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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 : Terminated (The study was stopped for futility based on efficacy results at the interim analysis; no unexpected safety findings were observed.)
First Posted : September 9, 2015
Last Update Posted : May 27, 2020
Sponsor:
Information provided by (Responsible Party):
Hoffmann-La Roche

Study Description
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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.

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

Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 447 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
Actual Primary Completion Date : November 1, 2019
Actual Study Completion Date : April 24, 2020

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Drug Information available for: Cytarabine

Arms and Interventions
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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.
Other Name: RG7388
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
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Primary Outcome Measures :
  1. Overall Survival in TP53 WT Population [ Time Frame: From randomization to death from any cause (up to approximately 5.5 years) ]

Secondary Outcome Measures :
  1. Percentage of Participants in Complete Response (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) ]
  2. Event-Free Survival (EFS) According to HMRA in TP53 WT Population [ Time Frame: From randomization up to treatment failure, relapse, or death from any cause (up to approximately 5.5 years) ]
  3. Percentage of Participants with Overall Remission (CR, CRp, and CRi) at the End of Induction According to HMRA in TP53 WT Population [ Time Frame: At the end of induction (up to Day 56) ]
  4. Duration of Remission Following CR (DOR) in TP53 WT Population [ Time Frame: From achieving CR until relapse or death from any cause (up to approximately 5.5 years) ]
  5. Percentage of Participants Undergoing HSCT Following Complete Response (CR), in TP53 WT Population [ Time Frame: Baseline up to approximately 5.5 years ]
  6. Percentage of Participants with Complete Response (CR) in Clinically Actionable Mutation-Defined Subpopulation (FLT3, IDH1 and IDH2) in TP53 WT Population [ Time Frame: At the end of induction (up to Day 56) ]
  7. Overall Survival in Clinically Actionable Mutation-Defined Subpopulation (FLT3, IDH1 and IDH2) in TP53 WT Population [ Time Frame: From randomization to death from any cause (up to approximately 5.5 years) ]
  8. 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) [ Time Frame: Baseline up to approximately 5.5 years ]
  9. Number of Participants with Adverse Events Leading to Discontinuation [ Time Frame: Baseline up to approximately 5.5 years ]
  10. Number of Participants with Adverse Events Leading to Death up to Day 30 [ Time Frame: Up to Day 30 ]
  11. Number of Participants with Adverse Events Leading to Death up to Day 60 [ Time Frame: Up to Day 60 ]
  12. Number of Participants with Clinical Laboratory Abnormalities in Biochemistry Tests at the Greatest Severity, According to NCI-CTCAE v4.03 [ Time Frame: Baseline; Cycles 1-3 Days 1, 2, 8, 15, 22, and 28 (1 cycle is 28 days); and, if incomplete blood count recovery, Cycle 1 Days 29-42, Days 43-56, Cycles 2 and 3 Days 29-56 (max delay between cycles is 56 days) ]
    Laboratory parameters for blood biochemistry will be measured and compared with a standard reference range. Values outside the standard reference range are considered abnormalities. Not every laboratory abnormality qualifies as an adverse event. A laboratory test result will be reported as an adverse event if it meets any of the following criteria: is accompanied by clinical symptoms; results in a change in study treatment or a medical intervention; or is clinically significant in the investigator's judgment.

  13. Number of Participants with Clinical Laboratory Abnormalities in Hematology Tests at the Greatest Severity, According to NCI-CTCAE v4.03 [ Time Frame: Baseline; Cycles 1-3 Days 1, 2, 8, 15, 22, and 28 (1 cycle is 28 days); and, 30 Days after CR or CRp in Cycle 1, or if incomplete blood count recovery, Cycle 1 Days 29-42, Days 43-56, Cycles 2 and 3 Days 29-56 (max delay between cycles is 56 days) ]
    Laboratory parameters for hematology will be measured and compared with a standard reference range. Values outside the standard reference range are considered abnormalities. Not every laboratory abnormality qualifies as an adverse event. A laboratory test result will be reported as an adverse event if it meets any of the following criteria: is accompanied by clinical symptoms; results in a change in study treatment or a medical intervention; or is clinically significant in the investigator's judgment.

  14. Body Temperature Over Time [ Time Frame: Baseline; Cycles 1-3 Days 1, 8, 15, 22, and 28 (1 cycle is 28 days); and, if incomplete blood count recovery, Cycle 1 Days 29-42, Days 43-56, Cycles 2 and 3 Days 29-56 (max delay between cycles is 56 days) ]
  15. Systolic Blood Pressure Over Time [ Time Frame: Baseline; Cycles 1-3 Days 1, 8, 15, 22, and 28 (1 cycle is 28 days); and, if incomplete blood count recovery, Cycle 1 Days 29-42, Days 43-56, Cycles 2 and 3 Days 29-56 (max delay between cycles is 56 days) ]
  16. Diastolic Blood Pressure Over Time [ Time Frame: Baseline; Cycles 1-3 Days 1, 8, 15, 22, and 28 (1 cycle is 28 days); and, if incomplete blood count recovery, Cycle 1 Days 29-42, Days 43-56, Cycles 2 and 3 Days 29-56 (max delay between cycles is 56 days) ]
  17. Pulse Rate Over Time [ Time Frame: Baseline; Cycles 1-3 Days 1, 8, 15, 22, and 28 (1 cycle is 28 days); and, if incomplete blood count recovery, Cycle 1 Days 29-42, Days 43-56, Cycles 2 and 3 Days 29-56 (max delay between cycles is 56 days) ]
  18. Respiratory Rate Over Time [ Time Frame: Baseline; Cycles 1-3 Days 1, 8, 15, 22, and 28 (1 cycle is 28 days); and, if incomplete blood count recovery, Cycle 1 Days 29-42, Days 43-56, Cycles 2 and 3 Days 29-56 (max delay between cycles is 56 days) ]
  19. Change from Baseline in Heart Rate, as Measured by Electrocardiogram [ Time Frame: 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) ]
  20. Change from Baseline in Electrocardiogram Parameters: PQ, PR, RR, QRS, QT and QTcF Intervals [ Time Frame: 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) ]
  21. Total Duration of Study Treatment [ Time Frame: Up to 3 cycles (1 cycle is 28 days) ]
  22. Number of Treatment Cycles Started [ Time Frame: Up to 3 cycles (1 cycle is 28 days) ]
  23. Cumulative Dose of Idasanutlin and Cytarabine [ Time Frame: Up to 3 cycles (1 cycle is 28 days) ]
  24. 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) ]
  25. 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) ]
  26. 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) ]
  27. Steady-State Concentration (Ctrough) 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) ]
  28. 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) ]
  29. 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) ]
  30. 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) ]
  31. 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) ]
  32. 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) ]
  33. 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) ]
  34. 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 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
Contacts and Locations
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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


Locations
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Sponsors and Collaborators
Hoffmann-La Roche
Investigators
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Study Director: Clinical Trials Hoffmann-La Roche
More Information
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Responsible Party: Hoffmann-La Roche
ClinicalTrials.gov Identifier: NCT02545283    
Other Study ID Numbers: WO29519
2014-003065-15 ( EudraCT Number )
First Posted: September 9, 2015    Key Record Dates
Last Update Posted: May 27, 2020
Last Verified: May 2020

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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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