E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Relapsed or refractory acute myeloid leukemia. |
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E.1.1.1 | Medical condition in easily understood language |
Acute myeloid leukemia (AML) is a type of cancer that starts in the blood-forming cells of the bone marrow, characterised by an over-production of immature 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 | 18.1 |
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 | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
Within the TP53 wild-type population: • To compare overall survival (OS) in patients with relapsed or refractory AML who have been randomized to idasanutlin in combination with cytarabine versus those who have been randomized to cytarabine and placebo. |
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E.2.2 | Secondary objectives of the trial |
Within the all-patient population • To compare OS in patients with relapsed or refractory AML who have been randomized to idasanutlin in combination with cytarabine versus those who have been randomized to cytarabine and placebo. Within the all-patient population and the TP53 wild-type population • To compare - the proportions of complete remission (CR), and CR with incomplete platelet count recovery (CRp) between treatment arms - the proportions of overall remissions (CR, CRp, CR with incomplete blood count recovery [Cri]) between treatment arms - event-free survival (EFS) and leukemia-free survival (LFS) between treatment arms - the proportions of allogeneic hematopoietic stem cell transplant (HSCT) following response between treatment arms - the differences in disease and treatment related symptoms and health related quality of life • To assess the safety between treatment arms • To characterize the pharmacokinetics of both idasanutlin and cytarabine |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Specimens for the Roche Clinical Repository will be collected from patients who give specific consent to participate in this optional research with the following objectives: • To study the association of biomarkers with efficacy, adverse events, or disease progression • To increase knowledge and understanding of disease biology • To study drug response, including drug effects and the processes of drug absorption and disposition • To develop biomarker or diagnostic assays and establish the performance characteristics of these assays |
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E.3 | Principal inclusion criteria |
- Age >=18 years - Documented/confirmed 1st/2nd refractory/relapsed AML using World Health Organization classification, except acute promyelocytic leukemia - No more than 2 prior induction regimens (excl. prior HSCT) and one must have included cytarabine with an anthracycline (or anthracenedione) - Eastern Cooperative Oncology Group performance status of 0 to 1 - Patient should be a potential candidate for allogeneic HSCT - Adequate hepatic and renal function. |
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E.4 | Principal exclusion criteria |
- Patients with CR1 duration of >1 year AND age <60 years - Patients with AML with myelodysplasia related changes, or AML that has developed as a consequence of an AHD - AML secondary to any prior chemotherapy unrelated to leukemia - Patients who have received more than two prior cytarabine containing induction regimens for AML - Patients who have relapsed within 90 days after therapy with intermediate-dose cytosine arabinoside (IDAC) or high-dose cytosine arabinoside (HiDAC) containing regimens - Patients who have received allogeneic HSCT within 90 days prior to randomization - Patients who have received immunosuppressive therapy for graft versus host disease (G versus HD) within 2 weeks prior to study start - Prior treatment with a Murine Double Minute 2 (MDM2) antagonist - Patients receiving any other investigational or commercial agents or therapies administered with the intention to treat their malignancy - Patients with a history of other malignancy within 5 years prior to screening - Patients who have any severe and/or uncontrolled medical conditions or other conditions that could affect their participation in the study - Pregnant or breastfeeding patients. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Overall survival (OS) in TP53 wild-type population. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
- Primary analysis: after 275 deaths observed in TP53 wild-type patients - Interim analysis: after 120 patients with TP53 wild-type enrolled |
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E.5.2 | Secondary end point(s) |
1. OS in the all-patient population 2. CR and CRp proportions at the end of induction in the TP53 wild-type population 3. Overall remission rate (ORR) (CR, CRp and CRi) proportion at the end of induction in the TP53 wild-type population 4. EFS in the TP53 wild-type population 5. LFS in the TP53 wild-type population 6. Proportion of HSCT in the TP53 wild-type population 7. CR and CRp proportions at the end of induction in the overall population 8. ORR (CR, CRp and CRi) proportion at the end of induction in the overall population 9. EFS in the overall population 10. LFS in the overall population 11. Proportion of HSCT in the overall population. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
- Primary analysis: after 275 deaths observed in TP53 wild-type patients - Interim analysis: after 120 patients with TP53 wild-type enrolled |
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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 | Yes |
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) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
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 | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
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 | 10 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 56 |
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 |
Austria |
Belgium |
Canada |
Finland |
France |
Germany |
Israel |
Italy |
Korea, Republic of |
Netherlands |
New Zealand |
Norway |
Russian Federation |
Spain |
Switzerland |
Taiwan |
United Kingdom |
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E.8.7 | Trial has a data monitoring committee | Yes |
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 | 5 |
E.8.9.1 | In the Member State concerned months | 1 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 6 |