| 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 |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| 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 |
Part I (Dose Confirmation): To determine the RPTD of venetoclax in combination with AZA as maintenance therapy in subjects with AML who have achieved CR or CRi with conventional induction and consolidation chemotherapy
Part III (Dose Finding): To determine the RPTD of venetoclax in combination with CC-486 as maintenance therapy in subjects with AML who have achieved CR or CRi with conventional induction and consolidation chemotherapy.
Part III Objectives (Randomization): To evaluate if venetoclax in combination with CC-486 as maintenance therapy improves RFS compared to placebo + CC-486 in subjects with AML who have achieved CR or CRi with conventional induction and consolidation chemotherapy.
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| E.2.2 | Secondary objectives of the trial |
Part 3 (Dose Finding)
Characterize safety, PK and toxicity profiles of venetoclax together with CC-486 as maintenance therapy in subjects with AML who have achieved CR or CRi with conventional chemotherapy
Part 3 Objectives (Randomization)
Evaluate:
If venetoclax with CC-486 as maintenance therapy improves OS versus placebo+CC-486
Safety of venetoclax with CC-486 as maintenance therapy versus to placebo+CC-486
If venetoclax with CC-486 as maintenance therapy improves the MRD conversion rate among MRD-positive subjectat screening versus placebo + CC-486
If venetoclax with CC-486 as maintenance therapy versus placebo+CC-486 delays time to deterioration in GHS/QoL score as measured by procedures outlined in the EORTC QLQ-C30) scoring manual
If venetoclax with CC-486 as maintenance therapy has impact on fatigue versus placebo + CC-486 based on PRO assessment of the PROMIS Fatigue SF7a
The impact of venetoclax-based therapy on remaining subscales/items from the EORTC QLQ-C30 |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Subject must be ≥ 18 years old, have newly diagnosed AML with intermediate or poor risk cytogenetics, have confirmed CR or CRi following completion of intensive Induction and Consolidation chemotherapies, have achieved first CR or CRi (after induction) within 120 days of the first dose of study drug or be no more than 75 days since last dose of intensive conventional (including both Induction and Consolidation) chemotherapies until enrollment, and have an Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2.
The key laboratory requirements are as follows:
- creatinine clearance ≥ 30 mL/minute; calculated by the Cockcroft Gault formula or measured by 24-hour urine collection;
- bilirubin < 3.0 × upper limit of normal (ULN) (adequate liver function) for Parts 1 and 2, or bilirubin < 2.0 × ULN for Part 3;
- absolute neutrophil count ≥ 1,500/μL;
- platelets ≥ 100,000/μL. |
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| E.4 | Principal exclusion criteria |
History of APL.
History of active central nervous system involvement with AML. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Part I: The primary endpoint is dose-limiting toxicities of venetoclax in combination with AZA
Part III (Dose Finding): The primary endpoint is DLTs of venetoclax in combniation with CC-486
Part III (Randomization): The primary endpoint is RFS (as assessed by the investigator) and is defined as the time from randomization to the date of relapse or the date of death from any cause, whichever comes first. If a subject does not experience an RFS event, the subject's data will be censored
at the date of the subject's last disease assessment date or date of randomization if the subject does not have any postbaseline disease assessment.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Timepoint for part I: After approximately 20 subjects have been treated for at least 28 days
Timepoint for part III: When RPTD has been reached. |
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| E.5.2 | Secondary end point(s) |
Part 3 (Randomization):
•Overall Survival: OS is defined as the number of days from the date of randomization to the date of death.
•Minimal Residual Disease: The MRD conversion is defined as subjects deemed MRD positive (≥ 10-3) at screening who converted to MRD of < 10-3 in the bone marrow after randomization or initiation of treatment.
•Patient-Reported Outcomes: GHS/QoL scale from the EORTC QLQ-C30 scores will be assessed and computed according to procedures outlined in EORTC QLQ-C30 scoring manual. Time to deterioration in GHS/QoL is defined as time from randomization to death from any cause or first-time decrease of ≥ 5 points from baseline.
•Patient-Reported Outcomes: Fatigue will be assessed using the PROMIS Fatigue SF 7a global fatigue score and calculated according to the procedure outlined in the PROMIS fatigue scoring manual. The impact on fatigue score will be evaluated by the change from baseline at all scheduled visits.
•Patient-Reported Outcomes: Additional subscales and items from EORTC QLQ-C30 and EQ-5D-5L will be evaluated for differences between Arms A and B. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
•Overall Survival: OS is defined as the number of days from the date of randomization to the date of death.
•The MRD conversion rate is defined as the proportion of subjects deemed MRD positive (≥ 10-3) at study initiation who converted to MRD of < 10-3 in the bone marrow after randomization or initiation of treatment.
•Time to deterioration in GHS/QoL is defined as time from randomization to death from any cause or first-time decrease of ≥ 5 points from baseline.
•The impact on fatigue score will be evaluated by the change from baseline at all scheduled visits.
• The differences between Arms A and B from additional subscales and items from EORTC QLQ-C30 and EQ5D5L will be evaluated.
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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 | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | Yes |
| 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) | 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) | Yes |
| 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 | 8 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 92 |
| 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 |
| Argentina |
| Australia |
| Brazil |
| Canada |
| China |
| Israel |
| Japan |
| Korea, Republic of |
| Mexico |
| New Zealand |
| South Africa |
| Taiwan |
| United States |
| Austria |
| France |
| Poland |
| Spain |
| Czechia |
| Germany |
| Greece |
| Italy |
| Hungary |
| Portugal |
| Russian Federation |
| Turkey |
| 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
|
| The end-of-study is defined as the date of the last subject's last visit or date of the last follow-up contact, whichever is later. |
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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 | 9 |
| E.8.9.1 | In the Member State concerned days | 0 |
| 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 | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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