Study of MK-8242 Alone and in Combination With Cytarabine in Participants With Acute Myelogenous Leukemia (P07649)
- Registration Number
- NCT01451437
- Lead Sponsor
- Merck Sharp & Dohme LLC
- 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.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- TERMINATED
- Sex
- All
- Target Recruitment
- 26
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Pt 1 Arm A: MK-8242 250 mg QD MK-8242 Participants received MK-8242 250 mg QD monotherapy on Days 1-7 and Days 15-21 of a 28-day cycle up to a maximum of 12 cycles in Part 1 Arm A. Pt 1 Arm A: MK-8242 60 mg QD MK-8242 Participants received MK-8242 60 mg QD monotherapy on Days 1-7 and Days 15-21 of a 28-day cycle up to a maximum of 12 cycles in Part 1 Arm A. Pt 1 Arm A: MK-8242 120 mg QD MK-8242 Participants received MK-8242 120 mg QD monotherapy on Days 1-7 and Days 15-21 of a 28-day cycle up to a maximum of 12 cycles in Part 1 Arm A. Pt 1 Arm A: MK-8242 120 mg BID MK-8242 Participants received MK-8242 120 mg twice daily (BID) monotherapy on Days 1-7 and Days 15-21 of a 28-day cycle up to a maximum of 12 cycles (except Cycle 1 Day 7 on which MK-8242 120 mg was administered QD in the morning) in Part 1 Arm A. Pt 1 Arm A: MK-8242 300 mg BID MK-8242 Participants received MK-8242 300 mg BID monotherapy on Days 1-7 of a 21-day cycle up to a maximum of 12 cycles (except Cycle 1 Day 7 on which MK-8242 300 mg was administered QD in the morning) in Part 1 Arm A. Pt 1 Arm A: MK-8242 170 mg BID MK-8242 Participants received MK-8242 170 mg BID monotherapy on Days 1-7 and Days 15-21 of a 28-day cycle up to a maximum of 12 cycles (except Cycle 1 Day 7 on which MK-8242 170 mg was administered QD in the morning) in Part 1 Arm A. Pt 1 Arm A: MK-8242 210 mg BID MK-8242 Participants received MK-8242 210 mg BID monotherapy on Days 1-7 of a 21-day cycle up to a maximum of 12 cycles (except Cycle 1 Day 7 on which MK-8242 210 mg was administered QD in the morning) in Part 1 Arm A. Pt 1 Arm A: MK-8242 30 mg QD MK-8242 Participants received MK-8242 30 mg once daily (QD) monotherapy on Days 1-7 and Days 15-21 of a 28-day cycle up to a maximum of 12 cycles in Part 1 Arm A. Pt 1 Arm A: MK-8242 250 mg BID MK-8242 Participants received MK-8242 250 mg BID monotherapy on Days 1-7 and Days 15-21 of a 28-day cycle up to a maximum of 12 cycles (except Cycle 1 Day 7 on which MK-8242 250 mg was administered QD in the morning) in Part 1 Arm A.
- Primary Outcome Measures
Name Time Method 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.
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 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.
- Secondary Outcome Measures
Name Time Method 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.
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).
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.
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).
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).
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).
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).
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).
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).
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).