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

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)

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.

Study Overview

• Status: Terminated
• Conditions: Leukemia, Myeloid, Acute
• Intervention / Treatment: Drug: Cytarabine; Drug: Idasanutlin; Other: Placebo

• Study Type: Interventional
• Enrollment (Actual): 447
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • Australian Capital Territory
    • Canberra, Australian Capital Territory, Australia, 2605
      • Canberra Hospital; Haematology Department
  • New South Wales
    • Sydney, New South Wales, Australia, 2139
      • Concord Repatriation General Hospital; Haematology
  • South Australia
    • Adelaide, South Australia, Australia, 5000
      • Royal Adelaide Hospital; Haematology Clinical Trials
  • Victoria
    • Geelong, Victoria, Australia, 3220
      • Geelong Hospital; Andrew Love Cancer Centre
    • Melbourne, Victoria, Australia, 3004
      • Alfred Hospital; Clinical Haematology and Bone Marrow Transplantation
• Austria
  • Graz, Austria, 8036
    • Lkh-Univ. Klinikum Graz; Klin. Abt. Für Hämatologie
• Belgium
  • Haine-Saint-Paul, Belgium, 7100
    • CH Jolimont - Lobbes (Jolimont)
  • Liège, Belgium, 4000
    • CHU Sart-Tilman
  • Roeselare, Belgium, 8800
    • AZ Delta (Campus Rumbeke)
• Canada
  • Ontario
    • Hamilton, Ontario, Canada, L8V 5C2
      • Juravinski Cancer Clinic; Clinical Trials Department
• Finland
  • Helsinki, Finland, 00290
    • Helsinki University Central Hospital; Hematology
  • Tampere, Finland, 33521
    • Tampere University Hospital; Hematology
• France
  • Angers Cedex 9, France, 49933
    • Centre Hospitalier Uni Ire; Service Des Maladies Du Sang
  • Lille, France, 59037
    • Hopital Claude Huriez; Hematologie
  • Marseille, France, 13273
    • Institut J Paoli I Calmettes; Onco Hematologie 2
  • Nantes, France, 44093
    • Hopital Hotel Dieu Et Hme;Hopital De Jour
  • Paris, France, 75475
    • Hopital Saint Louis; Oncologie Medicale
  • Paris, France, 75571
    • HOPITAL SAINT ANTOINE;Hematologie Clinique
  • Pessac, France, 33604
    • Hopital De Haut Leveque; Hematologie Clinique
  • Pierre Benite, France, 69495
    • Centre Hospitalier Lyon Sud; Hematolgie
  • Toulouse, France, 31059
    • IUCT Oncopole; Hematologie
  • Vandoeuvre Les Nancy, France, 54511
    • Hopitaux De Brabois; Hematologie Medecine Interne
• Germany
  • Aachen, Germany, 52074
    • Uniklinik RWTH Aachen; Klinik IV; Klinik Hämatologie, Onkologie, Hämostaseologie und Stamm.
  • Bonn, Germany, 53127
    • Universitätsklinikum Bonn; Med. Klinik und Poliklinik III; Hämatologie, Onkologie und Rheumatologie
  • Braunschweig, Germany, 38114
    • Klinikum Braunschweig; Medizinische Klinik III; Klinik für Hämatologie und Onkologie
  • Chemnitz, Germany, 09113
    • Klinikum Chemnitz gGmbH Krankenhaus Küchwald Klinik f.Innere Medizin III
  • Dresden, Germany, 01307
    • Universitätsklinikum "Carl Gustav Carus"; Medizinische Klinik und Poliklinik I
  • Hannover, Germany, 30625
    • Medizinische Hochschule Hannover; Zentrum Innere Medizin; Abt. Hämatologie u. Onkologie
  • Köln, Germany, 50937
    • Klinik der Uni zu Köln; I. Med. Klinik
  • Mainz, Germany, 55131
    • Uni. der Johannes Gutenberg-Universitaet Mainz; III. Medizinische Klinik und Poliklinik
  • Marburg, Germany, 35043
    • Universitätsklinikum Marburg Zentrum f. Innere Medizin
• Israel
  • Jerusalem, Israel, 9103102
    • Shaare Zedek Medical Center; Hematology Dept.
  • Jerusalem, Israel, 9112001
    • Hadassah Ein Karem Hospital; Haematology
  • Petach Tikva, Israel, 4941492
    • Rabin Medical Center-Beilinson Campus;Hematology-Oncology
  • Tel Aviv, Israel, 6423906
    • Ichilov Sourasky Medical Center; Heamatology
• Italy
  • Campania
    • Napoli, Campania, Italy, 80131
      • Ospedale Cardarelli; Divisione Di Ematologia
  • Emilia-Romagna
    • Bologna, Emilia-Romagna, Italy, 40138
      • Az. Osp. S. Orsola Malpighi; Istituto Di Oncologia Seragnoli
    • Meldola, Emilia-Romagna, Italy, 47014
      • Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST); Onco-Ematologia
    • Ravenna, Emilia-Romagna, Italy, 48100
      • Az. Osp. S. Maria Delle Croci; U.O. Di Ematologia
  • Friuli-Venezia Giulia
    • Udine, Friuli-Venezia Giulia, Italy, 33100
      • A.O. Universitaria S. Maria Della Misericordia Di Udine; Oncologia; Clinica Ematologica
  • Lazio
    • Roma, Lazio, Italy, 00133
      • Az. Osp. Uni Ria Policlinico Tor Vergata; Unita Di Ematologia
  • Liguria
    • Genova, Liguria, Italy, 16132
      • IRCCS AOU S.Martino; Clinica Ematologica
  • Lombardia
    • Bergamo, Lombardia, Italy, 24127
      • ASST PAPA GIOVANNI XXIII; Ematologia
    • Milano, Lombardia, Italy, 20162
      • Asst Grande Ospedale Metropolitano Niguarda; Dipartimento Di Ematologia Ed Oncologia
    • Milano, Lombardia, Italy, 20132
      • Ospedale San Raffaele, IRCCS
  • Piemonte
    • Orbassano (TO), Piemonte, Italy, 10043
      • A.O. Universitaria San Luigi Gonzaga di Orbassano; Ambulatorio per le Malattie Rare del Polmone
    • Torino, Piemonte, Italy, 10126
      • A.O.U. Citta' Della Salute E Della Scienza-P.O. Molinette;S.C. Ematologia
  • Toscana
    • Firenze, Toscana, Italy, 50135
      • Az. Osp. Di Careggi; Divisione Di Ematologia
    • Pisa, Toscana, Italy, 56100
      • Ospedale Santa Chiara; Unita Operativa Di Ematologia
• Korea, Republic of
  • Busan, Korea, Republic of, 49241
    • Pusan National University Hospital
  • Jeollanam-do, Korea, Republic of, 58128
    • Chonnam National University Hwasun Hospital
  • Seoul, Korea, Republic of, 03080
    • Seoul National University Hospital
  • Seoul, Korea, Republic of, 06351
    • Samsung Medical Center
  • Seoul, Korea, Republic of, 06591
    • Seoul St Mary's Hospital
• Netherlands
  • Amsterdam, Netherlands, 1105 AZ
    • Academisch Medisch Centrum; Hematologie
  • Maastricht, Netherlands, 6202 AZ
    • Academisch Ziekenhuis Maastricht
• New Zealand
  • Auckland, New Zealand, 1023
    • Auckland city hospital; Auckland Regional Cancer Centre and Blood Service
• Norway
  • Bergen, Norway, 5021
    • Haukeland Universitetssjukehus; Klinisk forskningspost
  • Oslo, Norway, 0372
    • Oslo Universitetssykehus HF, Rikshospitalet
• Panama
  • Panama City, Panama, 0824
    • Complejo Hospitalario Arnulfo Arias Madrid; Servicio de Hematología
• Russian Federation
  • Moscow, Russian Federation, 125167
    • "Hematological Scientific Center
  • Saint-Petersburg, Russian Federation, 197022
    • St. Petersburg State Medical University n.a. I.P. Pavlov; Hematology, transfusiology and transplanta
  • Sankt-Petersburg, Russian Federation, 197341
    • FGBU "Federal Medical and Research Center named after V.A.Almazov" Russian Ministry of Health
• Spain
  • Barcelona, Spain, 08036
    • Hospital Clínic i Provincial; Servicio de Hematología y Oncología
  • Barcelona, Spain, 08025
    • Hospital de la Santa Creu i Sant Pau; Servicio de Hematologia
  • Madrid, Spain, 28041
    • Hospital Univ. 12 de Octubre; Servicio de Hematologia
  • Sevilla, Spain, 41013
    • Hospital Universitario Virgen del Rocio
  • Valencia, Spain, 46026
    • Hospital Universitario la Fe; Servicio de Hematologia
• Switzerland
  • Basel, Switzerland, 4031
    • Universitätsspital Basel; Hämatologie
  • Zürich, Switzerland, 8091
    • Universitätsspital Zürich Medizin Hämatologie; Klinik für Hämatologie
• United Kingdom
  • Birmingham, United Kingdom, B9 5SS
    • Birmingham Heartlands Hospital
  • Cardiff, United Kingdom, CF14 4XW
    • University Hospital of Wales
  • London, United Kingdom, EC1M 6BQ
    • St Bartholomew's Hospital
  • Manchester, United Kingdom, M20 4BX
    • Christie Hospital Nhs Trust
  • Sutton, United Kingdom, SM2 5PT
    • Royal Marsden NHS Foundation Trust
• United States
  • New York
    • Great Neck, New York, United States, 11021
      • Northwell Health
    • Hawthorne, New York, United States, 10532
      • New York Medical College
    • New York, New York, United States, 10029
      • Ichan School of Medicine at Mount Sinai
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19107
      • Thomas Jefferson University
    • Philadelphia, Pennsylvania, United States, 19104
      • Abramson Cancer Center; Univ of Pennsylvania
  • Texas
    • Dallas, Texas, United States, 75204
      • Baylor University Medical Center
    • Houston, Texas, United States, 77030
      • M.D. Anderson Cancer Center; Department of Hematology

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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.	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 Names: RG7388
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.	Drug: Cytarabine; Participants will receive cytarabine 1 gram per square meter (g/m^2) intravenous (IV) infusion 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
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)
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)
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)
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)
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
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)
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)
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
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
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
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
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
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
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)
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)
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)
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)
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
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
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)
Total Duration of Study Treatment	Participants were planned to be treated up to 3 Cycles.	Up to 3 cycles (1 cycle is 28 days)
Number of Treatment Cycles Started	Participants who started the study treatment cycles are reported.	Up to 3 cycles (1 cycle is 28 days)
Cumulative Dose of Idasanutlin and Cytarabine	The cumulative doses of idasanutlin and cytaradine are reported.	Up to 3 cycles (1 cycle is 28 days)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)

Collaborators and Investigators

• Sponsor: Hoffmann-La Roche

Publications and helpful links

General Publications

• Montesinos P, Beckermann BM, Catalani O, Esteve J, Gamel K, Konopleva MY, Martinelli G, Monnet A, Papayannidis C, Park A, Recher C, Rodriguez-Veiga R, Rollig 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.

Study record dates

Study Major Dates

• Study Start (Actual): December 30, 2015
• Primary Completion (Actual): April 24, 2020
• Study Completion (Actual): April 24, 2020

Study Registration Dates

• First Submitted: August 31, 2015
• First Submitted That Met QC Criteria: September 8, 2015
• First Posted (Estimate): September 9, 2015

Study Record Updates

• Last Update Posted (Actual): January 11, 2022
• Last Update Submitted That Met QC Criteria: December 28, 2021
• Last Verified: December 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Cytarabine
• Other Study ID Numbers: WO29519; 2014-003065-15 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No