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

Primary Purpose

Leukemia, Myeloid, Acute

Status
Terminated
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
Cytarabine
Idasanutlin
Placebo
Sponsored by
Hoffmann-La Roche
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Leukemia, Myeloid, Acute

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Northwell Health
  • New York Medical College
  • Ichan School of Medicine at Mount Sinai
  • Abramson Cancer Center; Univ of Pennsylvania
  • Thomas Jefferson University
  • Baylor University Medical Center
  • M.D. Anderson Cancer Center; Department of Hematology
  • Canberra Hospital; Haematology Department
  • Concord Repatriation General Hospital; Haematology
  • Royal Adelaide Hospital; Haematology Clinical Trials
  • Geelong Hospital; Andrew Love Cancer Centre
  • Alfred Hospital; Clinical Haematology and Bone Marrow Transplantation
  • Lkh-Univ. Klinikum Graz; Klin. Abt. Für Hämatologie
  • CH Jolimont - Lobbes (Jolimont)
  • CHU Sart-Tilman
  • AZ Delta (Campus Rumbeke)
  • Juravinski Cancer Clinic; Clinical Trials Department
  • Helsinki University Central Hospital; Hematology
  • Tampere University Hospital; Hematology
  • Centre Hospitalier Uni Ire; Service Des Maladies Du Sang
  • Hopital Claude Huriez; Hematologie
  • Institut J Paoli I Calmettes; Onco Hematologie 2
  • Hopital Hotel Dieu Et Hme;Hopital De Jour
  • Hopital Saint Louis; Oncologie Medicale
  • HOPITAL SAINT ANTOINE;Hematologie Clinique
  • Hopital De Haut Leveque; Hematologie Clinique
  • Centre Hospitalier Lyon Sud; Hematolgie
  • IUCT Oncopole; Hematologie
  • Hopitaux De Brabois; Hematologie Medecine Interne
  • Uniklinik RWTH Aachen; Klinik IV; Klinik Hämatologie, Onkologie, Hämostaseologie und Stamm.
  • Universitätsklinikum Bonn; Med. Klinik und Poliklinik III; Hämatologie, Onkologie und Rheumatologie
  • Klinikum Braunschweig; Medizinische Klinik III; Klinik für Hämatologie und Onkologie
  • Klinikum Chemnitz gGmbH Krankenhaus Küchwald Klinik f.Innere Medizin III
  • Universitätsklinikum "Carl Gustav Carus"; Medizinische Klinik und Poliklinik I
  • Medizinische Hochschule Hannover; Zentrum Innere Medizin; Abt. Hämatologie u. Onkologie
  • Klinik der Uni zu Köln; I. Med. Klinik
  • Uni. der Johannes Gutenberg-Universitaet Mainz; III. Medizinische Klinik und Poliklinik
  • Universitätsklinikum Marburg Zentrum f. Innere Medizin
  • Shaare Zedek Medical Center; Hematology Dept.
  • Hadassah Ein Karem Hospital; Haematology
  • Rabin Medical Center-Beilinson Campus;Hematology-Oncology
  • Ichilov Sourasky Medical Center; Heamatology
  • Ospedale Cardarelli; Divisione Di Ematologia
  • Az. Osp. S. Orsola Malpighi; Istituto Di Oncologia Seragnoli
  • Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST); Onco-Ematologia
  • Az. Osp. S. Maria Delle Croci; U.O. Di Ematologia
  • A.O. Universitaria S. Maria Della Misericordia Di Udine; Oncologia; Clinica Ematologica
  • Az. Osp. Uni Ria Policlinico Tor Vergata; Unita Di Ematologia
  • IRCCS AOU S.Martino; Clinica Ematologica
  • ASST PAPA GIOVANNI XXIII; Ematologia
  • Ospedale San Raffaele, IRCCS
  • Asst Grande Ospedale Metropolitano Niguarda; Dipartimento Di Ematologia Ed Oncologia
  • A.O. Universitaria San Luigi Gonzaga di Orbassano; Ambulatorio per le Malattie Rare del Polmone
  • A.O.U. Citta' Della Salute E Della Scienza-P.O. Molinette;S.C. Ematologia
  • Az. Osp. Di Careggi; Divisione Di Ematologia
  • Ospedale Santa Chiara; Unita Operativa Di Ematologia
  • Pusan National University Hospital
  • Chonnam National University Hwasun Hospital
  • Seoul National University Hospital
  • Samsung Medical Center
  • Seoul St Mary's Hospital
  • Academisch Medisch Centrum; Hematologie
  • Academisch Ziekenhuis Maastricht
  • Auckland city hospital; Auckland Regional Cancer Centre and Blood Service
  • Haukeland Universitetssjukehus; Klinisk forskningspost
  • Oslo Universitetssykehus HF, Rikshospitalet
  • Complejo Hospitalario Arnulfo Arias Madrid; Servicio de Hematología
  • "Hematological Scientific Center
  • St. Petersburg State Medical University n.a. I.P. Pavlov; Hematology, transfusiology and transplanta
  • FGBU "Federal Medical and Research Center named after V.A.Almazov" Russian Ministry of Health
  • Hospital de la Santa Creu i Sant Pau; Servicio de Hematologia
  • Hospital Clínic i Provincial; Servicio de Hematología y Oncología
  • Hospital Univ. 12 de Octubre; Servicio de Hematologia
  • Hospital Universitario Virgen del Rocio
  • Hospital Universitario la Fe; Servicio de Hematologia
  • Universitätsspital Basel; Hämatologie
  • Universitätsspital Zürich Medizin Hämatologie; Klinik für Hämatologie
  • Birmingham Heartlands Hospital
  • University Hospital of Wales
  • St Bartholomew's Hospital
  • Christie Hospital NHS Trust
  • Royal Marsden NHS Foundation Trust

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Idasanutlin plus Cytarabine

Placebo plus Cytarabine

Arm Description

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.

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.

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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.
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.
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.
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.
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.
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.
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.
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.
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.
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
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
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.
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.
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.
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.
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.
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.
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.
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.
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.
Total Duration of Study Treatment
Participants were planned to be treated up to 3 Cycles.
Number of Treatment Cycles Started
Participants who started the study treatment cycles are reported.
Cumulative Dose of Idasanutlin and Cytarabine
The cumulative doses of idasanutlin and cytaradine are reported.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.

Full Information

First Posted
August 31, 2015
Last Updated
December 28, 2021
Sponsor
Hoffmann-La Roche
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1. Study Identification

Unique Protocol Identification Number
NCT02545283
Brief Title
A Study of Idasanutlin With Cytarabine Versus Cytarabine Plus Placebo in Participants With Relapsed or Refractory Acute Myeloid Leukemia (AML)
Acronym
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)
Study Type
Interventional

2. Study Status

Record Verification Date
December 2021
Overall Recruitment Status
Terminated
Why Stopped
The study was stopped for futility based on efficacy results at the interim analysis; no unexpected safety findings were observed.
Study Start Date
December 30, 2015 (Actual)
Primary Completion Date
April 24, 2020 (Actual)
Study Completion Date
April 24, 2020 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Hoffmann-La Roche

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This is a multicenter, double-blind, randomized, placebo-controlled study designed to compare overall survival in participants with relapsed or refractory AML treated with idasanutlin in combination with cytarabine versus participants treated with placebo and cytarabine. Participants will receive induction treatment with idasanutlin/placebo and cytarabine (Cycle 1). Responding participants may continue to receive a maximum of further two cycles of consolidation (Cycle 2 and Cycle 3). Complete remission (CR), CR with incomplete platelet count recovery (CRp), overall remission rate (ORR), event-free survival (EFS) and percentage of participants with an allogeneic hematopoietic stem cell transplant (HSCT) will also be compared between treatment arms. This study will include participants with and without TP53 wild type (TP53 WT) mutations.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Leukemia, Myeloid, Acute

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantInvestigator
Allocation
Randomized
Enrollment
447 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Idasanutlin plus Cytarabine
Arm Type
Experimental
Arm Description
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.
Arm Title
Placebo plus Cytarabine
Arm Type
Placebo Comparator
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Cytarabine
Intervention Description
Participants will receive cytarabine 1 gram per square meter (g/m^2) intravenous (IV) infusion for 5 days of every treatment cycle.
Intervention Type
Drug
Intervention Name(s)
Idasanutlin
Other Intervention Name(s)
RG7388
Intervention Description
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.
Intervention Type
Other
Intervention Name(s)
Placebo
Intervention Description
Participants will receive idasanutlin matching placebo PO BID or QD for 5 days of every treatment cycle.
Primary Outcome Measure Information:
Title
Overall Survival in TP53 WT Population
Description
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)
Secondary Outcome Measure Information:
Title
Percentage of Participants in Complete Response (CR) at the End of Induction According to Hematologic Malignancy Response Assessment (HMRA) in TP53 WT Population
Description
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)
Title
Event-Free Survival (EFS) According to HMRA in TP53 WT Population
Description
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)
Title
Percentage of Participants With Overall Remission (CR, CRp, and CRi) at the End of Induction According to HMRA in TP53 WT Population
Description
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)
Title
Duration of Remission Following CR (DOR) in TP53 WT Population
Description
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)
Title
Percentage of Participants Undergoing HSCT Following Complete Response (CR), in TP53 WT Population
Description
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
Title
Percentage of Participants With Complete Response (CR) in Clinically Actionable Mutation-Defined Subpopulation (FLT3, IDH1 and IDH2) in TP53 WT Population
Description
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)
Title
Overall Survival in Clinically Actionable Mutation-Defined Subpopulation (FLT3, IDH1 and IDH2) in TP53 WT Population
Description
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)
Title
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)
Description
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
Title
Number of Participants With Adverse Events Leading to Discontinuation
Description
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
Title
Number of Participants With Adverse Events Leading to Death up to Day 30
Description
The number of participants with AE resulted by death within 30 days from dosing is reported
Time Frame
Up to Day 30
Title
Number of Participants With Adverse Events Leading to Death up to Day 60
Description
The number of participants with AE resulted by death within 60 days from dosing is reported
Time Frame
Up to Day 60
Title
Number of Participants With Clinical Laboratory Abnormalities in Biochemistry Tests at the Greatest Severity, According to NCI-CTCAE v4.03
Description
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
Title
Number of Participants With Clinical Laboratory Abnormalities in Hematology Tests at the Greatest Severity, According to NCI-CTCAE v4.03
Description
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
Title
Change From Baseline in Body Temperature Over Time
Description
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)
Title
Change From Baseline in Systolic Blood Pressure Over Time
Description
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)
Title
Change From Baseline in Diastolic Blood Pressure Over Time
Description
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)
Title
Change From Baseline in Pulse Rate Over Time
Description
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)
Title
Change From Baseline in Respiratory Rate Over Time
Description
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
Title
Change From Baseline in Heart Rate, as Measured by Electrocardiogram
Description
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
Title
Change From Baseline in Electrocardiogram Parameters: PQ, PR, RR, QRS, QT and QTcF Intervals
Description
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)
Title
Total Duration of Study Treatment
Description
Participants were planned to be treated up to 3 Cycles.
Time Frame
Up to 3 cycles (1 cycle is 28 days)
Title
Number of Treatment Cycles Started
Description
Participants who started the study treatment cycles are reported.
Time Frame
Up to 3 cycles (1 cycle is 28 days)
Title
Cumulative Dose of Idasanutlin and Cytarabine
Description
The cumulative doses of idasanutlin and cytaradine are reported.
Time Frame
Up to 3 cycles (1 cycle is 28 days)
Title
Apparent Clearance (CL/F) of Idasanutlin
Description
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)
Title
Apparent Volume of Distribution (Vd/F) of Idasanutlin
Description
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)
Title
Maximum Concentration Observed (Cmax) of Idasanutlin
Description
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)
Title
Steady-State Concentration (Ctrough) of Idasanutlin
Description
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)
Title
Area Under the Concentration-Time Curve (AUC) During One Dosing Interval (AUCtau) of Idasanutlin
Description
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)
Title
AUC From Time Zero to 24 Hours Post Dose (AUC0-24) of Idasanutlin
Description
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)
Title
Half-Life (t 1/2) of Idasanutlin
Description
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)
Title
Total Clearance (CL) of Cytarabine
Description
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)
Title
Volume of Distribution (Vd) of Cytarabine
Description
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)
Title
Change From Baseline in European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) Score
Description
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)
Title
Change From Baseline in EuroQol 5 Dimension 5-Level (EQ-5D-5L) Questionnaire Score
Description
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)

10. Eligibility

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

12. IPD Sharing Statement

Citations:
PubMed Identifier
32167393
Citation
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.
Results Reference
derived

Learn more about this trial

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

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