E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Acute myeloid leukemia (AML) |
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E.1.1.1 | Medical condition in easily understood language |
AML is a type of cancer in which the bone marrow is being filled with abnormal myeloblasts (progenitors for red blood cells, platelets and white blood cells). |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10000886 |
E.1.2 | Term | Acute myeloid leukemia |
E.1.2 | System Organ Class | 100000004864 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
• To determine the recommended Phase II dose (RP2D) for idasanutlin when given in combination with cytarabine and daunorubicin during the dose-escalation phase
• To evaluate the safety and tolerability of idasanutlin when given in combination with cytarabine and daunorubicin in induction, in combination with cytarabine in consolidation, and as a single agent in maintenance
• To compare the differences in patient-reported treatment-related symptoms
• To evaluate the efficacy of idasanutlin when given in combination with cytarabine and daunorubicin as induction treatment. |
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E.2.2 | Secondary objectives of the trial |
• To characterize the PK profiles of idasanutlin (and its metabolites, if appropriate), cytarabine, and daunorubicin
• To assess potential PK interactions among idasanutlin, cytarabine, and daunorubicin
• To evaluate health status utility scores of patients treated with idasanutlin. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Inclusion Criteria for All Study Phases
- Age >=18 years
- Eastern Cooperative Oncology Group (ECOG) performance status <=2
- Adequate hepatic and renal function
- For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures, and agreement to refrain from donating eggs with a failure rate of <1% per year during the treatment period and for at least 6 months after the final dose of idasanutlin, cytarabine, or daunorubicin. Women must refrain from donating eggs during this same period.
- For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive, measures, and agreement to refrain from donating sperm that together result in a failure rate of <1% per year during the treatment period and for 6 months after the final dose of idasanutlin, cytarabine, or daunorubicin. Men must refrain from donating sperm during this same period.
Inclusion Criteria for Patients in the Dose-Escalation and Expansion Phases
- Documented/confirmed newly diagnosed AML not previously treated according to WHO
Inclusion Criteria for Patients in the Post-Consolidation Phase
- Documented/confirmed AML according to WHO in remission after induction, within 21 days of end of last chemotherapy consolidation cycle, and were minimum residual disease (MRD) positive at the end of induction as per local laboratory assessment.
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E.4 | Principal exclusion criteria |
Exclusion Criteria for All Study Phases
- Clinical evidence of CNS leukemia
- Any Grade >=2 non-hematologic toxicities prior to starting therapy
- Current treatment with any other investigational or commercial agents or therapies administered with the intention to treat their malignancy with the exception of hydroxyurea (HU) or 6-mercaptopurine (6-MP)
- Treatment-related AML
- Acute promyelocytic leukemia
- History of other malignancy that could affect compliance with the protocol or interpretation of results
- Any severe and/or uncontrolled medical conditions or other conditions that could affect their participation in the study, impair the ability of the investigator to evaluate the patient, or impair the patient’s ability to complete the study
- Echocardiogram (ECHO) or multiple-gated acquisition (MUGA) scan showing ejection fraction <=40%
- Non-malignant medical illnesses that are uncontrolled or whose control may be jeopardized by this study treatment, such as hereditary coagulation disorders, insulin-dependent diabetes mellitus not optimally controlled with medical management (e.g., presence of ketoacidosis), or active GI conditions affecting absorption
- Infection considered by the investigator to be clinically uncontrolled or of unacceptable risk to the patient upon the induction of neutropenia, that is, patients who are or should be on antimicrobial agents for the treatment of active infection
- Febrile patients within 72 hours of study treatment initiation
- Patients with a history of active or chronic infectious hepatitis unless serology demonstrates clearance of infection
- Patients who are unable to interrupt treatment with moderate to strong CYP2C8 inducers and inhibitors
- Patients who are unable to temporarily interrupt treatment with oral or parenteral anticoagulants/anti-platelet agents during treatment phase
- Patients who have a history of clinically significant liver cirrhosis
- Patients with extramedullary AML with no evidence of systemic involvement
- Pregnant or breastfeeding patients
- Known history of HIV-positive status
- Patients who might refuse to receive blood products and/or have a hypersensitivity to blood products
- Prior treatment with an MDM2 antagonist
- Patients with clinically relevant QTc prolongation, a family history of long QT syndrome
Exclusion Criteria for Patients in the Phase Ib Dose-Escalation Phase
- Adverse risk patients as per ELN 2017 criteria
Exclusion Criteria for Patients in Phase Ib Post-Consolidation Phase
- Any ongoing Grade >=2 hematologic adverse events prior to starting therapy
- Previous HSCT
Exclusion Criteria for Patients in the Dose-Escalation Phase and Patients in the Favorable/Intermediate-Risk Cohort of the Expansion Phase
- Secondary AML, defined as AML evolving from AHD. |
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E.5 End points |
E.5.1 | Primary end point(s) |
1. Incidence of dose-limiting toxicities (DLTs) during the first cycle of study treatment
2. Incidence and severity of adverse events, including DLTs, with severity determined according to National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0 (NCI CTCAE v5.0)
3. Change from baseline in targeted vital signs
4. Change from baseline in ECG parameters
5. Change from baseline in targeted clinical laboratory test results
6. Presence, frequency of occurrence, severity, and/or degree of interference with daily function of symptomatic treatment toxicities (nausea, vomiting, and diarrhea), as assessed through use of the NCI Patient-Reported Outcomes Common Terminology Criteria for Adverse Events (PRO-CTCAE)
7. Change from baseline in symptomatic treatment toxicities, as assessed through use of the PRO-CTCAE
8. Proportion of patients with a complete remission (CR) at the end of induction treatment. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. Up to Day 56 of Cycle 1
2. Up to 2 years
3-5. Baseline, Day 1 of all cycles
6. Day 1 of all cycles
7. Baseline, Day 1 of all cycles
8. At the end of induction treatment. |
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E.5.2 | Secondary end point(s) |
1. Proportion of patients with a CR, complete remission with incomplete blood count recovery (CRi), or complete remission with incomplete platelet count recovery (CRp) at the end of induction treatment
2. Proportion of patients with a CR or complete remission with partial hematologic recovery (CRh) at the end of induction treatment
3. Proportion of patients with a negative MRD status at the end of induction treatment
4. Event-free survival
5. Overall survival
6. Relapse-free survival in patients who achieve remission (CR, CRi, CRp, or CRh)
7. Change from baseline in patient-reported disease-related symptoms and health-related quality of life at specified timepoints, as assessed through use of the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue, European Organisation for Research and Treatment of Cancer Quality-of-Life Questionnaire, Core 30 (EORTC QLQ-C30) (selected scales), and European Organisation for Research and Treatment of Cancer (EORTC) Item Library (selected symptoms)
8. Change from baseline in EuroQol 5-Dimension, 5-Level Questionnaire (EQ-5D-5L) index-based and visual analogue scale (VAS) scores at specified timepoints
9. Plasma concentration of idasanutlin (and metabolites, if appropriate), cytarabine, and daunorubicin at specified timepoints. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1-3. At the end of induction treatment
4-6. Up to 6 years
7-8. Baseline, Day 1 of all cycles
9. Idasanutlin: Day 1, Day 3, Day 5 of induction cycle 1; Day 1 and Day 5 of consolidation cycle 1; Day 1 and Day 5 of maintenance cycle 1
Cytarabine: Day 1, Day 3, Day 5 of induction cycle 1; Day 1 and Day 5 of consolidation cycle 1
Daunorubicin: Day 1, Day 3, Day 5 of induction cycle 1. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 15 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Australia |
France |
Italy |
Spain |
United States |
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E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 6 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 6 |