A Study of Idasanutlin With Cytarabine Versus Cytarabine Plus Placebo in Participants With Relapsed or Refractory Acute Myeloid Leukemia (AML)

• Register: ClinicalTrials.gov
• Last refreshed on: 27 December 2021
• Main ID: NCT02545283
• Date of registration: 31/08/2015
• Prospective Registration: Yes
• Primary sponsor: Hoffmann-La Roche
• Public title: A Study of Idasanutlin With Cytarabine Versus Cytarabine Plus Placebo in Participants With Relapsed or Refractory Acute Myeloid Leukemia (AML) MIRROS
• Scientific 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)
• Date of first enrolment: December 30, 2015
• Target sample size: 447
• Recruitment status: Terminated
• URL: https://clinicaltrials.gov/show/NCT02545283
• Study type: Interventional
• Study design: Allocation: Randomized. Intervention model: Parallel Assignment. Primary purpose: Treatment. Masking: Double (Participant, Investigator).
• Phase: Phase 3

Countries of recruitment

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

Contacts

• Name: Clinical Trials
• Affiliation: Hoffmann-La Roche

Key inclusion & exclusion 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 ( 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



Age minimum: 18 Years
Age maximum: N/A
Gender: All

Health Condition(s) or Problem(s) studied

Leukemia, Myeloid, Acute

Intervention(s)

Drug: Idasanutlin

Drug: Cytarabine

Other: Placebo

Primary Outcome(s)

Overall Survival in TP53 WT Population [Time Frame: From randomization to death from any cause (up to approximately 4.5 years)]

Secondary Outcome(s)

Change From Baseline in Body Temperature Over Time [Time Frame: Baseline; Cycles 1-3, Days 8, 15, 22, 28 (1 cycle is 28 days); and, if incomplete blood count recovery, Days 29-42 and Days 43-56, Cycles 2 -3 Days 1, 8, 15, 22, 28 and 29-56 (max delay between cycles is 56 days)]

Change From Baseline in Diastolic Blood Pressure Over Time [Time Frame: Baseline; Cycles 1-3, Days 8, 15, 22, 28 (1 cycle is 28 days); and, if incomplete blood count recovery, Days 29-42 and Days 43-56, Cycles 2 -3 Days 1, 8, 15, 22, 28 and 29-56 (max delay between cycles is 56 days)]

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)]

Percentage of Participants Undergoing HSCT Following Complete Response (CR), in TP53 WT Population [Time Frame: Baseline up to approximately 4.5 years]

Number of Participants With Adverse Events Leading to Discontinuation [Time Frame: Baseline up to approximately 4.5 years]

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)]

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)]

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 4.5 years)]

Change From Baseline in Respiratory Rate Over Time [Time Frame: Up to Approximately 4.5 Years]

Change From Baseline in Systolic Blood Pressure Over Time [Time Frame: Baseline; Cycles 1-3, Days 8, 15, 22, 28 (1 cycle is 28 days); and, if incomplete blood count recovery, Days 29-42 and Days 43-56, Cycles 2 -3 Days 1, 8, 15, 22, 28 and 29-56 (max delay between cycles is 56 days)]

Number of Participants With Clinical Laboratory Abnormalities in Biochemistry Tests at the Greatest Severity, According to NCI-CTCAE v4.03 [Time Frame: Up to Approximately 4.5 Years]

Number of Treatment Cycles Started [Time Frame: Up to 3 cycles (1 cycle is 28 days)]

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 4.5 years)]

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)]

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)]

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)]

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)]

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)]

Change From Baseline in Pulse Rate Over Time [Time Frame: Baseline; Cycles 1-3, Days 8, 15, 22, 28 (1 cycle is 28 days); and, if incomplete blood count recovery, Days 29-42 and Days 43-56, Cycles 2 -3 Days 1, 8, 15, 22, 28 and 29-56 (max delay between cycles is 56 days)]

Number of Participants With Adverse Events Leading to Death up to Day 60 [Time Frame: Up to Day 60]

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)]

Total Duration of Study Treatment [Time Frame: Up to 3 cycles (1 cycle is 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)]

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)]

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)]

Cumulative Dose of Idasanutlin and Cytarabine [Time Frame: Up to 3 cycles (1 cycle is 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)]

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)]

Number of Participants With Adverse Events Leading to Death up to Day 30 [Time Frame: Up to Day 30]

Number of Participants With Clinical Laboratory Abnormalities in Hematology Tests at the Greatest Severity, According to NCI-CTCAE v4.03 [Time Frame: Up to Approximately 4.5 Years]

Change From Baseline in Heart Rate, as Measured by Electrocardiogram [Time Frame: Baseline; Cycles 1-3 Day 1 (2 hrs pre-dose, post-Cytarabine and 6 hrs post-Idasanutlin/Placebo ); Cycle 1-3 Day 2; Cycle 1 Day 5 (within 2 hrs Idanasanutlin/Placebo, post-Cytarabine and 6 hrs post-Idasanutlin/Placebo), Study Drug Completion]

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 4.5 years)]

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)]

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 4.5 years]

Secondary ID(s)

2014-003065-15

WO29519

Source(s) of Monetary Support

Please refer to primary and secondary sponsors

Results

• Results available: Yes
• Date Posted: 14/09/2021
• URL: https://clinicaltrials.gov/ct2/show/results/NCT02545283