| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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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 | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10000880 |
| E.1.2 | Term | Acute myeloid leukaemia |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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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 compare molecular event free survival (mEFS) in AML patients receiving venetoclax and low dose cytarabine with those receiving intensive chemotherapy. mEFS is defined as;
1.Failure to achieve complete remission or complete remission with incomplete blood count recovery after two cycles of treatment
2.Molecular persistence (not responding to treatment), progression or relapse requiring treatment change
3.Morphological Relapse
4.Death |
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| E.2.2 | Secondary objectives of the trial |
• Occurrence of complete remission by the end of the second cycle of treatment
• Death within 30 and 60 days from trial entry
• Overall survival time
• Time to haematological relapse
• Time to molecular relapse
• Cumulative occurrence of grade 3 and 4 toxicity
• Prevalence of molecular complete remission at month 3, 6 and 12
• Cumulative resource use at 12 and 24 months including hospital admission days, blood product usage and days on intravenous antibiotics and antifungals
• Health related quality of life at month 3, 6, 12, 18 and 24
• Change in performance status from baseline at month 3, 6, 12, 18 and 24
• Change in Comprehensive Geriatric Assessment (CGA) from baseline at month 12 and 24 |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
• Diagnosis of CD33 positive Acute Myeloid Leukaemia
• Age ≥60 years (prior to the interim analyses performed after enrolment of 50 and 100 patients)
• Genotype NPM1mut FLT3 ITDneg (FLT3- Tyrosine Kinase Domain mutation, TKD, is permitted)
• Eastern Cooperative Oncology Group (ECOG) performance status 0-2
• Serum creatinine ≤ 1.5 x ULN (upper limit of normal)
• Serum Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) ≤ 2.5 ULN and bilirubin ≤ 2 x ULN
• Able to provide written informed consent
• Considered fit for intensive chemotherapy with anthracyclines by treating physician
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| E.4 | Principal exclusion criteria |
• Previous chemotherapy for AML or any antedecent haematological condition, with the exception of hydroxycarbamide to control white blood cell count
• Other active malignancy requiring treatment
• Newly diagnosed or uncontrolled HIV or hepatitis B or C infection. Patients with known chronic infections may enrol if the last two tests for viral load have been negative and their current therapy does not include a protease inhibitor or a non-nucleoside reverse-transcriptase inhibitor
• Pregnant and lactating patients (patients of childbearing potential must have a negative pregnancy test prior to study entry)
• Females of childbearing potential, and their partners, not willing to use adequate contraception during and for up to 6 months after treatment
• Unable to swallow tablets whole
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Molecular event-free survival time (mEFS). An event is defined as follows:
o Failure to achieve morphological CR or CRi after two cycles of therapy
o Molecular persistence, progression or relapse requiring treatment change (at any time)
o Morphological relapse (at any time)
o Death (at any time) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| MEFS is calculated as the time from date of randomisation to the date of the first recorded event as stated above. Patients who have not experienced an event at the time of analysis will be censored at their date last seen without an event. |
|
| E.5.2 | Secondary end point(s) |
• Occurrence of morphological complete remission (CR) by the end of the second cycle of treatment is evaluated from the morphological response assessments taken at the end of cycles 1 and 2.
• Death within 30 and 60 days from trial entry will include deaths from any cause and can only be evaluated in those patients who have been followed up for these periods of time.
• Overall survival time is calculated as time from date of randomisation to date of death from any cause; patients alive at the time of analysis will be censored at their date last seen alive.
• Time to morphological relapse is calculated as the time from date complete morphological remission to date when morphological relapse is first recorded, where definition of morphological relapse and timings of assessments for morphological response are specified in protocol section 8.14.
• Time to molecular relapse is calculated as the time from date of molecular remission to date when molecular relapse is first recorded, where definition of molecular relapse and timings of assessments for molecular response are specified in protocol section 8.14.
• Cumulative occurrence of grade 3 and 4 adverse events (AE) at 12 and 24 months is evaluated as the total number of grade 3 and 4 AE that are reported during these periods, from all AE that are reported and graded according to CTCAE criteria throughout the duration of the trial.
• Prevalence of molecular complete remission at month 3, 6 and 12 is evaluated from the molecular response assessments taken at these approximate time points from trial entry.
• Cumulative resource use at 12 and 24 months is calculated as total number of hospital admission days, total blood product usage and total number of days on intravenous antibiotics and antifungals that are reported for these periods of time from trial entry.
• Health-related quality of life (QoL) at month 3, 6, 12, 18 and 24 is evaluated from the EORTC QLQ-C30 and EQ-5D questionnaires completed by patients at clinic visits occurring at these approximate time points from trial entry (further details given in section 8.9 and section 11); the questionnaires will yield 15 and 2 different measures of QoL respectively.
• Change in performance status from baseline at month 3, 6, 12, 18 and 24 is evaluated by clinical assessment according to the Eastern Cooperative Oncology Group classification (ECOG 0, 1, 2, 3 or 4) during clinic visits occurring at these approximate time points from trial entry.
• Change in Comprehensive Geriatric Assessment (CGA) from baseline at month 12 and 24 comprises multiple measures of frailty that are evaluated during clinic visits at these approximate time points from trial entry and includes: total number of medications prescribed, Hospital Anxiety and Depression score, Instrumental Activities of Daily Living score, Mini-Mental State Examination score, body mass index, degree of weight loss, serum albumin level and timed get-up and go measure.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| 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 | 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 | 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) | Yes |
| E.8.2.2 | Placebo | No |
| 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 4 |
| 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 |
| New Zealand |
| Denmark |
| United Kingdom |
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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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| The end of the trial will be 6 months after the data capture (last patient last visit) |
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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 | 5 |
| E.8.9.1 | In the Member State concerned days | 31 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 5 |
| E.8.9.2 | In all countries concerned by the trial days | 31 |
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