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
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Condition or disease | Intervention/treatment | Phase |
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Leukemia, Myeloid, Acute | Drug: Cytarabine Drug: Idasanutlin Other: Placebo | Phase 3 |
Study Type : | Interventional (Clinical Trial) |
Estimated Enrollment : | 440 participants |
Allocation: | Randomized |
Intervention Model: | Parallel Assignment |
Masking: | Double (Participant, Investigator) |
Primary Purpose: | Treatment |
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) |
Actual Study Start Date : | December 30, 2015 |
Estimated Primary Completion Date : | December 10, 2019 |
Estimated Study Completion Date : | May 26, 2021 |

Arm | Intervention/treatment |
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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.
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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. |
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.
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Drug: Cytarabine
Participants will receive cytarabine 1 gram per square meter (g/m^2) intravenous (IV) infusion 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. |
- Overall Survival in TP53 WT Population [ Time Frame: Baseline up to approximately 3.5 years ]
- 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) ]

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Ages Eligible for Study: | 18 Years and older (Adult, Older Adult) |
Sexes Eligible for Study: | All |
Accepts Healthy Volunteers: | No |
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

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02545283
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 |

Study Director: | Clinical Trials | Hoffmann-La Roche |
Responsible Party: | Hoffmann-La Roche |
ClinicalTrials.gov Identifier: | NCT02545283 History of Changes |
Other Study ID Numbers: |
WO29519 2014-003065-15 ( EudraCT Number ) |
First Posted: | September 9, 2015 Key Record Dates |
Last Update Posted: | February 11, 2019 |
Last Verified: | February 2019 |
Studies a U.S. FDA-regulated Drug Product: | Yes | |
Studies a U.S. FDA-regulated Device Product: | No |
Additional relevant MeSH terms:
Leukemia Leukemia, Myeloid Leukemia, Myeloid, Acute Neoplasms by Histologic Type Neoplasms Cytarabine Antimetabolites, Antineoplastic Antimetabolites |
Molecular Mechanisms of Pharmacological Action Antineoplastic Agents Antiviral Agents Anti-Infective Agents Immunosuppressive Agents Immunologic Factors Physiological Effects of Drugs |