NCT02545283: MIRROS

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

Terminated Phase 3 Results posted Last updated 11 January 2022

What this trial tests

Phase 3 trial testing Cytarabine in Leukemia, Myeloid, Acute in 447 participants. Terminated before completion.

Timeline

30 December 2015

Primary endpoint
24 April 2020

24 April 2020

Quick facts

Lead sponsor	Hoffmann-La Roche
Phase	Phase 3
Status	Terminated
Study type	INTERVENTIONAL
Allocation	randomized
Design	parallel
Masking	double
Primary purpose	treatment
Enrollment	447
Start date	30 December 2015
Primary completion	24 April 2020
Estimated completion	24 April 2020
Sites	82 locations across Italy, Panama, Finland, South Korea, New Zealand, Netherlands, Russia, Belgium

Drugs / interventions tested

• Cytarabine — full drug profile →
• Idasanutlin — full drug profile →
• Placebo

Conditions studied

• Leukemia, Myeloid, Acute — all drugs for Leukemia, Myeloid, Acute →

Sponsor

Hoffmann-La Roche — full company profile →

Who can join

18 and older, any sex, with Leukemia, Myeloid, Acute. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Overall Survival in TP53 WT Population Primary · From randomization to death from any cause (up to approximately 4.5 years)

P53 tumor protein Wild Type (TP53 WT) population's Overall Survival was compared in participants with relapsed or refractory (R/R) acute myeloid leukemia (AML) who had been randomized to idasanutlin in combination with cytarabine versus those who had been randomized to cytarabine and placebo. The study was terminated because of futility, therefore did not reach the planned end of the study.

Group	Value	95% CI
Placebo Plus Cytarabine	9.13	7.59 – 10.64
Idasanutlin Plus Cytarabine	8.28	6.67 – 10.87

Percentage of Participants in Complete Response (CR) at the End of Induction According to Hematologic Malignancy Response Assessment (HMRA) in TP53 WT Population Secondary · At the end of induction (up to Day 56)

Rate of complete response at the end of induction in the TP53 WT population was compared in participants who had been randomized to idasanutlin in combination with cytarabine versus those who had been randomized to cytarabine and placebo. The design followed a hierarchical statistical testing framework.

Group	Value	95% CI
Placebo Plus Cytarabine	20.3
Idasanutlin Plus Cytarabine	17.1

Event-Free Survival (EFS) According to HMRA in TP53 WT Population Secondary · From randomization up to treatment failure, relapse, or death from any cause (up to approximately 4.5 years)

Event Free Survival (EFS) is defined as the time from the date of randomization to whichever occurs first: treatment failure (failure to achieve CR, set as day of final response assessment), relapse from CR, or death from any cause. The study was terminated because of futility, therefore did not reach the planned end of the study. The design followed a hierarchical statistical testing framework.

Group	Value	95% CI
Placebo Plus Cytarabine	6.29	5.86 – 8.00
Idasanutlin Plus Cytarabine	4.36	4.14 – 5.00

Percentage of Participants With Overall Remission (CR, CRp, and CRi) at the End of Induction According to HMRA in TP53 WT Population Secondary · At the end of induction (up to Day 56)

Rate of overall remission (complete remission, complete remission with incomplete hematologic recovery, complete remission with incomplete platelet count recovery) at the end of induction in the TP53 WT population was compared in participants who had been randomized to idasanutlin in combination with cytarabine versus those who had been randomized to cytarabine and placebo. The design followed a hierarchical statistical testing framework.

Group	Value	95% CI
Placebo Plus Cytarabine	38.8
Idasanutlin Plus Cytarabine	22.0

Duration of Remission Following CR (DOR) in TP53 WT Population Secondary · From achieving CR until relapse or death from any cause (up to approximately 4.5 years)

DOR is defined for patients achieving complete remission and is the time from clinical remission until relapse or death from any cause, whichever occurs first. For patients with none of these events before time of analysis, DOR is censored at the date of the patient's last response assessment. The Median upper limits were set to 999 because they were not reached and therefore it was Not Evaluable (NE) and the field is numeric only. The study was terminated because of futility, therefore did not reach the planned end of the study.

Group	Value	95% CI
Placebo Plus Cytarabine	18.73	5.26 – NA
Idasanutlin Plus Cytarabine	16.76	7.82 – NA

Percentage of Participants Undergoing HSCT Following Complete Response (CR), in TP53 WT Population Secondary · Baseline up to approximately 4.5 years

Rate of complete response at the end of induction in mutation-defined subgroups (positive for mutation of FLT3, IDH1 and IDH2, respectively) of the TP53 WT population was compared in participants who had been randomized to idasanutlin in combination with cytarabine versus those who had been randomized to cytarabine and placebo. The study was terminated because of futility, therefore did not reach the planned end of the study.

Group	Value	95% CI
Placebo Plus Cytarabine	10.6
Idasanutlin Plus Cytarabine	11.6

Percentage of Participants With Complete Response (CR) in Clinically Actionable Mutation-Defined Subpopulation (FLT3, IDH1 and IDH2) in TP53 WT Population Secondary · At the end of induction (up to Day 56)

Rate of complete response at the end of induction in mutation-defined subgroups (positive for mutation of FLT3, IDH1 and IDH2, respectively) of the TP53 WT population was compared in participants who had been randomized to idasanutlin in combination with cytarabine versus those who had been randomized to cytarabine and placebo.

FLT3

Group	Value	95% CI
Placebo Plus Cytarabine	12.5
Idasanutlin Plus Cytarabine	15.3

IDH1

Group	Value	95% CI
Placebo Plus Cytarabine	11.1
Idasanutlin Plus Cytarabine	34.8

IDH2

Group	Value	95% CI
Placebo Plus Cytarabine	23.1
Idasanutlin Plus Cytarabine	29.5

Overall Survival in Clinically Actionable Mutation-Defined Subpopulation (FLT3, IDH1 and IDH2) in TP53 WT Population Secondary · From randomization to death from any cause (up to approximately 4.5 years)

Overall survival in mutation-defined subgroups (positive for mutation of FLT3, IDH1 and IDH2 respectively) of the TP53 WT population was compared in participants who had been randomized to idasanutlin in combination with cytarabine versus those who had been randomized to cytarabine and placebo. The Median upper limits were set to 999 because they were not reached and therefore it was Not Evaluable (NE) and the field is numeric only. The study was terminated because of futility, therefore did not reach the planned end of the study.

IDH2

Group	Value	95% CI
Placebo Plus Cytarabine	11.37	8.02 – NA
Idasanutlin Plus Cytarabine	11.01	6.87 – NA

IDH1

Group	Value	95% CI
Placebo Plus Cytarabine	9.13	2.50 – 16.69
Idasanutlin Plus Cytarabine	8.25	4.27 – 37.29

FLT3

Group	Value	95% CI
Placebo Plus Cytarabine	4.76	1.97 – 13.04
Idasanutlin Plus Cytarabine	5.55	4.50 – 8.25

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) Secondary · Baseline up to approximately 4.5 years

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) have been reported. The study was terminated because of futility, therefore did not reach the planned end of the study.

Group	Value	95% CI
Placebo Plus Cytarabine	149
Idasanutlin Plus Cytarabine	232

Number of Participants With Adverse Events Leading to Discontinuation Secondary · Baseline up to approximately 4.5 years

Participants with Adverse Events leading to discontinuation of the study have been reported. The study was terminated because of futility, therefore did not reach the planned end of the study.

Group	Value	95% CI
Placebo Plus Cytarabine	0
Idasanutlin Plus Cytarabine	0

Number of Participants With Adverse Events Leading to Death up to Day 30 Secondary · Up to Day 30

The number of participants with AE resulted by death within 30 days from dosing is reported

Group	Value	95% CI
Placebo Plus Cytarabine	9
Idasanutlin Plus Cytarabine	23

Number of Participants With Adverse Events Leading to Death up to Day 60 Secondary · Up to Day 60

The number of participants with AE resulted by death within 60 days from dosing is reported

Group	Value	95% CI
Placebo Plus Cytarabine	24
Idasanutlin Plus Cytarabine	60

Adverse events — posted to ClinicalTrials.gov

Time frame: The timeframe was planned to be from the Baseline up to approximately 4.5 years. The study was pre-maturely terminated due to mild benefit by the sponsor's decision, therefore did not reach the planned end of study.. Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Idasanutlin-Cytarabine

Serious: 173/292 (59%)

Deaths: 211/292

Placebo-Cytarabine

Serious: 72/149 (48%)

Deaths: 109/149

Serious adverse events (150 terms)

Reaction	System	Idasanutlin-Cytarabine	Placebo-Cytarabine
Sepsis	Infections and infestations	—	—
Febrile neutropenia	Blood and lymphatic system disorders	—	—
Pneumonia	Infections and infestations	—	—
Septic shock	Infections and infestations	—	—
Diarrhoea	Gastrointestinal disorders	—	—
Death	General disorders	—	—
Multiple organ dysfunction syndrome	General disorders	—	—
Pyrexia	General disorders	—	—
Hyperbilirubinaemia	Hepatobiliary disorders	—	—
Neutropenic sepsis	Infections and infestations	—	—
Hypotension	Vascular disorders	—	—
Thrombocytopenia	Blood and lymphatic system disorders	—	—
Graft versus host disease	Immune system disorders	—	—
Bacteraemia	Infections and infestations	—	—
Respiratory failure	Respiratory, thoracic and mediastinal disorders	—	—
Neutropenia	Blood and lymphatic system disorders	—	—
Graft versus host disease in gastrointestinal tract	Immune system disorders	—	—
Acute kidney injury	Renal and urinary disorders	—	—
Renal failure	Renal and urinary disorders	—	—
Pancytopenia	Blood and lymphatic system disorders	—	—
Myocarditis	Cardiac disorders	—	—
Pericarditis	Cardiac disorders	—	—
Pancreatitis	Gastrointestinal disorders	—	—
Anal infection	Infections and infestations	—	—
Bacterial sepsis	Infections and infestations	—	—

Other adverse events (56 terms — click to expand)

Reaction	System	Idasanutlin-Cytarabine	Placebo-Cytarabine
Diarrhoea	Gastrointestinal disorders	—	—
Nausea	Gastrointestinal disorders	—	—
Febrile neutropenia	Blood and lymphatic system disorders	—	—
Hypokalaemia	Metabolism and nutrition disorders	—	—
Thrombocytopenia	Blood and lymphatic system disorders	—	—
Pyrexia	General disorders	—	—
Vomiting	Gastrointestinal disorders	—	—
Anaemia	Blood and lymphatic system disorders	—	—
Constipation	Gastrointestinal disorders	—	—
Oedema peripheral	General disorders	—	—
Asthenia	General disorders	—	—
Rash	Skin and subcutaneous tissue disorders	—	—
Abdominal pain	Gastrointestinal disorders	—	—
Decreased appetite	Metabolism and nutrition disorders	—	—
Hyperbilirubinaemia	Hepatobiliary disorders	—	—
Hypomagnesaemia	Metabolism and nutrition disorders	—	—
Headache	Nervous system disorders	—	—
Mucosal inflammation	General disorders	—	—
Hypotension	Vascular disorders	—	—
Cough	Respiratory, thoracic and mediastinal disorders	—	—
Erythema	Skin and subcutaneous tissue disorders	—	—
Neutropenia	Blood and lymphatic system disorders	—	—
Hypocalcaemia	Metabolism and nutrition disorders	—	—
Hypophosphataemia	Metabolism and nutrition disorders	—	—
Epistaxis	Respiratory, thoracic and mediastinal disorders	—	—
Fatigue	General disorders	—	—
Dyspnoea	Respiratory, thoracic and mediastinal disorders	—	—
Back pain	Musculoskeletal and connective tissue disorders	—	—
Hypertension	Vascular disorders	—	—
Abdominal pain upper	Gastrointestinal disorders	—	—
Stomatitis	Gastrointestinal disorders	—	—
Insomnia	Psychiatric disorders	—	—
Oedema	General disorders	—	—
Oral herpes	Infections and infestations	—	—
Hypoalbuminaemia	Metabolism and nutrition disorders	—	—
Chest pain	General disorders	—	—
Haemorrhoids	Gastrointestinal disorders	—	—
Pneumonia	Infections and infestations	—	—
Hyperglycaemia	Metabolism and nutrition disorders	—	—
Dizziness	Nervous system disorders	—	—

Most-reported serious reactions: Sepsis, Febrile neutropenia, Pneumonia, Septic shock, Diarrhoea, Death, Multiple organ dysfunction syndrome, Pyrexia.

Data from ClinicalTrials.gov NCT02545283 adverse events section.

Sponsor's own description

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.

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

1. Targeting apoptosis in cancer therapy.
   Carneiro BA, El-Deiry WS. · · 2020 · cited 1823× · PMID 32203277 · DOI 10.1038/s41571-020-0341-y
2. Targeting p53 pathways: mechanisms, structures, and advances in therapy.
   Wang H, Guo M, Wei H, Chen Y. · · 2023 · cited 580× · PMID 36859359 · DOI 10.1038/s41392-023-01347-1
3. Recent advances in the development of protein-protein interactions modulators: mechanisms and clinical trials.
   Lu H, Zhou Q, He J, Jiang Z, et al · · 2020 · cited 570× · PMID 32968059 · DOI 10.1038/s41392-020-00315-3
4. Targeting mutant p53 for cancer therapy: direct and indirect strategies.
   Hu J, Cao J, Topatana W, Juengpanich S, et al · · 2021 · cited 379× · PMID 34583722 · DOI 10.1186/s13045-021-01169-0
5. Recent advances in targeting the "undruggable" proteins: from drug discovery to clinical trials.
   Xie X, Yu T, Li X, Zhang N, et al · · 2023 · cited 246× · PMID 37669923 · DOI 10.1038/s41392-023-01589-z
6. Emerging agents and regimens for AML.
   Liu H. · · 2021 · cited 210× · PMID 33757574 · DOI 10.1186/s13045-021-01062-w
7. MDM2/X inhibitors under clinical evaluation: perspectives for the management of hematological malignancies and pediatric cancer.
   Tisato V, Voltan R, Gonelli A, Secchiero P, et al · · 2017 · cited 191× · PMID 28673313 · DOI 10.1186/s13045-017-0500-5
8. Role of p53 in breast cancer progression: An insight into p53 targeted therapy.
   Marvalim C, Datta A, Lee SC. · · 2023 · cited 142× · PMID 36923534 · DOI 10.7150/thno.81847