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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/show/NCT02545283




Registration number
NCT02545283
Ethics application status
Date submitted
31/08/2015
Date registered
9/09/2015
Date last updated
14/09/2021

Titles & IDs
Public title
A Study of Idasanutlin With Cytarabine Versus Cytarabine Plus Placebo in Participants With Relapsed or Refractory Acute Myeloid Leukemia (AML)
Scientific title
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)
Secondary ID [1] 0 0
2014-003065-15
Secondary ID [2] 0 0
WO29519
Universal Trial Number (UTN)
Trial acronym
MIRROS
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Leukemia, Myeloid, Acute 0 0
Condition category
Condition code
Cancer 0 0 0 0
Leukaemia - Acute leukaemia
Cancer 0 0 0 0
Leukaemia - Chronic leukaemia
Cancer 0 0 0 0
Children's - Leukaemia & Lymphoma

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Cytarabine
Treatment: Drugs - Idasanutlin
Other interventions - Placebo

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.

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.


Treatment: Drugs: Cytarabine
Participants will receive cytarabine 1 gram per square meter (g/m^2) intravenous (IV) infusion for 5 days of every treatment cycle.

Treatment: Drugs: 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 interventions: Placebo
Participants will receive idasanutlin matching placebo PO BID or QD for 5 days of every treatment cycle.

Intervention code [1] 0 0
Treatment: Drugs
Intervention code [2] 0 0
Other interventions
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Overall Survival in TP53 WT Population - 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.
Timepoint [1] 0 0
From randomization to death from any cause (up to approximately 4.5 years)
Secondary outcome [1] 0 0
Percentage of Participants in Complete Response (CR) at the End of Induction According to Hematologic Malignancy Response Assessment (HMRA) in TP53 WT Population - 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.
Timepoint [1] 0 0
At the end of induction (up to Day 56)
Secondary outcome [2] 0 0
Event-Free Survival (EFS) According to HMRA in TP53 WT Population - 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.
Timepoint [2] 0 0
From randomization up to treatment failure, relapse, or death from any cause (up to approximately 4.5 years)
Secondary outcome [3] 0 0
Percentage of Participants With Overall Remission (CR, CRp, and CRi) at the End of Induction According to HMRA in TP53 WT Population - 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.
Timepoint [3] 0 0
At the end of induction (up to Day 56)
Secondary outcome [4] 0 0
Duration of Remission Following CR (DOR) in TP53 WT Population - 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.
Timepoint [4] 0 0
From achieving CR until relapse or death from any cause (up to approximately 4.5 years)
Secondary outcome [5] 0 0
Percentage of Participants Undergoing HSCT Following Complete Response (CR), in TP53 WT Population - 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.
Timepoint [5] 0 0
Baseline up to approximately 4.5 years
Secondary outcome [6] 0 0
Percentage of Participants With Complete Response (CR) in Clinically Actionable Mutation-Defined Subpopulation (FLT3, IDH1 and IDH2) in TP53 WT Population - 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.
Timepoint [6] 0 0
At the end of induction (up to Day 56)
Secondary outcome [7] 0 0
Overall Survival in Clinically Actionable Mutation-Defined Subpopulation (FLT3, IDH1 and IDH2) in TP53 WT Population - 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.
Timepoint [7] 0 0
From randomization to death from any cause (up to approximately 4.5 years)
Secondary outcome [8] 0 0
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) - 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.
Timepoint [8] 0 0
Baseline up to approximately 4.5 years
Secondary outcome [9] 0 0
Number of Participants With Adverse Events Leading to Discontinuation - 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.
Timepoint [9] 0 0
Baseline up to approximately 4.5 years
Secondary outcome [10] 0 0
Number of Participants With Adverse Events Leading to Death up to Day 30 - The number of participants with AE resulted by death within 30 days from dosing is reported
Timepoint [10] 0 0
Up to Day 30
Secondary outcome [11] 0 0
Number of Participants With Adverse Events Leading to Death up to Day 60 - The number of participants with AE resulted by death within 60 days from dosing is reported
Timepoint [11] 0 0
Up to Day 60
Secondary outcome [12] 0 0
Number of Participants With Clinical Laboratory Abnormalities in Biochemistry Tests at the Greatest Severity, According to NCI-CTCAE v4.03 - 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.
Timepoint [12] 0 0
Up to Approximately 4.5 Years
Secondary outcome [13] 0 0
Number of Participants With Clinical Laboratory Abnormalities in Hematology Tests at the Greatest Severity, According to NCI-CTCAE v4.03 - 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.
Timepoint [13] 0 0
Up to Approximately 4.5 Years
Secondary outcome [14] 0 0
Change From Baseline in Body Temperature Over Time - 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.
Timepoint [14] 0 0
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)
Secondary outcome [15] 0 0
Change From Baseline in Systolic Blood Pressure Over Time - 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.
Timepoint [15] 0 0
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)
Secondary outcome [16] 0 0
Change From Baseline in Diastolic Blood Pressure Over Time - 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.
Timepoint [16] 0 0
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)
Secondary outcome [17] 0 0
Change From Baseline in Pulse Rate Over Time - 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.
Timepoint [17] 0 0
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)
Secondary outcome [18] 0 0
Change From Baseline in Respiratory Rate Over Time - 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.
Timepoint [18] 0 0
Up to Approximately 4.5 Years
Secondary outcome [19] 0 0
Change From Baseline in Heart Rate, as Measured by Electrocardiogram - 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.
Timepoint [19] 0 0
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
Secondary outcome [20] 0 0
Change From Baseline in Electrocardiogram Parameters: PQ, PR, RR, QRS, QT and QTcF Intervals - 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.
Timepoint [20] 0 0
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)
Secondary outcome [21] 0 0
Total Duration of Study Treatment - Participants were planned to be treated up to 3 Cycles.
Timepoint [21] 0 0
Up to 3 cycles (1 cycle is 28 days)
Secondary outcome [22] 0 0
Number of Treatment Cycles Started - Participants who started the study treatment cycles are reported.
Timepoint [22] 0 0
Up to 3 cycles (1 cycle is 28 days)
Secondary outcome [23] 0 0
Cumulative Dose of Idasanutlin and Cytarabine - The cumulative doses of idasanutlin and cytaradine are reported.
Timepoint [23] 0 0
Up to 3 cycles (1 cycle is 28 days)
Secondary outcome [24] 0 0
Apparent Clearance (CL/F) of Idasanutlin - 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.
Timepoint [24] 0 0
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)
Secondary outcome [25] 0 0
Apparent Volume of Distribution (Vd/F) of Idasanutlin - 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.
Timepoint [25] 0 0
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)
Secondary outcome [26] 0 0
Maximum Concentration Observed (Cmax) of Idasanutlin - 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.
Timepoint [26] 0 0
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)
Secondary outcome [27] 0 0
Steady-State Concentration (Ctrough) of Idasanutlin - 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.
Timepoint [27] 0 0
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)
Secondary outcome [28] 0 0
Area Under the Concentration-Time Curve (AUC) During One Dosing Interval (AUCtau) of Idasanutlin - 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.
Timepoint [28] 0 0
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)
Secondary outcome [29] 0 0
AUC From Time Zero to 24 Hours Post Dose (AUC0-24) of Idasanutlin - 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.
Timepoint [29] 0 0
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)
Secondary outcome [30] 0 0
Half-Life (t 1/2) of Idasanutlin - 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.
Timepoint [30] 0 0
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)
Secondary outcome [31] 0 0
Total Clearance (CL) of Cytarabine - 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.
Timepoint [31] 0 0
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)
Secondary outcome [32] 0 0
Volume of Distribution (Vd) of Cytarabine - 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.
Timepoint [32] 0 0
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)
Secondary outcome [33] 0 0
Change From Baseline in European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) Score - 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.
Timepoint [33] 0 0
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)
Secondary outcome [34] 0 0
Change From Baseline in EuroQol 5 Dimension 5-Level (EQ-5D-5L) Questionnaire Score - 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.
Timepoint [34] 0 0
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)

Eligibility
Key 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)
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key 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

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s


The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Terminated
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
ACT,NSW,SA,VIC
Recruitment hospital [1] 0 0
Canberra Hospital; Haematology Department - Canberra
Recruitment hospital [2] 0 0
Concord Repatriation General Hospital; Haematology - Sydney
Recruitment hospital [3] 0 0
Royal Adelaide Hospital; Haematology Clinical Trials - Adelaide
Recruitment hospital [4] 0 0
Geelong Hospital; Andrew Love Cancer Centre - Geelong
Recruitment hospital [5] 0 0
Alfred Hospital; Clinical Haematology and Bone Marrow Transplantation - Melbourne
Recruitment postcode(s) [1] 0 0
2605 - Canberra
Recruitment postcode(s) [2] 0 0
2139 - Sydney
Recruitment postcode(s) [3] 0 0
5000 - Adelaide
Recruitment postcode(s) [4] 0 0
3220 - Geelong
Recruitment postcode(s) [5] 0 0
3004 - Melbourne
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
New York
Country [2] 0 0
United States of America
State/province [2] 0 0
Pennsylvania
Country [3] 0 0
United States of America
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Sutton

Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
Name
Hoffmann-La Roche
Address
Country

Ethics approval
Ethics application status

Summary
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.
Trial website
https://clinicaltrials.gov/show/NCT02545283
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Clinical Trials
Address 0 0
Hoffmann-La Roche
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries

Summary results
For IPD and results data, please see https://clinicaltrials.gov/show/NCT02545283