Clinical trial NCT02545283: A Study of Idasanutlin With Cytarabine Versus Cytarabine Plus Placebo in Participants With Relapsed or Refractory Acute Myeloid Leukemia (AML)
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
Overall status: TERMINATED
Phase: PHASE3
Conditions: Leukemia, Myeloid, Acute
Lead sponsor: Hoffmann-La Roche
Sponsor class: INDUSTRY
First posted: 2015-09-09
Enrollment: 447
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


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

Primary outcomes:
measure: Overall Survival in TP53 WT Population
timeFrame: From randomization to death from any cause (up to approximately 4.5 years)
Secondary outcomes:
measure: Percentage of Participants in Complete Response (CR) at the End of Induction According to Hematologic Malignancy Response Assessment (HMRA) in TP53 WT Population
timeFrame: At the end of induction (up to Day 56)
measure: Event-Free Survival (EFS) According to HMRA in TP53 WT Population
timeFrame: From randomization up to treatment failure, relapse, or death from any cause (up to approximately 4.5 years)
measure: Percentage of Participants With Overall Remission (CR, CRp, and CRi) at the End of Induction According to HMRA in TP53 WT Population
timeFrame: At the end of induction (up to Day 56)
measure: Duration of Remission Following CR (DOR) in TP53 WT Population
timeFrame: From achieving CR until relapse or death from any cause (up to approximately 4.5 years)
measure: Percentage of Participants Undergoing HSCT Following Complete Response (CR), in TP53 WT Population
timeFrame: Baseline up to approximately 4.5 years
measure: Percentage of Participants With Complete Response (CR) in Clinically Actionable Mutation-Defined Subpopulation (FLT3, IDH1 and IDH2) in TP53 WT Population
timeFrame: At the end of induction (up to Day 56)
measure: Overall Survival in Clinically Actionable Mutation-Defined Subpopulation (FLT3, IDH1 and IDH2) in TP53 WT Population
timeFrame: From randomization to death from any cause (up to approximately 4.5 years)
measure: 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)
timeFrame: Baseline up to approximately 4.5 years
measure: Number of Participants With Adverse Events Leading to Discontinuation
timeFrame: Baseline up to approximately 4.5 years
measure: Number of Participants With Adverse Events Leading to Death up to Day 30
timeFrame: Up to Day 30
measure: Number of Participants With Adverse Events Leading to Death up to Day 60
timeFrame: Up to Day 60
measure: Number of Participants With Clinical Laboratory Abnormalities in Biochemistry Tests at the Greatest Severity, According to NCI-CTCAE v4.03
timeFrame: Up to Approximately 4.5 Years
measure: Number of Participants With Clinical Laboratory Abnormalities in Hematology Tests at the Greatest Severity, According to NCI-CTCAE v4.03
timeFrame: Up to Approximately 4.5 Years
measure: Change From Baseline in Body Temperature Over Time
timeFrame: 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)
measure: Change From Baseline in Systolic Blood Pressure Over Time
timeFrame: 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)
measure: Change From Baseline in Diastolic Blood Pressure Over Time
timeFrame: 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)
measure: Change From Baseline in Pulse Rate Over Time
timeFrame: 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)
measure: Change From Baseline in Respiratory Rate Over Time
timeFrame: Up to Approximately 4.5 Years
measure: Change From Baseline in Heart Rate, as Measured by Electrocardiogram
timeFrame: 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
measure: Change From Baseline in Electrocardiogram Parameters: PQ, PR, RR, QRS, QT and QTcF Intervals
timeFrame: 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)
measure: Total Duration of Study Treatment
timeFrame: Up to 3 cycles (1 cycle is 28 days)
measure: Number of Treatment Cycles Started
timeFrame: Up to 3 cycles (1 cycle is 28 days)
measure: Cumulative Dose of Idasanutlin and Cytarabine
timeFrame: Up to 3 cycles (1 cycle is 28 days)
measure: Apparent Clearance (CL/F) of Idasanutlin
timeFrame: 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)
measure: Apparent Volume of Distribution (Vd/F) of Idasanutlin
timeFrame: 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)
measure: Maximum Concentration Observed (Cmax) of Idasanutlin
timeFrame: 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)
measure: Steady-State Concentration (Ctrough) of Idasanutlin
timeFrame: 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)
measure: Area Under the Concentration-Time Curve (AUC) During One Dosing Interval (AUCtau) of Idasanutlin
timeFrame: 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)
measure: AUC From Time Zero to 24 Hours Post Dose (AUC0-24) of Idasanutlin
timeFrame: 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)
measure: Half-Life (t 1/2) of Idasanutlin
timeFrame: 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)
measure: Total Clearance (CL) of Cytarabine
timeFrame: 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)
measure: Volume of Distribution (Vd) of Cytarabine
timeFrame: 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)
measure: Change From Baseline in European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) Score
timeFrame: 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)
measure: Change From Baseline in EuroQol 5 Dimension 5-Level (EQ-5D-5L) Questionnaire Score
timeFrame: 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)
Other outcomes:
Locations:
city: Great Neck
country: United States
facility: Northwell Health
state: New York
city: Hawthorne
country: United States
facility: New York Medical College
state: New York
city: New York
country: United States
facility: Ichan School of Medicine at Mount Sinai
state: New York
city: Philadelphia
country: United States
facility: Abramson Cancer Center; Univ of Pennsylvania
state: Pennsylvania
city: Philadelphia
country: United States
facility: Thomas Jefferson University
state: Pennsylvania
city: Dallas
country: United States
facility: Baylor University Medical Center
state: Texas
city: Houston
country: United States
facility: M.D. Anderson Cancer Center; Department of Hematology
state: Texas
city: Canberra
country: Australia
facility: Canberra Hospital; Haematology Department
state: Australian Capital Territory
city: Sydney
country: Australia
facility: Concord Repatriation General Hospital; Haematology
state: New South Wales
city: Adelaide
country: Australia
facility: Royal Adelaide Hospital; Haematology Clinical Trials
state: South Australia
city: Geelong
country: Australia
facility: Geelong Hospital; Andrew Love Cancer Centre
state: Victoria
city: Melbourne
country: Australia
facility: Alfred Hospital; Clinical Haematology and Bone Marrow Transplantation
state: Victoria
city: Graz
country: Austria
facility: Lkh-Univ. Klinikum Graz; Klin. Abt. Für Hämatologie
city: Haine-Saint-Paul
country: Belgium
facility: CH Jolimont - Lobbes (Jolimont)
city: Liège
country: Belgium
facility: CHU Sart-Tilman
city: Roeselare
country: Belgium
facility: AZ Delta (Campus Rumbeke)
city: Hamilton
country: Canada
facility: Juravinski Cancer Clinic; Clinical Trials Department
state: Ontario
city: Helsinki
country: Finland
facility: Helsinki University Central Hospital; Hematology
city: Tampere
country: Finland
facility: Tampere University Hospital; Hematology
city: Angers Cedex 9
country: France
facility: Centre Hospitalier Uni Ire; Service Des Maladies Du Sang
city: Lille
country: France
facility: Hopital Claude Huriez; Hematologie
city: Marseille
country: France
facility: Institut J Paoli I Calmettes; Onco Hematologie 2
city: Nantes
country: France
facility: Hopital Hotel Dieu Et Hme;Hopital De Jour
city: Paris
country: France
facility: Hopital Saint Louis; Oncologie Medicale
city: Paris
country: France
facility: HOPITAL SAINT ANTOINE;Hematologie Clinique
city: Pessac
country: France
facility: Hopital De Haut Leveque; Hematologie Clinique
city: Pierre Benite
country: France
facility: Centre Hospitalier Lyon Sud; Hematolgie
city: Toulouse
country: France
facility: IUCT Oncopole; Hematologie
city: Vandoeuvre Les Nancy
country: France
facility: Hopitaux De Brabois; Hematologie Medecine Interne
city: Aachen
country: Germany
facility: Uniklinik RWTH Aachen; Klinik IV; Klinik Hämatologie, Onkologie, Hämostaseologie und Stamm.
city: Bonn
country: Germany
facility: Universitätsklinikum Bonn; Med. Klinik und Poliklinik III; Hämatologie, Onkologie und Rheumatologie
city: Braunschweig
country: Germany
facility: Klinikum Braunschweig; Medizinische Klinik III; Klinik für Hämatologie und Onkologie
city: Chemnitz
country: Germany
facility: Klinikum Chemnitz gGmbH Krankenhaus Küchwald Klinik f.Innere Medizin III
city: Dresden
country: Germany
facility: Universitätsklinikum "Carl Gustav Carus"; Medizinische Klinik und Poliklinik I
city: Hannover
country: Germany
facility: Medizinische Hochschule Hannover; Zentrum Innere Medizin; Abt. Hämatologie u. Onkologie
city: Köln
country: Germany
facility: Klinik der Uni zu Köln; I. Med. Klinik
city: Mainz
country: Germany
facility: Uni. der Johannes Gutenberg-Universitaet Mainz; III. Medizinische Klinik und Poliklinik
city: Marburg
country: Germany
facility: Universitätsklinikum Marburg Zentrum f. Innere Medizin
city: Jerusalem
country: Israel
facility: Shaare Zedek Medical Center; Hematology Dept.
city: Jerusalem
country: Israel
facility: Hadassah Ein Karem Hospital; Haematology
city: Petach Tikva
country: Israel
facility: Rabin Medical Center-Beilinson Campus;Hematology-Oncology
city: Tel Aviv
country: Israel
facility: Ichilov Sourasky Medical Center; Heamatology
city: Napoli
country: Italy
facility: Ospedale Cardarelli; Divisione Di Ematologia
state: Campania
city: Bologna
country: Italy
facility: Az. Osp. S. Orsola Malpighi; Istituto Di Oncologia Seragnoli
state: Emilia-Romagna
city: Meldola
country: Italy
facility: Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST); Onco-Ematologia
state: Emilia-Romagna
city: Ravenna
country: Italy
facility: Az. Osp. S. Maria Delle Croci; U.O. Di Ematologia
state: Emilia-Romagna
city: Udine
country: Italy
facility: A.O. Universitaria S. Maria Della Misericordia Di Udine; Oncologia; Clinica Ematologica
state: Friuli-Venezia Giulia
city: Roma
country: Italy
facility: Az. Osp. Uni Ria Policlinico Tor Vergata; Unita Di Ematologia
state: Lazio
city: Genova
country: Italy
facility: IRCCS AOU S.Martino; Clinica Ematologica
state: Liguria
city: Bergamo
country: Italy
facility: ASST PAPA GIOVANNI XXIII; Ematologia
state: Lombardia
city: Milano
country: Italy
facility: Ospedale San Raffaele, IRCCS
state: Lombardia
city: Milano
country: Italy
facility: Asst Grande Ospedale Metropolitano Niguarda; Dipartimento Di Ematologia Ed Oncologia
state: Lombardia
city: Orbassano (TO)
country: Italy
facility: A.O. Universitaria San Luigi Gonzaga di Orbassano; Ambulatorio per le Malattie Rare del Polmone
state: Piemonte
city: Torino
country: Italy
facility: A.O.U. Citta' Della Salute E Della Scienza-P.O. Molinette;S.C. Ematologia
state: Piemonte
city: Firenze
country: Italy
facility: Az. Osp. Di Careggi; Divisione Di Ematologia
state: Toscana
city: Pisa
country: Italy
facility: Ospedale Santa Chiara; Unita Operativa Di Ematologia
state: Toscana
city: Busan
country: Korea, Republic of
facility: Pusan National University Hospital
city: Jeollanam-do
country: Korea, Republic of
facility: Chonnam National University Hwasun Hospital
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center
city: Seoul
country: Korea, Republic of
facility: Seoul St Mary's Hospital
city: Amsterdam
country: Netherlands
facility: Academisch Medisch Centrum; Hematologie
city: Maastricht
country: Netherlands
facility: Academisch Ziekenhuis Maastricht
city: Auckland
country: New Zealand
facility: Auckland city hospital; Auckland Regional Cancer Centre and Blood Service
city: Bergen
country: Norway
facility: Haukeland Universitetssjukehus; Klinisk forskningspost
city: Oslo
country: Norway
facility: Oslo Universitetssykehus HF, Rikshospitalet
city: Panama City
country: Panama
facility: Complejo Hospitalario Arnulfo Arias Madrid; Servicio de Hematología
city: Moscow
country: Russian Federation
facility: "Hematological Scientific Center
city: Saint-Petersburg
country: Russian Federation
facility: St. Petersburg State Medical University n.a. I.P. Pavlov; Hematology, transfusiology and transplanta
city: Sankt-Petersburg
country: Russian Federation
facility: FGBU "Federal Medical and Research Center named after V.A.Almazov" Russian Ministry of Health
city: Barcelona
country: Spain
facility: Hospital de la Santa Creu i Sant Pau; Servicio de Hematologia
city: Barcelona
country: Spain
facility: Hospital Clínic i Provincial; Servicio de Hematología y Oncología
city: Madrid
country: Spain
facility: Hospital Univ. 12 de Octubre; Servicio de Hematologia
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen del Rocio
city: Valencia
country: Spain
facility: Hospital Universitario la Fe; Servicio de Hematologia
city: Basel
country: Switzerland
facility: Universitätsspital Basel; Hämatologie
city: Zürich
country: Switzerland
facility: Universitätsspital Zürich Medizin Hämatologie; Klinik für Hämatologie
city: Birmingham
country: United Kingdom
facility: Birmingham Heartlands Hospital
city: Cardiff
country: United Kingdom
facility: University Hospital of Wales
city: London
country: United Kingdom
facility: St Bartholomew's Hospital
city: Manchester
country: United Kingdom
facility: Christie Hospital NHS Trust
city: Sutton
country: United Kingdom
facility: Royal Marsden NHS Foundation Trust
Study officials:
affiliation: Hoffmann-La Roche
name: Clinical Trials
role: STUDY_DIRECTOR
References:
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.