A Study of Idasanutlin With Cytarabine Versus Cytarabine Plus Placebo in Participants With Relapsed or Refractory Acute Myeloid Leukemia (AML)

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.

Time frame: From randomization to death from any cause (up to approximately 4.5 years)

Population: TP53-WT ITT Population

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.

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)

Population: Due to futility the planned participant enrollment was observed, therefore result data were not collected.

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.

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)

Population: Due to insufficient participant compliance the planned enrollment was observed, therefore result data were not collected.

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.

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)

Population: Due to insufficient participant compliance the planned enrollment was observed, therefore result data were not collected.

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.

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)

Population: Due to insufficient participant compliance the planned enrollment was observed, therefore result data were not collected.

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.

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)

Population: Safety Population. The number analyzed includes participants who were evaluable at each timepoint.

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.

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)

Population: Safety Population. The number analyzed includes participants who were evaluable at each timepoint.

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.

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)

Population: Safety Population. The number analyzed includes participants who were evaluable at each timepoint.

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.

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)

Population: Due to insufficient participant compliance rate, an insufficient enrollment was observed and result data were not collected.

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.

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)

Population: Due to insufficient participant compliance the planned enrollment was observed, therefore result data were not collected.

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.

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

Population: Safety Population. The number analyzed includes participants who were evaluable at each timepoint.

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.

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)

Population: Safety Population. The number analyzed includes participants who were evaluable at each timepoint.

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.

Time frame: Up to Approximately 4.5 Years

Population: Safety Population. The number analyzed includes participants who were evaluable at each timepoint.

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.

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)

Population: Safety Population. The number analyzed includes participants who were evaluable at each timepoint.

The cumulative doses of idasanutlin and cytaradine are reported.

Time frame: Up to 3 cycles (1 cycle is 28 days)

Population: Safety Population. Participants did not receive Idasanutlin in the Placebo Plus Cytarabine Arm, so this data were not collected.

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.

Time frame: From achieving CR until relapse or death from any cause (up to approximately 4.5 years)

Population: TP53-WT Population. The number analyzed includes participants who were evaluable at each timepoint.

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.

Time frame: From randomization up to treatment failure, relapse, or death from any cause (up to approximately 4.5 years)

Population: TP53-WT ITT Population

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.

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)

Population: Due to insufficient participant compliance the planned enrollment was observed, therefore result data were not collected.

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.

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)

Population: Due to insufficient participant compliance the planned enrollment was observed, therefore result data were not collected.

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.

Time frame: Baseline up to approximately 4.5 years

Population: Safety-Evaluable Population

The number of participants with AE resulted by death within 30 days from dosing is reported

Time frame: Up to Day 30

Population: Safety Population

The number of participants with AE resulted by death within 60 days from dosing is reported

Time frame: Up to Day 60

Population: Safety Population

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.

Time frame: Baseline up to approximately 4.5 years

Population: Safety Population

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.

Time frame: Up to Approximately 4.5 Years

Population: Safety Population. The number analyzed includes participants who were evaluable at each timepoint.

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.

Time frame: Up to Approximately 4.5 Years

Population: Safety Population. The number analyzed includes participants who were evaluable at each timepoint.

Participants who started the study treatment cycles are reported.

Time frame: Up to 3 cycles (1 cycle is 28 days)

Population: Safety 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.

Time frame: From randomization to death from any cause (up to approximately 4.5 years)

Population: TP53-WT ITT Population. The number analyzed includes participants who were evaluable at each timepoint.

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.

Time frame: At the end of induction (up to Day 56)

Population: TP53-WT ITT 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.

Time frame: Baseline up to approximately 4.5 years

Population: TP53-WT ITT 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.

Time frame: At the end of induction (up to Day 56)

Population: TP53-WT Population. The number analyzed includes participants who were evaluable at each timepoint.

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.

Time frame: At the end of induction (up to Day 56)

Population: TP53-WT ITT Population

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.

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)

Population: Due to insufficient participant compliance the planned enrollment was observed, therefore result data were not collected.

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.

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)

Population: Due to insufficient participant compliance the planned enrollment was observed, therefore result data were not collected.

Participants were planned to be treated up to 3 Cycles.

Time frame: Up to 3 cycles (1 cycle is 28 days)

Population: ITT Population

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.

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)

Population: Due to insufficient participant compliance the planned enrollment was observed, therefore result data were not collected.