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

Leukemia, Myeloid, Acute Clinical Trial

— MIRROS  

Official 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)

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT02545283
• Other study ID #: WO29519
• Secondary ID: 2014-003065-15
• Status: Terminated
• Phase: Phase 3
• Start date: December 30, 2015
• Est. completion date: April 24, 2020

Study information

• Verified date: December 2021
• Source: Hoffmann-La Roche
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 447
• Est. completion date: April 24, 2020
• Est. primary completion date: April 24, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Leukemia
• Leukemia, Myeloid
• Leukemia, Myeloid, Acute

Intervention

Drug:
• Cytarabine
Participants will receive cytarabine 1 gram per square meter (g/m^2) intravenous (IV) infusion for 5 days of every treatment cycle.
• 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:
• Placebo
Participants will receive idasanutlin matching placebo PO BID or QD for 5 days of every treatment cycle.

Locations

Country	Name	City	State
Australia	Royal Adelaide Hospital; Haematology Clinical Trials	Adelaide	South Australia
Australia	Canberra Hospital; Haematology Department	Canberra	Australian Capital Territory
Australia	Geelong Hospital; Andrew Love Cancer Centre	Geelong	Victoria
Australia	Alfred Hospital; Clinical Haematology and Bone Marrow Transplantation	Melbourne	Victoria
Australia	Concord Repatriation General Hospital; Haematology	Sydney	New South Wales
Austria	Lkh-Univ. Klinikum Graz; Klin. Abt. Für Hämatologie	Graz
Belgium	CH Jolimont - Lobbes (Jolimont)	Haine-Saint-Paul
Belgium	CHU Sart-Tilman	Liège
Belgium	AZ Delta (Campus Rumbeke)	Roeselare
Canada	Juravinski Cancer Clinic; Clinical Trials Department	Hamilton	Ontario
Finland	Helsinki University Central Hospital; Hematology	Helsinki
Finland	Tampere University Hospital; Hematology	Tampere
France	Centre Hospitalier Uni Ire; Service Des Maladies Du Sang	Angers Cedex 9
France	Hopital Claude Huriez; Hematologie	Lille
France	Institut J Paoli I Calmettes; Onco Hematologie 2	Marseille
France	Hopital Hotel Dieu Et Hme;Hopital De Jour	Nantes
France	HOPITAL SAINT ANTOINE;Hematologie Clinique	Paris
France	Hopital Saint Louis; Oncologie Medicale	Paris
France	Hopital De Haut Leveque; Hematologie Clinique	Pessac
France	Centre Hospitalier Lyon Sud; Hematolgie	Pierre Benite
France	IUCT Oncopole; Hematologie	Toulouse
France	Hopitaux De Brabois; Hematologie Medecine Interne	Vandoeuvre Les Nancy
Germany	Uniklinik RWTH Aachen; Klinik IV; Klinik Hämatologie, Onkologie, Hämostaseologie und Stamm.	Aachen
Germany	Universitätsklinikum Bonn; Med. Klinik und Poliklinik III; Hämatologie, Onkologie und Rheumatologie	Bonn
Germany	Klinikum Braunschweig; Medizinische Klinik III; Klinik für Hämatologie und Onkologie	Braunschweig
Germany	Klinikum Chemnitz gGmbH Krankenhaus Küchwald Klinik f.Innere Medizin III	Chemnitz
Germany	Universitätsklinikum "Carl Gustav Carus"; Medizinische Klinik und Poliklinik I	Dresden
Germany	Medizinische Hochschule Hannover; Zentrum Innere Medizin; Abt. Hämatologie u. Onkologie	Hannover
Germany	Klinik der Uni zu Köln; I. Med. Klinik	Köln
Germany	Uni. der Johannes Gutenberg-Universitaet Mainz; III. Medizinische Klinik und Poliklinik	Mainz
Germany	Universitätsklinikum Marburg Zentrum f. Innere Medizin	Marburg
Israel	Hadassah Ein Karem Hospital; Haematology	Jerusalem
Israel	Shaare Zedek Medical Center; Hematology Dept.	Jerusalem
Israel	Rabin Medical Center-Beilinson Campus;Hematology-Oncology	Petach Tikva
Israel	Ichilov Sourasky Medical Center; Heamatology	Tel Aviv
Italy	ASST PAPA GIOVANNI XXIII; Ematologia	Bergamo	Lombardia
Italy	Az. Osp. S. Orsola Malpighi; Istituto Di Oncologia Seragnoli	Bologna	Emilia-Romagna
Italy	Az. Osp. Di Careggi; Divisione Di Ematologia	Firenze	Toscana
Italy	IRCCS AOU S.Martino; Clinica Ematologica	Genova	Liguria
Italy	Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST); Onco-Ematologia	Meldola	Emilia-Romagna
Italy	Asst Grande Ospedale Metropolitano Niguarda; Dipartimento Di Ematologia Ed Oncologia	Milano	Lombardia
Italy	Ospedale San Raffaele, IRCCS	Milano	Lombardia
Italy	Ospedale Cardarelli; Divisione Di Ematologia	Napoli	Campania
Italy	A.O. Universitaria San Luigi Gonzaga di Orbassano; Ambulatorio per le Malattie Rare del Polmone	Orbassano (TO)	Piemonte
Italy	Ospedale Santa Chiara; Unita Operativa Di Ematologia	Pisa	Toscana
Italy	Az. Osp. S. Maria Delle Croci; U.O. Di Ematologia	Ravenna	Emilia-Romagna
Italy	Az. Osp. Uni Ria Policlinico Tor Vergata; Unita Di Ematologia	Roma	Lazio
Italy	A.O.U. Citta' Della Salute E Della Scienza-P.O. Molinette;S.C. Ematologia	Torino	Piemonte
Italy	A.O. Universitaria S. Maria Della Misericordia Di Udine; Oncologia; Clinica Ematologica	Udine	Friuli-Venezia Giulia
Korea, Republic of	Pusan National University Hospital	Busan
Korea, Republic of	Chonnam National University Hwasun Hospital	Jeollanam-do
Korea, Republic of	Samsung Medical Center	Seoul
Korea, Republic of	Seoul National University Hospital	Seoul
Korea, Republic of	Seoul St Mary's Hospital	Seoul
Netherlands	Academisch Medisch Centrum; Hematologie	Amsterdam
Netherlands	Academisch Ziekenhuis Maastricht	Maastricht
New Zealand	Auckland city hospital; Auckland Regional Cancer Centre and Blood Service	Auckland
Norway	Haukeland Universitetssjukehus; Klinisk forskningspost	Bergen
Norway	Oslo Universitetssykehus HF, Rikshospitalet	Oslo
Panama	Complejo Hospitalario Arnulfo Arias Madrid; Servicio de Hematología	Panama City
Russian Federation	"Hematological Scientific Center	Moscow
Russian Federation	St. Petersburg State Medical University n.a. I.P. Pavlov; Hematology, transfusiology and transplanta	Saint-Petersburg
Russian Federation	FGBU "Federal Medical and Research Center named after V.A.Almazov" Russian Ministry of Health	Sankt-Petersburg
Spain	Hospital Clínic i Provincial; Servicio de Hematología y Oncología	Barcelona
Spain	Hospital de la Santa Creu i Sant Pau; Servicio de Hematologia	Barcelona
Spain	Hospital Univ. 12 de Octubre; Servicio de Hematologia	Madrid
Spain	Hospital Universitario Virgen del Rocio	Sevilla
Spain	Hospital Universitario la Fe; Servicio de Hematologia	Valencia
Switzerland	Universitätsspital Basel; Hämatologie	Basel
Switzerland	Universitätsspital Zürich Medizin Hämatologie; Klinik für Hämatologie	Zürich
United Kingdom	Birmingham Heartlands Hospital	Birmingham
United Kingdom	University Hospital of Wales	Cardiff
United Kingdom	St Bartholomew's Hospital	London
United Kingdom	Christie Hospital NHS Trust	Manchester
United Kingdom	Royal Marsden NHS Foundation Trust	Sutton
United States	Baylor University Medical Center	Dallas	Texas
United States	Northwell Health	Great Neck	New York
United States	New York Medical College	Hawthorne	New York
United States	M.D. Anderson Cancer Center; Department of Hematology	Houston	Texas
United States	Ichan School of Medicine at Mount Sinai	New York	New York
United States	Abramson Cancer Center; Univ of Pennsylvania	Philadelphia	Pennsylvania
United States	Thomas Jefferson University	Philadelphia	Pennsylvania

Sponsors (1)

Lead Sponsor	Collaborator
Hoffmann-La Roche

Countries where clinical trial is conducted

United States,  Australia,  Austria,  Belgium,  Canada,  Finland,  France,  Germany,  Israel,  Italy,  Korea, Republic of,  Netherlands,  New Zealand,  Norway,  Panama,  Russian Federation,  Spain,  Switzerland,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.	From randomization to death from any cause (up to approximately 4.5 years)
Secondary	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.	At the end of induction (up to Day 56)
Secondary	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.	From randomization up to treatment failure, relapse, or death from any cause (up to approximately 4.5 years)
Secondary	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.	At the end of induction (up to Day 56)
Secondary	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.	From achieving CR until relapse or death from any cause (up to approximately 4.5 years)
Secondary	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.	Baseline up to approximately 4.5 years
Secondary	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.	At the end of induction (up to Day 56)
Secondary	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.	From randomization to death from any cause (up to approximately 4.5 years)
Secondary	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.	Baseline up to approximately 4.5 years
Secondary	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.	Baseline up to approximately 4.5 years
Secondary	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	Up to Day 30
Secondary	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	Up to Day 60
Secondary	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.	Up to Approximately 4.5 Years
Secondary	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.	Up to Approximately 4.5 Years
Secondary	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.	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	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.	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	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.	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	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.	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	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.	Up to Approximately 4.5 Years
Secondary	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.	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	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.	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	Total Duration of Study Treatment	Participants were planned to be treated up to 3 Cycles.	Up to 3 cycles (1 cycle is 28 days)
Secondary	Number of Treatment Cycles Started	Participants who started the study treatment cycles are reported.	Up to 3 cycles (1 cycle is 28 days)
Secondary	Cumulative Dose of Idasanutlin and Cytarabine	The cumulative doses of idasanutlin and cytaradine are reported.	Up to 3 cycles (1 cycle is 28 days)
Secondary	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.	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	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.	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	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.	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	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.	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	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.	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	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.	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	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.	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	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.	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	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.	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	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.	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	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.	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)