Etude : MIRROS / WO29519



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Acronyme
Nom
Traitement
Type d'étude
MÀJ
Présentation de l'étude
Acronyme : MIRROS

Nom : WO29519

Traitement :

Type d'étude : Hors ciblage moléculaire

Dernière MÀJ : 03/09/2019
Titre
Spécialité(s)
CIM10 - Localisation(s)
Informations principales
Titre : 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)

Spécialité : Tissus lymphoïde, hématopoïétique et apparentés
Localisation : C92 - Leucémie myéloïde
Schéma
Phase
Stade
Ligne(s)
Informations complémentaires
Schéma : 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), leukemia-free survival (LFS) and percentage of participants with an allogeneic hematopoietic stem cell transplant (HSCT) will also be compared between treatment arms. This study will include participants with and without TP53 wild type (TP53 WT) mutations.

Study Arms:
- Experimental: Idasanutlin plus Cytarabine
Participants will receive induction therapy idasanutlin and cytarabine for 5 days followed by 23 days of rest in Cycle 1 (treatment cycle length=28 days). Responding participants may continue with consolidation therapy for a maximum of 2 additional cycles including idasanutlin and cytarabine for 5 days followed by 23 days of rest in each cycle (treatment cycle length=28 days). After each cycle, for participants achieving CRp or complete remission with incomplete blood count recovery (CRi), up to 28 additional days are allowed for blood count recovery, if needed.
Interventions:
Drug: Cytarabine
Drug: Idasanutlin
- Placebo Comparator: Placebo plus Cytarabine
Participants will receive induction therapy idasanutlin matching placebo and cytarabine for 5 days followed by 23 days of rest in Cycle 1 (treatment cycle length=28 days). Responding participants may continue with consolidation therapy for a maximum of 2 additional cycles including idasanutlin matching placebo and cytarabine for 5 days followed by 23 days of rest in each cycle (treatment cycle length=28 days). After each cycle, for participants achieving CRp or CRi, up to 28 additional days are allowed for blood count recovery, if needed.
Interventions:
Drug: Cytarabine
Other: Placebo

Current Primary outcome:
Overall Survival in TP53 WT Population [ Time Frame: Baseline up to approximately 3.5 years ]

Current secondary outcomes:
- Overall Survival in the Overall Population [ Time Frame: Baseline up to approximately 3.5 years ]
- Percentage of Participants in CR at the End of Induction According to Hematologic Malignancy Response Assessment (HMRA) in TP53 WT Population [ Time Frame: At the end of induction (up to Day 56) ]
- Percentage of Participants in CRp at the End of Induction According to HMRA in TP53 WT Population [ Time Frame: At the end of induction (up to Day 56) ]
- Percentage of Participants with Overall Remission at the End of Induction According to HMRA in TP53 WT Population [ Time Frame: At the end of induction (up to Day 56) ]
- EFS According to HMRA in TP53 WT Population [ Time Frame: Baseline up to treatment failure, relapse or death from any cause (up to approximately 3.5 years) ]
- LFS According to HMRA in TP53 WT Population [ Time Frame: Date of remission to date of relapse or death (up to approximately 3.5 years) ]
- Percentage of Participants Undergoing HSCT Following Response, in TP53 WT Population [ Time Frame: Baseline up to approximately 3.5 years ]
- Percentage of Participants in CR at the End of Induction According to HMRA in Overall Population [ Time Frame: At the end of induction (up to Day 56) ]
- Percentage of Participants in CRp at the End of Induction According to HMRA in Overall Population [ Time Frame: At the end of induction (up to Day 56) ]
- Percentage of Participants with Overall Remission at the End of Infusion According to HMRA in Overall Population [ Time Frame: At the end of induction (up to Day 56) ]
- EFS According to HMRA in Overall Population [ Time Frame: Baseline up to treatment failure, relapse or death from any cause (up to approximately 3.5 years) ]
- LFS According to HMRA in Overall Population [ Time Frame: Date of remission to date of relapse or death (up to approximately 3.5 years) ]
- Percentage of Participants Undergoing HSCT Following Response, in Overall Population [ Time Frame: Baseline up to approximately 3.5 years ]
- Apparent Clearance (CL/F) of Idasanutlin [ 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) ]
- Apparent Volume of Distribution (Vd/F) of Idasanutlin [ 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) ]
- Maximum Concentration Observed (Cmax) of Idasanutlin [ 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) ]
- Steady-State Concentration (C trough) of Idasanutlin [ 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) ]
- Area Under the Concentration-Time Curve (AUC) During One Dosing Interval (AUCtau) of Idasanutlin [ 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) ]
- AUC from Time Zero to 24 Hours Post Dose (AUC0-24) of Idasanutlin [ 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) ]
- Half-Life (t 1/2) of Idasanutlin [ 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) ]
- Total Clearance (CL) of Cytarabine [ 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) ]
- Volume of Distribution (Vd) of Cytarabine [ 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) ]
- Percentage of Participants with Adverse Events [ Time Frame: Baseline up to approximately 3.5 years ]
- Change from Baseline in European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) Score [ 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) ]
- Change from Baseline in EuroQol 5 Dimension 5-Level (EQ-5D-5L) Questionnaire Score [ 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) ]

Phase : III

Stade : NA

NA
Informations libres de droit
Critères d'inclusion
Critères de non-inclusion
Informations libres de droit
Critères d'inclusion et de non-inclusion
Critères d'inclusion : - 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 1
- Adequate hepatic and renal function
- White blood cell (WBC) count at randomization less than or equal to (=) 50000 cells per cubic millimeter (/mm^3)

Critères de non-inclusion : - 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 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
- 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
NCT
Promoteur
Coordonnateur
Informations relatives au promoteur
NCT :
NCT02545283
Promoteur :
HOFFMANN-LA ROCHE
Type de sponsor : Industriel
00000 HORS FRANCE

Coordonnateur :
Centre investigateur
Investigateur
TEC / ARC / IDE
État
MÀJ
Informations relatives aux investigateurs
Centre investigateur :
Centre Hospitalier Universitaire de Lille - 2 Avenue Oscar Lambret - 59000 LILLE

Investigateur :
Professeur Bruno QUESNEL

TEC / ARC / IDE :
Secrétariat de recherche
fanny.miquel@
chru-lille.fr
03.20.44.57.13

Ouverture de l'essai : OUVERT

MAJ : 17/05/2019