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 : January 14, 2019

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Sponsor:

Information provided by (Responsible Party):

Hoffmann-La Roche

Study Description

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), 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.

Condition or disease	Intervention/treatment	Phase
Leukemia, Myeloid, Acute	Drug: Cytarabine Drug: Idasanutlin Other: Placebo	Phase 3

Study Design


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

Resource links provided by the National Library of Medicine

Genetics Home Reference related topics: Core binding factor acute myeloid leukemia Cytogenetically normal acute myeloid leukemia Familial acute myeloid leukemia with mutated CEBPA

MedlinePlus related topics: Acute Myeloid Leukemia Leukemia

Drug Information available for: Cytarabine

Genetic and Rare Diseases Information Center resources: Myeloid Leukemia Acute Myeloid Leukemia Acute Non Lymphoblastic Leukemia

U.S. FDA Resources

Arms and Interventions

Arm	Intervention/treatment
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.	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.	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.

Arm

Intervention/treatment

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.

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.

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.

Outcome Measures

Primary Outcome Measures :

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

Secondary Outcome Measures :

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) ]

Eligibility Criteria

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

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 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

Contacts and Locations

Information from the National Library of Medicine

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

Contacts


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

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Sponsors and Collaborators

Hoffmann-La Roche

Investigators


Study Director:	Clinical Trials	Hoffmann-La Roche

More Information


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:	January 14, 2019
Last Verified:	January 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

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