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Clinical Trial Details — Status: Terminated

Administrative data

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

Study information

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

Clinical Trial Summary

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


Recruitment information / eligibility

Status Terminated
Enrollment 447
Est. completion date April 24, 2020
Est. primary completion date April 24, 2020
Accepts healthy volunteers No
Gender All
Age group 18 Years and older
Eligibility Inclusion Criteria: - Documented/confirmed first/second refractory/relapsed AML using World Health Organization classification, except acute promyelocytic leukemia - No more than 2 prior induction regimens (excluding prior HSCT) in their first line treatment and one must have included cytarabine with an anthracycline (or anthracenedione) - Eastern Cooperative Oncology Group performance status of 0 to 2 - Adequate hepatic and renal function - White blood cell (WBC) count at randomization less than or equal to (</=) 50000 cells per cubic millimeter (/mm^3) Exclusion Criteria: - First relapsed participants aged less than (<) 60 years with first CR duration greater than (>) 1 year - Participants with prior documented antecedent hematological disorder (AHD) - AML secondary to any prior chemotherapy unrelated to leukemia - Participants who are either refractory to or relapsed within 90 days of receiving a regimen containing a cumulative dose of greater than or equal to (>/=) 18 g/m^2 of cytarabine - Participants who have received allogeneic HSCT within 90 days prior to randomization - Participants who have received immunosuppressive therapy for graft versus host disease or for engraftment syndrome after autologous stem cell transplantation within 2 weeks prior to randomization - Prior treatment with an Murine Double Minute 2 (MDM2) antagonist - Participants receiving any other investigational or commercial agents or therapies administered with the intention to treat their malignancy within 30 days from first receipt of study drug - Participants with a history of other malignancy within 5 years prior to screening except for malignancy that has been in remission without treatment for at least 2 years prior to randomization - Participants who have any severe and/or uncontrolled medical conditions or other conditions that could affect their participation in the study - Participants with extramedullary AML with no evidence of systemic involvement - Pregnant or breastfeeding participants

Study Design


Related Conditions & MeSH terms


Intervention

Drug:
Cytarabine
Participants will receive cytarabine 1 gram per square meter (g/m^2) intravenous (IV) infusion for 5 days of every treatment cycle.
Idasanutlin
Participants will receive idasanutlin 300 mg per oral (PO) twice daily (BID) (in Cycle 1) or once daily (QD) (in Cycles 2 and 3) for 5 days of every treatment cycle.
Other:
Placebo
Participants will receive idasanutlin matching placebo PO BID or QD for 5 days of every treatment cycle.

Locations

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

Sponsors (1)

Lead Sponsor Collaborator
Hoffmann-La Roche

Countries where clinical trial is conducted

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

Outcome

Type Measure Description Time frame Safety issue
Primary Overall Survival in TP53 WT Population P53 tumor protein Wild Type (TP53 WT) population's Overall Survival was compared in participants with relapsed or refractory (R/R) acute myeloid leukemia (AML) who had been randomized to idasanutlin in combination with cytarabine versus those who had been randomized to cytarabine and placebo.
The study was terminated because of futility, therefore did not reach the planned end of the study.
From randomization to death from any cause (up to approximately 4.5 years)
Secondary Percentage of Participants in Complete Response (CR) at the End of Induction According to Hematologic Malignancy Response Assessment (HMRA) in TP53 WT Population Rate of complete response at the end of induction in the TP53 WT population was compared in participants who had been randomized to idasanutlin in combination with cytarabine versus those who had been randomized to cytarabine and placebo.
The design followed a hierarchical statistical testing framework.
At the end of induction (up to Day 56)
Secondary Event-Free Survival (EFS) According to HMRA in TP53 WT Population Event Free Survival (EFS) is defined as the time from the date of randomization to whichever occurs first: treatment failure (failure to achieve CR, set as day of final response assessment), relapse from CR, or death from any cause. The study was terminated because of futility, therefore did not reach the planned end of the study.
The design followed a hierarchical statistical testing framework.
From randomization up to treatment failure, relapse, or death from any cause (up to approximately 4.5 years)
Secondary Percentage of Participants With Overall Remission (CR, CRp, and CRi) at the End of Induction According to HMRA in TP53 WT Population Rate of overall remission (complete remission, complete remission with incomplete hematologic recovery, complete remission with incomplete platelet count recovery) at the end of induction in the TP53 WT population was compared in participants who had been randomized to idasanutlin in combination with cytarabine versus those who had been randomized to cytarabine and placebo.
The design followed a hierarchical statistical testing framework.
At the end of induction (up to Day 56)
Secondary Duration of Remission Following CR (DOR) in TP53 WT Population DOR is defined for patients achieving complete remission and is the time from clinical remission until relapse or death from any cause, whichever occurs first. For patients with none of these events before time of analysis, DOR is censored at the date of the patient's last response assessment.
The Median upper limits were set to 999 because they were not reached and therefore it was Not Evaluable (NE) and the field is numeric only. The study was terminated because of futility, therefore did not reach the planned end of the study.
From achieving CR until relapse or death from any cause (up to approximately 4.5 years)
Secondary Percentage of Participants Undergoing HSCT Following Complete Response (CR), in TP53 WT Population Rate of complete response at the end of induction in mutation-defined subgroups (positive for mutation of FLT3, IDH1 and IDH2, respectively) of the TP53 WT population was compared in participants who had been randomized to idasanutlin in combination with cytarabine versus those who had been randomized to cytarabine and placebo. The study was terminated because of futility, therefore did not reach the planned end of the study. Baseline up to approximately 4.5 years
Secondary Percentage of Participants With Complete Response (CR) in Clinically Actionable Mutation-Defined Subpopulation (FLT3, IDH1 and IDH2) in TP53 WT Population Rate of complete response at the end of induction in mutation-defined subgroups (positive for mutation of FLT3, IDH1 and IDH2, respectively) of the TP53 WT population was compared in participants who had been randomized to idasanutlin in combination with cytarabine versus those who had been randomized to cytarabine and placebo. At the end of induction (up to Day 56)
Secondary Overall Survival in Clinically Actionable Mutation-Defined Subpopulation (FLT3, IDH1 and IDH2) in TP53 WT Population Overall survival in mutation-defined subgroups (positive for mutation of FLT3, IDH1 and IDH2 respectively) of the TP53 WT population was compared in participants who had been randomized to idasanutlin in combination with cytarabine versus those who had been randomized to cytarabine and placebo. The Median upper limits were set to 999 because they were not reached and therefore it was Not Evaluable (NE) and the field is numeric only. The study was terminated because of futility, therefore did not reach the planned end of the study. From randomization to death from any cause (up to approximately 4.5 years)
Secondary Number of Participants Who Experienced at Least One Adverse Event by Severity, According to National Cancer Institute Common Terminology Criteria for Adverse Events, Version 4.03 (NCI-CTCAE v4.03) Participants who experienced at least one Adverse Event by severity, According to National Cancer Institute common terminology criteria for Adverse Events, version 4.03 (NCI-CTCAE v4.03) have been reported. The study was terminated because of futility, therefore did not reach the planned end of the study. Baseline up to approximately 4.5 years
Secondary Number of Participants With Adverse Events Leading to Discontinuation Participants with Adverse Events leading to discontinuation of the study have been reported. The study was terminated because of futility, therefore did not reach the planned end of the study. Baseline up to approximately 4.5 years
Secondary Number of Participants With Adverse Events Leading to Death up to Day 30 The number of participants with AE resulted by death within 30 days from dosing is reported Up to Day 30
Secondary Number of Participants With Adverse Events Leading to Death up to Day 60 The number of participants with AE resulted by death within 60 days from dosing is reported Up to Day 60
Secondary Number of Participants With Clinical Laboratory Abnormalities in Biochemistry Tests at the Greatest Severity, According to NCI-CTCAE v4.03 Laboratory parameters for blood biochemistry will be measured and compared with a standard reference range. Values outside the standard reference range are considered abnormalities. A laboratory test result will be reported as an adverse event if it meets any of the following criteria: is accompanied by clinical symptoms; results in a change in study treatment or a medical intervention; or is clinically significant in the investigator's judgment.
For each patient, baseline is the last observation prior to initiation of study drug. For each laboratory test, patients with at least 1 post-baseline assessment are included in the analysis. For each cell, the denominator is the number of patients with baseline NCI-CTCAE Grade 0-2 in the specified direction of abnormality, or Grade 1-4 in the opposite direction of abnormality.
Up to Approximately 4.5 Years
Secondary Number of Participants With Clinical Laboratory Abnormalities in Hematology Tests at the Greatest Severity, According to NCI-CTCAE v4.03 Laboratory parameters for hematology will be measured and compared with a standard reference range. Values outside the standard reference range are considered abnormalities. A laboratory test result will be reported as an adverse event if it meets any of the following criteria: is accompanied by clinical symptoms; results in a change in study treatment or a medical intervention; or is clinically significant in the investigator's judgment.
For each patient, baseline is the last observation prior to initiation of study drug. For each laboratory test, patients with at least 1 post-baseline assessment are included in the analysis. For each cell, the denominator is the number of patients with baseline NCI-CTCAE Grade 0-2 in the specified direction of abnormality, or Grade 1-4 in the opposite direction of abnormality.
Up to Approximately 4.5 Years
Secondary Change From Baseline in Body Temperature Over Time Vital signs were measured prior to the infusion while the participant was in a seated position. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.
The study was terminated because of futility, therefore did not reach the planned end of study.
Baseline; Cycles 1-3, Days 8, 15, 22, 28 (1 cycle is 28 days); and, if incomplete blood count recovery, Days 29-42 and Days 43-56, Cycles 2 -3 Days 1, 8, 15, 22, 28 and 29-56 (max delay between cycles is 56 days)
Secondary Change From Baseline in Systolic Blood Pressure Over Time Vital signs were measured prior to the infusion while the participant was in a seated position. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.
The study was terminated because of futility, therefore did not reach the planned end of study.
Baseline; Cycles 1-3, Days 8, 15, 22, 28 (1 cycle is 28 days); and, if incomplete blood count recovery, Days 29-42 and Days 43-56, Cycles 2 -3 Days 1, 8, 15, 22, 28 and 29-56 (max delay between cycles is 56 days)
Secondary Change From Baseline in Diastolic Blood Pressure Over Time Vital signs were measured prior to the infusion while the participant was in a seated position. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.
The study was terminated because of futility, therefore did not reach the planned end of study.
Baseline; Cycles 1-3, Days 8, 15, 22, 28 (1 cycle is 28 days); and, if incomplete blood count recovery, Days 29-42 and Days 43-56, Cycles 2 -3 Days 1, 8, 15, 22, 28 and 29-56 (max delay between cycles is 56 days)
Secondary Change From Baseline in Pulse Rate Over Time Vital signs were measured prior to the infusion while the participant was in a seated position. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.
The study was terminated because of futility, therefore did not reach the planned end of study.
Baseline; Cycles 1-3, Days 8, 15, 22, 28 (1 cycle is 28 days); and, if incomplete blood count recovery, Days 29-42 and Days 43-56, Cycles 2 -3 Days 1, 8, 15, 22, 28 and 29-56 (max delay between cycles is 56 days)
Secondary Change From Baseline in Respiratory Rate Over Time Vital signs were measured prior to the infusion while the participant was in a seated position. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.
The study was terminated because of futility, therefore did not reach the planned end of study.
Up to Approximately 4.5 Years
Secondary Change From Baseline in Heart Rate, as Measured by Electrocardiogram Single 12-lead ECGs was obtained using an ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, and QTc intervals. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.
The study was terminated because of futility, therefore did not reach the planned end of study.
Baseline; Cycles 1-3 Day 1 (2 hrs pre-dose, post-Cytarabine and 6 hrs post-Idasanutlin/Placebo ); Cycle 1-3 Day 2; Cycle 1 Day 5 (within 2 hrs Idanasanutlin/Placebo, post-Cytarabine and 6 hrs post-Idasanutlin/Placebo), Study Drug Completion
Secondary Change From Baseline in Electrocardiogram Parameters: PQ, PR, RR, QRS, QT and QTcF Intervals Single 12-lead ECGs was obtained using an ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, and QTc intervals. The baseline value at visit and the change from baseline value at each timepoint are reported. The change from baseline value was calculated by subtracting the post-baseline value from the baseline value.
The study was terminated because of futility, therefore did not reach the planned end of study.
Baseline, Days 1, 2, and 5 of Cycle 1, Days 1, 2 of Cycles 2 and 3 (1 cycle is 28 days), Treatment Discontinuation Visit (28 days after last dose of study drug)
Secondary Total Duration of Study Treatment Participants were planned to be treated up to 3 Cycles. Up to 3 cycles (1 cycle is 28 days)
Secondary Number of Treatment Cycles Started Participants who started the study treatment cycles are reported. Up to 3 cycles (1 cycle is 28 days)
Secondary Cumulative Dose of Idasanutlin and Cytarabine The cumulative doses of idasanutlin and cytaradine are reported. Up to 3 cycles (1 cycle is 28 days)
Secondary Apparent Clearance (CL/F) of Idasanutlin Apparent Clearance (CL/F) of Idasanutlin was planned as part of the PK analyses. The Independent Data Monitoring Committee recommended stopping the study for futility based on a lack of OS benefit due to Hazard Ratio (HR) being greater than 1. The benefit-risk profile of idasanutlin combined with 1g/m2 cytarabine in fit R/R AML was not positive, as the observed marginal benefit does not outweigh the risks of idasanutlin in the relapsed or refractory AML population.
Therefore the study was prematurely terminated by the sponsor's decision and the result data did not derive.The benefit-risk profile of idasanutlin combined with 1g/m2 cytarabine in fit R/R AML was not positive, as the observed marginal benefit does not outweigh the risks of idasanutlin in the relapsed or refractory AML population. The planned CL/F did not derive for the result data and was not reported.
Cycle 1: Predose (0 hour [Hr]), end of 1-3 Hr cytarabine infusion, 6 Hr postdose on Days 1, 5; Predose (0 Hr) on Day 2; at Days 8, 10; Cycle 2, 3: predose (0 Hr) on Days 2, 5 (predose/postdose: relative to idasanutlin morning dose; cycle length= 28 days)
Secondary Apparent Volume of Distribution (Vd/F) of Idasanutlin Apparent Volume of Distribution (Vd/F) of Idasanutlin was planned as part of the PK analyses. The Independent Data Monitoring Committee recommended stopping the study for futility based on a lack of OS benefit due to Hazard Ratio (HR) being greater than 1. The benefit-risk profile of idasanutlin combined with 1g/m2 cytarabine in fit R/R AML was not positive, as the observed marginal benefit does not outweigh the risks of idasanutlin in the relapsed or refractory AML population.
Therefore the study was prematurely terminated by the sponsor's decision and the result data did not derive.
Cycle 1: Predose (0 Hr), end of 1-3 Hr cytarabine infusion, 6 Hr postdose on Days 1, 5; Predose (0 Hr) on Day 2; at Days 8, 10; Cycle 2, 3: predose (0 Hr) on Days 2, 5 (predose/postdose: relative to idasanutlin morning dose; cycle length= 28 days)
Secondary Maximum Concentration Observed (Cmax) of Idasanutlin Maximum Concentration Observed (Cmax) of Idasanutlin was planned as part of the PK analyses. The Independent Data Monitoring Committee recommended stopping the study for futility based on a lack of OS benefit due to Hazard Ratio (HR) being greater than 1. The benefit-risk profile of idasanutlin combined with 1g/m2 cytarabine in fit R/R AML was not positive, as the observed marginal benefit does not outweigh the risks of idasanutlin in the relapsed or refractory AML population.
Therefore the study was prematurely terminated by the sponsor's decision and the result data did not derive.
Cycle 1: Predose (0 Hr), end of 1-3 Hr cytarabine infusion, 6 Hr postdose on Days 1, 5; Predose (0 Hr) on Day 2; at Days 8, 10; Cycle 2, 3: predose (0 Hr) on Days 2, 5 (predose/postdose: relative to idasanutlin morning dose; cycle length= 28 days)
Secondary Steady-State Concentration (Ctrough) of Idasanutlin Steady-State Concentration (Ctrough) of Idasanutlin was planned as part of the PK analyses. The Independent Data Monitoring Committee recommended stopping the study for futility based on a lack of OS benefit due to Hazard Ratio (HR) being greater than 1. The benefit-risk profile of idasanutlin combined with 1g/m2 cytarabine in fit R/R AML was not positive, as the observed marginal benefit does not outweigh the risks of idasanutlin in the relapsed or refractory AML population.
Therefore the study was prematurely terminated by the sponsor's decision and the result data did not derive.
Cycle 1: Predose (0 Hr), end of 1-3 Hr cytarabine infusion, 6 Hr postdose on Days 1, 5; Predose (0 Hr) on Day 2; at Days 8, 10; Cycle 2, 3: predose (0 Hr) on Days 2, 5 (predose/postdose: relative to idasanutlin morning dose; cycle length= 28 days)
Secondary Area Under the Concentration-Time Curve (AUC) During One Dosing Interval (AUCtau) of Idasanutlin Area Under the Concentration-Time Curve (AUC) During One Dosing Interval (AUCtau) of Idasanutlin was planned as part of the PK analyses. The Independent Data Monitoring Committee recommended stopping the study for futility based on a lack of OS benefit due to Hazard Ratio (HR) being greater than 1. The benefit-risk profile of idasanutlin combined with 1g/m2 cytarabine in fit R/R AML was not positive, as the observed marginal benefit does not outweigh the risks of idasanutlin in the relapsed or refractory AML population.
Therefore the study was prematurely terminated by the sponsor's decision and the result data did not derive.
Cycle 1: Predose (0 Hr), end of 1-3 Hr cytarabine infusion, 6 Hr postdose on Days 1, 5; Predose (0 Hr) on Day 2; at Days 8, 10; Cycle 2, 3: predose (0 Hr) on Days 2, 5 (predose/postdose: relative to idasanutlin morning dose; cycle length= 28 days)
Secondary AUC From Time Zero to 24 Hours Post Dose (AUC0-24) of Idasanutlin AUC from Time Zero to 24 Hours Post Dose (AUC0-24) of Idasanutlin was planned as part of the PK analyses. The Independent Data Monitoring Committee recommended stopping the study for futility based on a lack of OS benefit due to Hazard Ratio (HR) being greater than 1. The benefit-risk profile of idasanutlin combined with 1g/m2 cytarabine in fit R/R AML was not positive, as the observed marginal benefit does not outweigh the risks of idasanutlin in the relapsed or refractory AML population.
Therefore the study was prematurely terminated by the sponsor's decision and the result data did not derive.
Cycle 1: Predose (0 Hr), end of 1-3 Hr cytarabine infusion, 6 Hr postdose on Days 1, 5; Predose (0 Hr) on Day 2; at Days 8, 10; Cycle 2, 3: predose (0 Hr) on Days 2, 5 (predose/postdose: relative to idasanutlin morning dose; cycle length= 28 days)
Secondary Half-Life (t 1/2) of Idasanutlin Half-Life (t 1/2) of Idasanutlin was planned as part of the PK analyses. The Independent Data Monitoring Committee recommended stopping the study for futility based on a lack of OS benefit due to Hazard Ratio (HR) being greater than 1. The benefit-risk profile of idasanutlin combined with 1g/m2 cytarabine in fit R/R AML was not positive, as the observed marginal benefit does not outweigh the risks of idasanutlin in the relapsed or refractory AML population.
Therefore the study was prematurely terminated by the sponsor's decision and the result data did not derive.
Cycle 1: Predose (0 Hr), end of 1-3 Hr cytarabine infusion, 6 Hr postdose on Days 1, 5; Predose (0 Hr) on Day 2; at Days 8, 10; Cycle 2, 3: predose (0 Hr) on Days 2, 5 (predose/postdose: relative to idasanutlin morning dose; cycle length= 28 days)
Secondary Total Clearance (CL) of Cytarabine The Total Clearance (CL) of Cytarabine was planned as part of the PK analyses. The Independent Data Monitoring Committee recommended stopping the study for futility based on a lack of OS benefit due to Hazard Ratio (HR) being greater than 1. The benefit-risk profile of idasanutlin combined with 1g/m2 cytarabine in fit R/R AML was not positive, as the observed marginal benefit does not outweigh the risks of idasanutlin in the relapsed or refractory AML population.
Therefore the study was prematurely terminated by the sponsor's decision and the result data did not derive.
Cycle 1: Within 2 Hr pre-cytarabine dose, end of 1-3 Hr cytarabine infusion, 6 Hr post idasanutlin morning dose on Days 1, 5; Within 2 Hr pre-cytarabine dose on Day 2; Cycle 2, 3: Within 2 Hr pre-cytarabine dose on Day 2 (Cycle length= 28 days)
Secondary Volume of Distribution (Vd) of Cytarabine The Volume of Distribution (Vd) of Cytarabine was planned as part of the PK analyses. The Independent Data Monitoring Committee recommended stopping the study for futility based on a lack of OS benefit due to Hazard Ratio (HR) being greater than 1. The benefit-risk profile of idasanutlin combined with 1g/m2 cytarabine in fit R/R AML was not positive, as the observed marginal benefit does not outweigh the risks of idasanutlin in the relapsed or refractory AML population.
Therefore the study was prematurely terminated by the sponsor's decision and the result data did not derive.
Cycle 1: Within 2 Hr pre-cytarabine dose, end of 1-3 Hr cytarabine infusion, 6 Hr post idasanutlin morning dose on Days 1, 5; Within 2 Hr pre-cytarabine dose on Day 2; Cycle 2, 3: Within 2 Hr pre-cytarabine dose on Day 2 (Cycle length= 28 days)
Secondary Change From Baseline in European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) Score The compliance rate (defined as the number of patients who completed as least 1 question on the measure) at baseline was 56% and 61% for the Idasanutlin arm and the placebo arm, respectively. This compliance rate remained the same post-baseline in both arms. Due to the low compliance rates in both arms during the entire treatment period, the planned analyses were not performed. Cycle 1 Day 1 (Baseline), Days 8, 15, 28 of Cycle 1, Days 1, 8, 15, 28 of Cycles 2, 3, 28 days after last dose (last dose on Cycle 3 Day 5), thereafter every 3 months until relapse (maximum up to 3.5 years)
Secondary Change From Baseline in EuroQol 5 Dimension 5-Level (EQ-5D-5L) Questionnaire Score The compliance rate (defined as the number of patients who completed as least 1 question on the measure) at baseline was 56% and 61% for the Idasanutlin arm and the placebo arm, respectively. Compliance remained the same post-baseline in both arms Due to the low compliance rates in both arms during the entire treatment period, the planned analyses were not performed. Cycle 1 Day 1 (Baseline), Days 8, 15, 28 of Cycle 1, Days 1, 8, 15, 28 of Cycles 2, 3, 28 days after last dose (last dose on Cycle 3 Day 5), thereafter every 3 months until relapse (maximum up to 3.5 years)
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