variation 51.9 |
| Pt 1 Arm A: MK-8242 120 mg BID | Maximum Plasma Concentration (Cmax) of MK-8242 Alone and in Combination With Cytarabine | Day 7 (n=1,1,3,1,3,3,5,3,3) | 744 nM | Geometric Coefficient of Variation 56.1 |
| Pt 1 Arm A: MK-8242 170 mg BID | Maximum Plasma Concentration (Cmax) of MK-8242 Alone and in Combination With Cytarabine | Day 7 (n=1,1,3,1,3,3,5,3,3) | 1200 nM | Geometric Coefficient of Variation 65.2 |
| Pt 1 Arm A: MK-8242 170 mg BID | Maximum Plasma Concentration (Cmax) of MK-8242 Alone and in Combination With Cytarabine | Day 1 (n=1,1,3,1,4,3,5,3,3) | 984 nM | Geometric Coefficient of Variation 93.2 |
| Pt 1 Arm A: MK-8242 210 mg BID | Maximum Plasma Concentration (Cmax) of MK-8242 Alone and in Combination With Cytarabine | Day 7 (n=1,1,3,1,3,3,5,3,3) | 1550 nM | Geometric Coefficient of Variation 50.7 |
| Pt 1 Arm A: MK-8242 210 mg BID | Maximum Plasma Concentration (Cmax) of MK-8242 Alone and in Combination With Cytarabine | Day 1 (n=1,1,3,1,4,3,5,3,3) | 1310 nM | Geometric Coefficient of Variation 52.5 |
| Pt 1 Arm A: MK-8242 250 mg BID | Maximum Plasma Concentration (Cmax) of MK-8242 Alone and in Combination With Cytarabine | Day 1 (n=1,1,3,1,4,3,5,3,3) | 1510 nM | Geometric Coefficient of Variation 65.7 |
| Pt 1 Arm A: MK-8242 250 mg BID | Maximum Plasma Concentration (Cmax) of MK-8242 Alone and in Combination With Cytarabine | Day 7 (n=1,1,3,1,3,3,5,3,3) | 1500 nM | Geometric Coefficient of Variation 108 |
| Pt 1 Arm A: MK-8242 300 mg BID | Maximum Plasma Concentration (Cmax) of MK-8242 Alone and in Combination With Cytarabine | Day 1 (n=1,1,3,1,4,3,5,3,3) | 1940 nM | Geometric Coefficient of Variation 25.8 |
| Pt 1 Arm A: MK-8242 300 mg BID | Maximum Plasma Concentration (Cmax) of MK-8242 Alone and in Combination With Cytarabine | Day 7 (n=1,1,3,1,3,3,5,3,3) | 1920 nM | Geometric Coefficient of Variation 80.8 |
Secondary
Number of Participants With CR at Dose Levels Other Than RP2D
Clinical activity of MK-8242 given as monotherapy in participants with refractory or recurrent AML measured as participants who achieved CR according to Cheson (2003) criteria at dose levels other than RP2D. CR is defined as a morphologic leukemia-free state with a neutrophil count ≥1,000/µL, a platelet count ≥100,000/µL, no extramedullary disease, and RBC transfusion independence. Presented outcome values are not stratified for dose levels other than RP2D; the RP2D for MK-8242 monotherapy could not be established due to early termination of the study.
Time frame: End of Treatment (up to 198 days)
Population: Modified Full Analysis Set for Efficacy: all participants with confirmed p53 WT status who received at least one dose of MK-8242.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pt 1 Arm A: MK-8242 30 mg QD | Number of Participants With CR at Dose Levels Other Than RP2D | 0 Participants |
| Pt 1 Arm A: MK-8242 60 mg QD | Number of Participants With CR at Dose Levels Other Than RP2D | 0 Participants |
| Pt 1 Arm A: MK-8242 120 mg QD | Number of Participants With CR at Dose Levels Other Than RP2D | 0 Participants |
| Pt 1 Arm A: MK-8242 250 mg QD | Number of Participants With CR at Dose Levels Other Than RP2D | 0 Participants |
| Pt 1 Arm A: MK-8242 120 mg BID | Number of Participants With CR at Dose Levels Other Than RP2D | 0 Participants |
| Pt 1 Arm A: MK-8242 170 mg BID | Number of Participants With CR at Dose Levels Other Than RP2D | 0 Participants |
| Pt 1 Arm A: MK-8242 210 mg BID | Number of Participants With CR at Dose Levels Other Than RP2D | 0 Participants |
| Pt 1 Arm A: MK-8242 250 mg BID | Number of Participants With CR at Dose Levels Other Than RP2D | 0 Participants |
| Pt 1 Arm A: MK-8242 300 mg BID | Number of Participants With CR at Dose Levels Other Than RP2D | 0 Participants |
Secondary
Number of Participants With CRi at Dose Levels Other Than RP2D
Clinical activity of MK-8242 given as monotherapy in participants with refractory or recurrent AML measured as participants who achieved CRi according to Cheson (2003) criteria at dose levels other than RP2D. CRi is defined as fulfillment of all CR criteria with exceptions for residual neutropenia (\<1,000/µL), thrombocytopenia (\<100,000/µL), and RBC transfusion dependence. Presented outcome values are not stratified for dose levels other than RP2D; the RP2D for MK-8242 monotherapy could not be established due to early termination of the study.
Time frame: End of Treatment (up to 198 days)
Population: Modified Full Analysis Set for Efficacy: all participants with confirmed p53 WT status who received at least one dose of MK-8242.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pt 1 Arm A: MK-8242 30 mg QD | Number of Participants With CRi at Dose Levels Other Than RP2D | 0 Participants |
| Pt 1 Arm A: MK-8242 60 mg QD | Number of Participants With CRi at Dose Levels Other Than RP2D | 0 Participants |
| Pt 1 Arm A: MK-8242 120 mg QD | Number of Participants With CRi at Dose Levels Other Than RP2D | 0 Participants |
| Pt 1 Arm A: MK-8242 250 mg QD | Number of Participants With CRi at Dose Levels Other Than RP2D | 0 Participants |
| Pt 1 Arm A: MK-8242 120 mg BID | Number of Participants With CRi at Dose Levels Other Than RP2D | 0 Participants |
| Pt 1 Arm A: MK-8242 170 mg BID | Number of Participants With CRi at Dose Levels Other Than RP2D | 0 Participants |
| Pt 1 Arm A: MK-8242 210 mg BID | Number of Participants With CRi at Dose Levels Other Than RP2D | 1 Participants |
| Pt 1 Arm A: MK-8242 250 mg BID | Number of Participants With CRi at Dose Levels Other Than RP2D | 0 Participants |
| Pt 1 Arm A: MK-8242 300 mg BID | Number of Participants With CRi at Dose Levels Other Than RP2D | 0 Participants |
Secondary
Time to Maximum Concentration (Tmax) of MK-8242 Alone and in Combination With Cytarabine
Tmax was determined for Cycle 1 Days 1 and 7 of MK-8226 QD and BID dosing. Analysis for the combination therapy was not performed due to early termination of the study (Study Arm B was not performed).
Time frame: Cycle 1, Day 1 and Day 7 (QD arms: predose and 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 10, 24, and 48 [Day 7 only] hrs postdose; BID arms: predose and 0.5, 1, 2, 4, 6, 8, 12 [optional], 24 [Day 7 only], 48 [Day 7 only] hrs postdose)
Population: Participants who received at least one dose of MK-8242, were compliant with study procedures, and had available pharmacokinetic data (Tmax) at the time of assessment.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Pt 1 Arm A: MK-8242 30 mg QD | Time to Maximum Concentration (Tmax) of MK-8242 Alone and in Combination With Cytarabine | Day 7 (n=1,1,3,1,3,3,5,3,3) | 2.00 Hours |
| Pt 1 Arm A: MK-8242 30 mg QD | Time to Maximum Concentration (Tmax) of MK-8242 Alone and in Combination With Cytarabine | Day 1 (n=1,1,3,1,4,3,5,3,3) | 6.25 Hours |
| Pt 1 Arm A: MK-8242 60 mg QD | Time to Maximum Concentration (Tmax) of MK-8242 Alone and in Combination With Cytarabine | Day 7 (n=1,1,3,1,3,3,5,3,3) | 2.00 Hours |
| Pt 1 Arm A: MK-8242 60 mg QD | Time to Maximum Concentration (Tmax) of MK-8242 Alone and in Combination With Cytarabine | Day 1 (n=1,1,3,1,4,3,5,3,3) | 2.00 Hours |
| Pt 1 Arm A: MK-8242 120 mg QD | Time to Maximum Concentration (Tmax) of MK-8242 Alone and in Combination With Cytarabine | Day 1 (n=1,1,3,1,4,3,5,3,3) | 4.00 Hours |
| Pt 1 Arm A: MK-8242 120 mg QD | Time to Maximum Concentration (Tmax) of MK-8242 Alone and in Combination With Cytarabine | Day 7 (n=1,1,3,1,3,3,5,3,3) | 2.00 Hours |
| Pt 1 Arm A: MK-8242 250 mg QD | Time to Maximum Concentration (Tmax) of MK-8242 Alone and in Combination With Cytarabine | Day 7 (n=1,1,3,1,3,3,5,3,3) | 2.00 Hours |
| Pt 1 Arm A: MK-8242 250 mg QD | Time to Maximum Concentration (Tmax) of MK-8242 Alone and in Combination With Cytarabine | Day 1 (n=1,1,3,1,4,3,5,3,3) | 4.00 Hours |
| Pt 1 Arm A: MK-8242 120 mg BID | Time to Maximum Concentration (Tmax) of MK-8242 Alone and in Combination With Cytarabine | Day 7 (n=1,1,3,1,3,3,5,3,3) | 4.00 Hours |
| Pt 1 Arm A: MK-8242 120 mg BID | Time to Maximum Concentration (Tmax) of MK-8242 Alone and in Combination With Cytarabine | Day 1 (n=1,1,3,1,4,3,5,3,3) | 4.00 Hours |
| Pt 1 Arm A: MK-8242 170 mg BID | Time to Maximum Concentration (Tmax) of MK-8242 Alone and in Combination With Cytarabine | Day 7 (n=1,1,3,1,3,3,5,3,3) | 4.15 Hours |
| Pt 1 Arm A: MK-8242 170 mg BID | Time to Maximum Concentration (Tmax) of MK-8242 Alone and in Combination With Cytarabine | Day 1 (n=1,1,3,1,4,3,5,3,3) | 2.00 Hours |
| Pt 1 Arm A: MK-8242 210 mg BID | Time to Maximum Concentration (Tmax) of MK-8242 Alone and in Combination With Cytarabine | Day 1 (n=1,1,3,1,4,3,5,3,3) | 2.00 Hours |
| Pt 1 Arm A: MK-8242 210 mg BID | Time to Maximum Concentration (Tmax) of MK-8242 Alone and in Combination With Cytarabine | Day 7 (n=1,1,3,1,3,3,5,3,3) | 4.00 Hours |
| Pt 1 Arm A: MK-8242 250 mg BID | Time to Maximum Concentration (Tmax) of MK-8242 Alone and in Combination With Cytarabine | Day 1 (n=1,1,3,1,4,3,5,3,3) | 2.00 Hours |
| Pt 1 Arm A: MK-8242 250 mg BID | Time to Maximum Concentration (Tmax) of MK-8242 Alone and in Combination With Cytarabine | Day 7 (n=1,1,3,1,3,3,5,3,3) | 2.00 Hours |
| Pt 1 Arm A: MK-8242 300 mg BID | Time to Maximum Concentration (Tmax) of MK-8242 Alone and in Combination With Cytarabine | Day 7 (n=1,1,3,1,3,3,5,3,3) | 4.00 Hours |
| Pt 1 Arm A: MK-8242 300 mg BID | Time to Maximum Concentration (Tmax) of MK-8242 Alone and in Combination With Cytarabine | Day 1 (n=1,1,3,1,4,3,5,3,3) | 2.08 Hours |
Secondary
Urine Concentration of MK-8242 (Part 2 Arm A Only)
The urine concentration of MK-8242 assessed as a measure of drug bioavailability was not determined due to early termination of the study (Study Part 2 was not performed).
Time frame: Day 1 (predose and postdose) and Day 7 (postdose)
Population: Participants who received at least one dose of MK-8242, were compliant with study procedures, and had available pharmacokinetic data (urine concentration) at the time of assessment