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Trial record 1 of 1 for:    NCT02545283
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A Study of Idasanutlin With Cytarabine Versus Cytarabine Plus Placebo in Participants With Relapsed or Refractory Acute Myeloid Leukemia (AML) (MIRROS)

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ClinicalTrials.gov Identifier: NCT02545283
Recruitment Status : Terminated (The study was stopped for futility based on efficacy results at the interim analysis; no unexpected safety findings were observed.)
First Posted : September 9, 2015
Results First Posted : September 14, 2021
Last Update Posted : January 11, 2022
Sponsor:
Information provided by (Responsible Party):
Hoffmann-La Roche

Tracking Information
First Submitted Date  ICMJE August 31, 2015
First Posted Date  ICMJE September 9, 2015
Results First Submitted Date  ICMJE April 22, 2021
Results First Posted Date  ICMJE September 14, 2021
Last Update Posted Date January 11, 2022
Actual Study Start Date  ICMJE December 30, 2015
Actual Primary Completion Date April 24, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 17, 2021)
Overall Survival in TP53 WT Population [ Time Frame: From randomization to death from any cause (up to approximately 4.5 years) ]
P53 tumor protein Wild Type (TP53 WT) population's Overall Survival was compared in participants with relapsed or refractory (R/R) acute myeloid leukemia (AML) who had been randomized to idasanutlin in combination with cytarabine versus those who had been randomized to cytarabine and placebo. The study was terminated because of futility, therefore did not reach the planned end of the study.
Original Primary Outcome Measures  ICMJE
 (submitted: September 8, 2015)
Overall Survival (OS) in TP53 Wild-Type Population [ Time Frame: From start of study up to 4.5 years ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: August 17, 2021)
  • Percentage of Participants in Complete Response (CR) at the End of Induction According to Hematologic Malignancy Response Assessment (HMRA) in TP53 WT Population [ Time Frame: At the end of induction (up to Day 56) ]
    Rate of complete response at the end of induction in the TP53 WT population was compared in participants who had been randomized to idasanutlin in combination with cytarabine versus those who had been randomized to cytarabine and placebo. The design followed a hierarchical statistical testing framework.
  • Event-Free Survival (EFS) According to HMRA in TP53 WT Population [ Time Frame: From randomization up to treatment failure, relapse, or death from any cause (up to approximately 4.5 years) ]
    Event Free Survival (EFS) is defined as the time from the date of randomization to whichever occurs first: treatment failure (failure to achieve CR, set as day of final response assessment), relapse from CR, or death from any cause. The study was terminated because of futility, therefore did not reach the planned end of the study. The design followed a hierarchical statistical testing framework.
  • Percentage of Participants With Overall Remission (CR, CRp, and CRi) at the End of Induction According to HMRA in TP53 WT Population [ Time Frame: At the end of induction (up to Day 56) ]
    Rate of overall remission (complete remission, complete remission with incomplete hematologic recovery, complete remission with incomplete platelet count recovery) at the end of induction in the TP53 WT population was compared in participants who had been randomized to idasanutlin in combination with cytarabine versus those who had been randomized to cytarabine and placebo. The design followed a hierarchical statistical testing framework.
  • Duration of Remission Following CR (DOR) in TP53 WT Population [ Time Frame: From achieving CR until relapse or death from any cause (up to approximately 4.5 years) ]
    DOR is defined for patients achieving complete remission and is the time from clinical remission until relapse or death from any cause, whichever occurs first. For patients with none of these events before time of analysis, DOR is censored at the date of the patient's last response assessment. The Median upper limits were set to 999 because they were not reached and therefore it was Not Evaluable (NE) and the field is numeric only. The study was terminated because of futility, therefore did not reach the planned end of the study.
  • Percentage of Participants Undergoing HSCT Following Complete Response (CR), in TP53 WT Population [ Time Frame: Baseline up to approximately 4.5 years ]
    Rate of complete response at the end of induction in mutation-defined subgroups (positive for mutation of FLT3, IDH1 and IDH2, respectively) of the TP53 WT population was compared in participants who had been randomized to idasanutlin in combination with cytarabine versus those who had been randomized to cytarabine and placebo. The study was terminated because of futility, therefore did not reach the planned end of the study.
  • Percentage of Participants With Complete Response (CR) in Clinically Actionable Mutation-Defined Subpopulation (FLT3, IDH1 and IDH2) in TP53 WT Population [ Time Frame: At the end of induction (up to Day 56) ]
    Rate of complete response at the end of induction in mutation-defined subgroups (positive for mutation of FLT3, IDH1 and IDH2, respectively) of the TP53 WT population was compared in participants who had been randomized to idasanutlin in combination with cytarabine versus those who had been randomized to cytarabine and placebo.
  • Overall Survival in Clinically Actionable Mutation-Defined Subpopulation (FLT3, IDH1 and IDH2) in TP53 WT Population [ Time Frame: From randomization to death from any cause (up to approximately 4.5 years) ]
    Overall survival in mutation-defined subgroups (positive for mutation of FLT3, IDH1 and IDH2 respectively) of the TP53 WT population was compared in participants who had been randomized to idasanutlin in combination with cytarabine versus those who had been randomized to cytarabine and placebo. The Median upper limits were set to 999 because they were not reached and therefore it was Not Evaluable (NE) and the field is numeric only. The study was terminated because of futility, therefore did not reach the planned end of the study.
  • Number of Participants Who Experienced at Least One Adverse Event by Severity, According to National Cancer Institute Common Terminology Criteria for Adverse Events, Version 4.03 (NCI-CTCAE v4.03) [ Time Frame: Baseline up to approximately 4.5 years ]
    Participants who experienced at least one Adverse Event by severity, According to National Cancer Institute common terminology criteria for Adverse Events, version 4.03 (NCI-CTCAE v4.03) have been reported. The study was terminated because of futility, therefore did not reach the planned end of the study.
  • Number of Participants With Adverse Events Leading to Discontinuation [ Time Frame: Baseline up to approximately 4.5 years ]
    Participants with Adverse Events leading to discontinuation of the study have been reported. The study was terminated because of futility, therefore did not reach the planned end of the study.
  • Number of Participants With Adverse Events Leading to Death up to Day 30 [ Time Frame: Up to Day 30 ]
    The number of participants with AE resulted by death within 30 days from dosing is reported
  • Number of Participants With Adverse Events Leading to Death up to Day 60 [ Time Frame: Up to Day 60 ]
    The number of participants with AE resulted by death within 60 days from dosing is reported
  • Number of Participants With Clinical Laboratory Abnormalities in Biochemistry Tests at the Greatest Severity, According to NCI-CTCAE v4.03 [ Time Frame: Up to Approximately 4.5 Years ]
    Laboratory parameters for blood biochemistry will be measured and compared with a standard reference range. Values outside the standard reference range are considered abnormalities. A laboratory test result will be reported as an adverse event if it meets any of the following criteria: is accompanied by clinical symptoms; results in a change in study treatment or a medical intervention; or is clinically significant in the investigator's judgment. For each patient, baseline is the last observation prior to initiation of study drug. For each laboratory test, patients with at least 1 post-baseline assessment are included in the analysis. For each cell, the denominator is the number of patients with baseline NCI-CTCAE Grade 0-2 in the specified direction of abnormality, or Grade 1-4 in the opposite direction of abnormality.
  • Number of Participants With Clinical Laboratory Abnormalities in Hematology Tests at the Greatest Severity, According to NCI-CTCAE v4.03 [ Time Frame: Up to Approximately 4.5 Years ]
    Laboratory parameters for hematology will be measured and compared with a standard reference range. Values outside the standard reference range are considered abnormalities. A laboratory test result will be reported as an adverse event if it meets any of the following criteria: is accompanied by clinical symptoms; results in a change in study treatment or a medical intervention; or is clinically significant in the investigator's judgment. For each patient, baseline is the last observation prior to initiation of study drug. For each laboratory test, patients with at least 1 post-baseline assessment are included in the analysis. For each cell, the denominator is the number of patients with baseline NCI-CTCAE Grade 0-2 in the specified direction of abnormality, or Grade 1-4 in the opposite direction of abnormality.
  • Change From Baseline in Body Temperature Over Time [ Time Frame: Baseline; Cycles 1-3, Days 8, 15, 22, 28 (1 cycle is 28 days); and, if incomplete blood count recovery, Days 29-42 and Days 43-56, Cycles 2 -3 Days 1, 8, 15, 22, 28 and 29-56 (max delay between cycles is 56 days) ]
    Vital signs were measured prior to the infusion while the participant was in a seated position. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value. The study was terminated because of futility, therefore did not reach the planned end of study.
  • Change From Baseline in Systolic Blood Pressure Over Time [ Time Frame: Baseline; Cycles 1-3, Days 8, 15, 22, 28 (1 cycle is 28 days); and, if incomplete blood count recovery, Days 29-42 and Days 43-56, Cycles 2 -3 Days 1, 8, 15, 22, 28 and 29-56 (max delay between cycles is 56 days) ]
    Vital signs were measured prior to the infusion while the participant was in a seated position. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value. The study was terminated because of futility, therefore did not reach the planned end of study.
  • Change From Baseline in Diastolic Blood Pressure Over Time [ Time Frame: Baseline; Cycles 1-3, Days 8, 15, 22, 28 (1 cycle is 28 days); and, if incomplete blood count recovery, Days 29-42 and Days 43-56, Cycles 2 -3 Days 1, 8, 15, 22, 28 and 29-56 (max delay between cycles is 56 days) ]
    Vital signs were measured prior to the infusion while the participant was in a seated position. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value. The study was terminated because of futility, therefore did not reach the planned end of study.
  • Change From Baseline in Pulse Rate Over Time [ Time Frame: Baseline; Cycles 1-3, Days 8, 15, 22, 28 (1 cycle is 28 days); and, if incomplete blood count recovery, Days 29-42 and Days 43-56, Cycles 2 -3 Days 1, 8, 15, 22, 28 and 29-56 (max delay between cycles is 56 days) ]
    Vital signs were measured prior to the infusion while the participant was in a seated position. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value. The study was terminated because of futility, therefore did not reach the planned end of study.
  • Change From Baseline in Respiratory Rate Over Time [ Time Frame: Up to Approximately 4.5 Years ]
    Vital signs were measured prior to the infusion while the participant was in a seated position. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value. The study was terminated because of futility, therefore did not reach the planned end of study.
  • Change From Baseline in Heart Rate, as Measured by Electrocardiogram [ Time Frame: Baseline; Cycles 1-3 Day 1 (2 hrs pre-dose, post-Cytarabine and 6 hrs post-Idasanutlin/Placebo ); Cycle 1-3 Day 2; Cycle 1 Day 5 (within 2 hrs Idanasanutlin/Placebo, post-Cytarabine and 6 hrs post-Idasanutlin/Placebo), Study Drug Completion ]
    Single 12-lead ECGs was obtained using an ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, and QTc intervals. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value. The study was terminated because of futility, therefore did not reach the planned end of study.
  • Change From Baseline in Electrocardiogram Parameters: PQ, PR, RR, QRS, QT and QTcF Intervals [ Time Frame: Baseline, Days 1, 2, and 5 of Cycle 1, Days 1, 2 of Cycles 2 and 3 (1 cycle is 28 days), Treatment Discontinuation Visit (28 days after last dose of study drug) ]
    Single 12-lead ECGs was obtained using an ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, and QTc intervals. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value. The study was terminated because of futility, therefore did not reach the planned end of study.
  • Total Duration of Study Treatment [ Time Frame: Up to 3 cycles (1 cycle is 28 days) ]
    Participants were planned to be treated up to 3 Cycles.
  • Number of Treatment Cycles Started [ Time Frame: Up to 3 cycles (1 cycle is 28 days) ]
    Participants who started the study treatment cycles are reported.
  • Cumulative Dose of Idasanutlin and Cytarabine [ Time Frame: Up to 3 cycles (1 cycle is 28 days) ]
    The cumulative doses of idasanutlin and cytaradine are reported.
  • Apparent Clearance (CL/F) of Idasanutlin [ Time Frame: Cycle 1: Predose (0 hour [Hr]), end of 1-3 Hr cytarabine infusion, 6 Hr postdose on Days 1, 5; Predose (0 Hr) on Day 2; at Days 8, 10; Cycle 2, 3: predose (0 Hr) on Days 2, 5 (predose/postdose: relative to idasanutlin morning dose; cycle length= 28 days) ]
    Apparent Clearance (CL/F) of Idasanutlin was planned as part of the PK analyses. The Independent Data Monitoring Committee recommended stopping the study for futility based on a lack of OS benefit due to Hazard Ratio (HR) being greater than 1. The benefit-risk profile of idasanutlin combined with 1g/m2 cytarabine in fit R/R AML was not positive, as the observed marginal benefit does not outweigh the risks of idasanutlin in the relapsed or refractory AML population. Therefore the study was prematurely terminated by the sponsor's decision and the result data did not derive.The benefit-risk profile of idasanutlin combined with 1g/m2 cytarabine in fit R/R AML was not positive, as the observed marginal benefit does not outweigh the risks of idasanutlin in the relapsed or refractory AML population. The planned CL/F did not derive for the result data and was not reported.
  • Apparent Volume of Distribution (Vd/F) of Idasanutlin [ Time Frame: Cycle 1: Predose (0 Hr), end of 1-3 Hr cytarabine infusion, 6 Hr postdose on Days 1, 5; Predose (0 Hr) on Day 2; at Days 8, 10; Cycle 2, 3: predose (0 Hr) on Days 2, 5 (predose/postdose: relative to idasanutlin morning dose; cycle length= 28 days) ]
    Apparent Volume of Distribution (Vd/F) of Idasanutlin was planned as part of the PK analyses. The Independent Data Monitoring Committee recommended stopping the study for futility based on a lack of OS benefit due to Hazard Ratio (HR) being greater than 1. The benefit-risk profile of idasanutlin combined with 1g/m2 cytarabine in fit R/R AML was not positive, as the observed marginal benefit does not outweigh the risks of idasanutlin in the relapsed or refractory AML population. Therefore the study was prematurely terminated by the sponsor's decision and the result data did not derive.
  • Maximum Concentration Observed (Cmax) of Idasanutlin [ Time Frame: Cycle 1: Predose (0 Hr), end of 1-3 Hr cytarabine infusion, 6 Hr postdose on Days 1, 5; Predose (0 Hr) on Day 2; at Days 8, 10; Cycle 2, 3: predose (0 Hr) on Days 2, 5 (predose/postdose: relative to idasanutlin morning dose; cycle length= 28 days) ]
    Maximum Concentration Observed (Cmax) of Idasanutlin was planned as part of the PK analyses. The Independent Data Monitoring Committee recommended stopping the study for futility based on a lack of OS benefit due to Hazard Ratio (HR) being greater than 1. The benefit-risk profile of idasanutlin combined with 1g/m2 cytarabine in fit R/R AML was not positive, as the observed marginal benefit does not outweigh the risks of idasanutlin in the relapsed or refractory AML population. Therefore the study was prematurely terminated by the sponsor's decision and the result data did not derive.
  • Steady-State Concentration (Ctrough) of Idasanutlin [ Time Frame: Cycle 1: Predose (0 Hr), end of 1-3 Hr cytarabine infusion, 6 Hr postdose on Days 1, 5; Predose (0 Hr) on Day 2; at Days 8, 10; Cycle 2, 3: predose (0 Hr) on Days 2, 5 (predose/postdose: relative to idasanutlin morning dose; cycle length= 28 days) ]
    Steady-State Concentration (Ctrough) of Idasanutlin was planned as part of the PK analyses. The Independent Data Monitoring Committee recommended stopping the study for futility based on a lack of OS benefit due to Hazard Ratio (HR) being greater than 1. The benefit-risk profile of idasanutlin combined with 1g/m2 cytarabine in fit R/R AML was not positive, as the observed marginal benefit does not outweigh the risks of idasanutlin in the relapsed or refractory AML population. Therefore the study was prematurely terminated by the sponsor's decision and the result data did not derive.
  • Area Under the Concentration-Time Curve (AUC) During One Dosing Interval (AUCtau) of Idasanutlin [ Time Frame: Cycle 1: Predose (0 Hr), end of 1-3 Hr cytarabine infusion, 6 Hr postdose on Days 1, 5; Predose (0 Hr) on Day 2; at Days 8, 10; Cycle 2, 3: predose (0 Hr) on Days 2, 5 (predose/postdose: relative to idasanutlin morning dose; cycle length= 28 days) ]
    Area Under the Concentration-Time Curve (AUC) During One Dosing Interval (AUCtau) of Idasanutlin was planned as part of the PK analyses. The Independent Data Monitoring Committee recommended stopping the study for futility based on a lack of OS benefit due to Hazard Ratio (HR) being greater than 1. The benefit-risk profile of idasanutlin combined with 1g/m2 cytarabine in fit R/R AML was not positive, as the observed marginal benefit does not outweigh the risks of idasanutlin in the relapsed or refractory AML population. Therefore the study was prematurely terminated by the sponsor's decision and the result data did not derive.
  • AUC From Time Zero to 24 Hours Post Dose (AUC0-24) of Idasanutlin [ Time Frame: Cycle 1: Predose (0 Hr), end of 1-3 Hr cytarabine infusion, 6 Hr postdose on Days 1, 5; Predose (0 Hr) on Day 2; at Days 8, 10; Cycle 2, 3: predose (0 Hr) on Days 2, 5 (predose/postdose: relative to idasanutlin morning dose; cycle length= 28 days) ]
    AUC from Time Zero to 24 Hours Post Dose (AUC0-24) of Idasanutlin was planned as part of the PK analyses. The Independent Data Monitoring Committee recommended stopping the study for futility based on a lack of OS benefit due to Hazard Ratio (HR) being greater than 1. The benefit-risk profile of idasanutlin combined with 1g/m2 cytarabine in fit R/R AML was not positive, as the observed marginal benefit does not outweigh the risks of idasanutlin in the relapsed or refractory AML population. Therefore the study was prematurely terminated by the sponsor's decision and the result data did not derive.
  • Half-Life (t 1/2) of Idasanutlin [ Time Frame: Cycle 1: Predose (0 Hr), end of 1-3 Hr cytarabine infusion, 6 Hr postdose on Days 1, 5; Predose (0 Hr) on Day 2; at Days 8, 10; Cycle 2, 3: predose (0 Hr) on Days 2, 5 (predose/postdose: relative to idasanutlin morning dose; cycle length= 28 days) ]
    Half-Life (t 1/2) of Idasanutlin was planned as part of the PK analyses. The Independent Data Monitoring Committee recommended stopping the study for futility based on a lack of OS benefit due to Hazard Ratio (HR) being greater than 1. The benefit-risk profile of idasanutlin combined with 1g/m2 cytarabine in fit R/R AML was not positive, as the observed marginal benefit does not outweigh the risks of idasanutlin in the relapsed or refractory AML population. Therefore the study was prematurely terminated by the sponsor's decision and the result data did not derive.
  • Total Clearance (CL) of Cytarabine [ Time Frame: Cycle 1: Within 2 Hr pre-cytarabine dose, end of 1-3 Hr cytarabine infusion, 6 Hr post idasanutlin morning dose on Days 1, 5; Within 2 Hr pre-cytarabine dose on Day 2; Cycle 2, 3: Within 2 Hr pre-cytarabine dose on Day 2 (Cycle length= 28 days) ]
    The Total Clearance (CL) of Cytarabine was planned as part of the PK analyses. The Independent Data Monitoring Committee recommended stopping the study for futility based on a lack of OS benefit due to Hazard Ratio (HR) being greater than 1. The benefit-risk profile of idasanutlin combined with 1g/m2 cytarabine in fit R/R AML was not positive, as the observed marginal benefit does not outweigh the risks of idasanutlin in the relapsed or refractory AML population. Therefore the study was prematurely terminated by the sponsor's decision and the result data did not derive.
  • Volume of Distribution (Vd) of Cytarabine [ Time Frame: Cycle 1: Within 2 Hr pre-cytarabine dose, end of 1-3 Hr cytarabine infusion, 6 Hr post idasanutlin morning dose on Days 1, 5; Within 2 Hr pre-cytarabine dose on Day 2; Cycle 2, 3: Within 2 Hr pre-cytarabine dose on Day 2 (Cycle length= 28 days) ]
    The Volume of Distribution (Vd) of Cytarabine was planned as part of the PK analyses. The Independent Data Monitoring Committee recommended stopping the study for futility based on a lack of OS benefit due to Hazard Ratio (HR) being greater than 1. The benefit-risk profile of idasanutlin combined with 1g/m2 cytarabine in fit R/R AML was not positive, as the observed marginal benefit does not outweigh the risks of idasanutlin in the relapsed or refractory AML population. Therefore the study was prematurely terminated by the sponsor's decision and the result data did not derive.
  • Change From Baseline in European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) Score [ Time Frame: Cycle 1 Day 1 (Baseline), Days 8, 15, 28 of Cycle 1, Days 1, 8, 15, 28 of Cycles 2, 3, 28 days after last dose (last dose on Cycle 3 Day 5), thereafter every 3 months until relapse (maximum up to 3.5 years) ]
    The compliance rate (defined as the number of patients who completed as least 1 question on the measure) at baseline was 56% and 61% for the Idasanutlin arm and the placebo arm, respectively. This compliance rate remained the same post-baseline in both arms. Due to the low compliance rates in both arms during the entire treatment period, the planned analyses were not performed.
  • Change From Baseline in EuroQol 5 Dimension 5-Level (EQ-5D-5L) Questionnaire Score [ Time Frame: Cycle 1 Day 1 (Baseline), Days 8, 15, 28 of Cycle 1, Days 1, 8, 15, 28 of Cycles 2, 3, 28 days after last dose (last dose on Cycle 3 Day 5), thereafter every 3 months until relapse (maximum up to 3.5 years) ]
    The compliance rate (defined as the number of patients who completed as least 1 question on the measure) at baseline was 56% and 61% for the Idasanutlin arm and the placebo arm, respectively. Compliance remained the same post-baseline in both arms Due to the low compliance rates in both arms during the entire treatment period, the planned analyses were not performed.
Original Secondary Outcome Measures  ICMJE
 (submitted: September 8, 2015)
  • Overall Survival (OS) in the Overall Population [ Time Frame: From start of study up to 4.5 years ]
  • Percentage of Participants in Complete Remission with incomplete blood count recovery (CRi) [ Time Frame: From start of study up to 4.5 years ]
  • Overall Remission Rate (ORR), including CR, CRp and CRi [ Time Frame: From start of study up to 4.5 years ]
  • Event Free Survival (EFS) [ Time Frame: From start of study up to 4.5 years ]
  • Leukemia Free Survival (LFS) [ Time Frame: From start of study up to 4.5 years ]
  • Apparent Clearance (CL/F) of Idasanutlin [ Time Frame: Cycle 1 (28 Days) Days 1, 2, 5, 8 and 10 and Cycles 2 and 3 (28 Days) Days 2 and 5 ]
  • Apparent Volume of Distribution (Vd/F) of Idasanutlin [ Time Frame: Cycle 1 (28 Days) Days 1, 2, 5, 8 and 10 and Cycles 2 and 3 (28 Days) Days 2 and 5 ]
  • Maximum Concentration Observed (Cmax) of Idasanutlin [ Time Frame: Cycle 1 (28 Days) Days 1, 2, 5, 8 and 10 and Cycles 2 and 3 (28 Days) Days 2 and 5 ]
  • Steady-State Concentration (C trough) of Idasanutlin [ Time Frame: Cycle 1 (28 Days) Days 1, 2, 5, 8 and 10 and Cycles 2 and 3 (28 Days) Days 2 and 5 ]
  • Area Under the Concentration-Time Curve (AUC) of Idasanutlin [ Time Frame: Cycle 1 (28 Days) Days 1, 2, 5, 8 and 10 and Cycles 2 and 3 (28 Days) Days 2 and 5 ]
  • Half-Life (t 1/2) of Idasanutlin [ Time Frame: Cycle 1 (28 Days) Days 1, 2, 5, 8 and 10 and Cycles 2 and 3 (28 Days) Days 2 and 5 ]
  • Total clearance (CL) of Cytarabine [ Time Frame: Cycle 1 (28 Days) Days 1, 2 and 5 and Cycles 2 and 3 (28 Days) Day 2 ]
  • Volume of Distribution (Vd) of Cytarabine [ Time Frame: Cycle 1 (28 Days) Days 1, 2 and 5 and Cycles 2 and 3 (28 Days) Day 2 ]
  • Percentage of Participants with Hematopoietic Stem Cell Transplant (HSCT) Following Response [ Time Frame: From start of study up to 4.5 years ]
  • Percentage of Participants with Adverse Events [ Time Frame: From start of study up to 4.5 years ]
  • Percentage of Participants in Complete Remission with Incomplete Platelet Count Recovery (CRp) [ Time Frame: From start of study up to 4.5 years ]
  • Percentage of Participants in Complete Remission (CR) [ Time Frame: From start of study up to 4.5 years ]
  • Percentage of Participants With Clinically Significant Changes in Safety Measurements [ Time Frame: From start of study up to 4.5 years ]
  • Score in Patient-Reported Outcome (PRO) Measures [ Time Frame: From start of study up to 4.5 years ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Study of Idasanutlin With Cytarabine Versus Cytarabine Plus Placebo in Participants With Relapsed or Refractory Acute Myeloid Leukemia (AML)
Official Title  ICMJE A Multicenter, Double-Blind, Randomized, Placebo-Controlled, Phase III Study of Idasanutlin, an MDM2 Antagonist, With Cytarabine Versus Cytarabine Plus Placebo in Patients With Relapsed or Refractory Acute Myeloid Leukemia (AML)
Brief Summary This is a multicenter, double-blind, randomized, placebo-controlled study designed to compare overall survival in participants with relapsed or refractory AML treated with idasanutlin in combination with cytarabine versus participants treated with placebo and cytarabine. Participants will receive induction treatment with idasanutlin/placebo and cytarabine (Cycle 1). Responding participants may continue to receive a maximum of further two cycles of consolidation (Cycle 2 and Cycle 3). Complete remission (CR), CR with incomplete platelet count recovery (CRp), overall remission rate (ORR), event-free survival (EFS) and percentage of participants with an allogeneic hematopoietic stem cell transplant (HSCT) will also be compared between treatment arms. This study will include participants with and without TP53 wild type (TP53 WT) mutations.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Condition  ICMJE Leukemia, Myeloid, Acute
Intervention  ICMJE
  • Drug: Cytarabine
    Participants will receive cytarabine 1 gram per square meter (g/m^2) intravenous (IV) infusion for 5 days of every treatment cycle.
  • Drug: Idasanutlin
    Participants will receive idasanutlin 300 mg per oral (PO) twice daily (BID) (in Cycle 1) or once daily (QD) (in Cycles 2 and 3) for 5 days of every treatment cycle.
    Other Name: RG7388
  • Other: Placebo
    Participants will receive idasanutlin matching placebo PO BID or QD for 5 days of every treatment cycle.
Study Arms  ICMJE
  • Experimental: Idasanutlin plus Cytarabine
    Participants will receive induction therapy idasanutlin and cytarabine for 5 Days followed by 23 days of rest in Cycle 1 (treatment cycle length=28 days). Responding participants may continue with consolidation therapy for a maximum of 2 additional cycles including idasanutlin and cytarabine for 5 days followed by 23 days of rest in each cycle (treatment cycle length=28 days). After each cycle, for participants achieving CRp or complete remission with incomplete blood count recovery (CRi), up to 28 additional days are allowed for blood count recovery, if needed.
    Interventions:
    • Drug: Cytarabine
    • Drug: Idasanutlin
  • Placebo Comparator: Placebo plus Cytarabine
    Participants will receive induction therapy idasanutlin matching placebo and cytarabine for 5 days followed by 23 days of rest in Cycle 1 (treatment cycle length=28 days). Responding participants may continue with consolidation therapy for a maximum of 2 additional cycles including idasanutlin matching placebo and cytarabine for 5 days followed by 23 days of rest in each cycle (treatment cycle length=28 days). After each cycle, for participants achieving CRp or CRi, up to 28 additional days are allowed for blood count recovery, if needed.
    Interventions:
    • Drug: Cytarabine
    • Other: Placebo
Publications * Montesinos P, Beckermann BM, Catalani O, Esteve J, Gamel K, Konopleva MY, Martinelli G, Monnet A, Papayannidis C, Park A, Récher C, Rodríguez-Veiga R, Röllig C, Vey N, Wei AH, Yoon SS, Fenaux P. MIRROS: a randomized, placebo-controlled, Phase III trial of cytarabine ± idasanutlin in relapsed or refractory acute myeloid leukemia. Future Oncol. 2020 May;16(13):807-815. doi: 10.2217/fon-2020-0044. Epub 2020 Mar 13.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Terminated
Actual Enrollment  ICMJE
 (submitted: February 12, 2020)
447
Original Estimated Enrollment  ICMJE
 (submitted: September 8, 2015)
440
Actual Study Completion Date  ICMJE April 24, 2020
Actual Primary Completion Date April 24, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Documented/confirmed first/second refractory/relapsed AML using World Health Organization classification, except acute promyelocytic leukemia
  • No more than 2 prior induction regimens (excluding prior HSCT) in their first line treatment and one must have included cytarabine with an anthracycline (or anthracenedione)
  • Eastern Cooperative Oncology Group performance status of 0 to 2
  • Adequate hepatic and renal function
  • White blood cell (WBC) count at randomization less than or equal to (</=) 50000 cells per cubic millimeter (/mm^3)

Exclusion Criteria:

  • First relapsed participants aged less than (<) 60 years with first CR duration greater than (>) 1 year
  • Participants with prior documented antecedent hematological disorder (AHD)
  • AML secondary to any prior chemotherapy unrelated to leukemia
  • Participants who are either refractory to or relapsed within 90 days of receiving a regimen containing a cumulative dose of greater than or equal to (>/=) 18 g/m^2 of cytarabine
  • Participants who have received allogeneic HSCT within 90 days prior to randomization
  • Participants who have received immunosuppressive therapy for graft versus host disease or for engraftment syndrome after autologous stem cell transplantation within 2 weeks prior to randomization
  • Prior treatment with an Murine Double Minute 2 (MDM2) antagonist
  • Participants receiving any other investigational or commercial agents or therapies administered with the intention to treat their malignancy within 30 days from first receipt of study drug
  • Participants with a history of other malignancy within 5 years prior to screening except for malignancy that has been in remission without treatment for at least 2 years prior to randomization
  • Participants who have any severe and/or uncontrolled medical conditions or other conditions that could affect their participation in the study
  • Participants with extramedullary AML with no evidence of systemic involvement
  • Pregnant or breastfeeding participants
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Australia,   Austria,   Belgium,   Canada,   Finland,   France,   Germany,   Israel,   Italy,   Korea, Republic of,   Netherlands,   New Zealand,   Norway,   Panama,   Russian Federation,   Spain,   Switzerland,   United Kingdom,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02545283
Other Study ID Numbers  ICMJE WO29519
2014-003065-15 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Current Responsible Party Hoffmann-La Roche
Original Responsible Party Same as current
Current Study Sponsor  ICMJE Hoffmann-La Roche
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Clinical Trials Hoffmann-La Roche
PRS Account Hoffmann-La Roche
Verification Date December 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP