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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)

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ClinicalTrials.gov Identifier: NCT02545283
Recruitment Status : Recruiting
First Posted : September 9, 2015
Last Update Posted : February 11, 2019
Sponsor:
Information provided by (Responsible Party):
Hoffmann-La Roche

August 31, 2015
September 9, 2015
February 11, 2019
December 30, 2015
December 10, 2019   (Final data collection date for primary outcome measure)
Overall Survival in TP53 WT Population [ Time Frame: Baseline up to approximately 3.5 years ]
Overall Survival (OS) in TP53 Wild-Type Population [ Time Frame: From start of study up to 4.5 years ]
Complete list of historical versions of study NCT02545283 on ClinicalTrials.gov Archive Site
  • 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) ]
  • Overall Survival (OS) in the Overall Population [ Time Frame: From start of study up to 4.5 years ]
  • Percentage of Participants in Complete Remission with incomplete blood count recovery (CRi) [ Time Frame: From start of study up to 4.5 years ]
  • Overall Remission Rate (ORR), including CR, CRp and CRi [ Time Frame: From start of study up to 4.5 years ]
  • Event Free Survival (EFS) [ Time Frame: From start of study up to 4.5 years ]
  • Leukemia Free Survival (LFS) [ Time Frame: From start of study up to 4.5 years ]
  • Apparent Clearance (CL/F) of Idasanutlin [ Time Frame: Cycle 1 (28 Days) Days 1, 2, 5, 8 and 10 and Cycles 2 and 3 (28 Days) Days 2 and 5 ]
  • Apparent Volume of Distribution (Vd/F) of Idasanutlin [ Time Frame: Cycle 1 (28 Days) Days 1, 2, 5, 8 and 10 and Cycles 2 and 3 (28 Days) Days 2 and 5 ]
  • Maximum Concentration Observed (Cmax) of Idasanutlin [ Time Frame: Cycle 1 (28 Days) Days 1, 2, 5, 8 and 10 and Cycles 2 and 3 (28 Days) Days 2 and 5 ]
  • Steady-State Concentration (C trough) of Idasanutlin [ Time Frame: Cycle 1 (28 Days) Days 1, 2, 5, 8 and 10 and Cycles 2 and 3 (28 Days) Days 2 and 5 ]
  • Area Under the Concentration-Time Curve (AUC) of Idasanutlin [ Time Frame: Cycle 1 (28 Days) Days 1, 2, 5, 8 and 10 and Cycles 2 and 3 (28 Days) Days 2 and 5 ]
  • Half-Life (t 1/2) of Idasanutlin [ Time Frame: Cycle 1 (28 Days) Days 1, 2, 5, 8 and 10 and Cycles 2 and 3 (28 Days) Days 2 and 5 ]
  • Total clearance (CL) of Cytarabine [ Time Frame: Cycle 1 (28 Days) Days 1, 2 and 5 and Cycles 2 and 3 (28 Days) Day 2 ]
  • Volume of Distribution (Vd) of Cytarabine [ Time Frame: Cycle 1 (28 Days) Days 1, 2 and 5 and Cycles 2 and 3 (28 Days) Day 2 ]
  • Percentage of Participants with Hematopoietic Stem Cell Transplant (HSCT) Following Response [ Time Frame: From start of study up to 4.5 years ]
  • Percentage of Participants with Adverse Events [ Time Frame: From start of study up to 4.5 years ]
  • Percentage of Participants in Complete Remission with Incomplete Platelet Count Recovery (CRp) [ Time Frame: From start of study up to 4.5 years ]
  • Percentage of Participants in Complete Remission (CR) [ Time Frame: From start of study up to 4.5 years ]
  • Percentage of Participants With Clinically Significant Changes in Safety Measurements [ Time Frame: From start of study up to 4.5 years ]
  • Score in Patient-Reported Outcome (PRO) Measures [ Time Frame: From start of study up to 4.5 years ]
Not Provided
Not Provided
 
A Study of Idasanutlin With Cytarabine Versus Cytarabine Plus Placebo in Participants With Relapsed or Refractory Acute Myeloid Leukemia (AML)
A Multicenter, Double-Blind, Randomized, Placebo-Controlled, Phase III Study of Idasanutlin, an MDM2 Antagonist, With Cytarabine Versus Cytarabine Plus Placebo in Patients With Relapsed or Refractory Acute Myeloid Leukemia (AML)
This is a multicenter, double-blind, randomized, placebo-controlled study designed to compare overall survival in participants with relapsed or refractory AML treated with idasanutlin in combination with cytarabine versus participants treated with placebo and cytarabine. Participants will receive induction treatment with idasanutlin/placebo and cytarabine (Cycle 1). Responding participants may continue to receive a maximum of further two cycles of consolidation (Cycle 2 and Cycle 3). Complete remission (CR), CR with incomplete platelet count recovery (CRp), overall remission rate (ORR), event-free survival (EFS), 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.
Not Provided
Interventional
Phase 3
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Leukemia, Myeloid, Acute
  • Drug: Cytarabine
    Participants will receive cytarabine 1 gram per square meter (g/m^2) intravenous (IV) infusion for 5 days of every treatment cycle.
  • Drug: Idasanutlin
    Participants will receive idasanutlin 300 mg per oral (PO) twice daily (BID) (in Cycle 1) or once daily (QD) (in Cycles 2 and 3) for 5 days of every treatment cycle.
  • Other: Placebo
    Participants will receive idasanutlin matching placebo PO BID or QD for 5 days of every treatment cycle.
  • 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
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
440
Same as current
May 26, 2021
December 10, 2019   (Final data collection date for primary outcome measure)

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 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)

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 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
Sexes Eligible for Study: All
18 Years and older   (Adult, Older Adult)
No
Contact: Reference Study ID Number: WO29519 www.roche.com/about_roche/roche_worldwide.htm 888-662-6728 (U.S. and Canada) global-roche-genentech-trials@gene.com
Australia,   Austria,   Belgium,   Canada,   Finland,   France,   Germany,   Israel,   Italy,   Korea, Republic of,   Netherlands,   New Zealand,   Norway,   Panama,   Russian Federation,   Spain,   Switzerland,   United Kingdom,   United States
 
 
NCT02545283
WO29519
2014-003065-15 ( EudraCT Number )
Yes
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Not Provided
Hoffmann-La Roche
Hoffmann-La Roche
Not Provided
Study Director: Clinical Trials Hoffmann-La Roche
Hoffmann-La Roche
February 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP