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: To determine the recommended Phase 3 dose of venetoclax in combination with azacitidine in AML patients when given as maintenance therapy following allogeneic stem cell transplantation.
Part II:To evaluate the efficacy of venetoclax in combination with azacitidine to improve Relapse Free Survival (RFS) in AML patients compared to Best Supportive Care (BSC) when given as maintenance therapy following allogeneic stem cell transplantation |
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E.2.2 | Secondary objectives of the trial |
*To confirm the safety of venetoclax in combination with azacitidine after allogeneic transplantation in subjects diagnosed with AML. *To determine the efficacy of venetoclax in combination with azacitidine on overall survival. *To determine the effect of venetoclax in combination with azacitidine on the frequency and severity of GvHD. *To determine the effect of venetoclax in combination with azacitidine on Quality of life (QoL). |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Adult male or female ≥ 18 years old for Part 1 and, male or female at least 12 years old for Part 2. Subject must be diagnosed with AML by World Health Organization (WHO) criteria (2017) and either be planning for allogeneic stem cell transplantation or have received allogeneic stem cell transplantation within the past 14 days. Blast percentage in bone marrow before transplant must be < 10%. Blast count in peripheral blood must be “0” and Blast percentage in bone marrow must be < 5% after transplant within 7 days prior to Cycle 1 Day 1. Bilirubin ≤ 3 × ULN. Cycle 1 Day 1 must occur within 28 to 200 days after transplant and no later than 60 days since meeting count recovery criteria post-transplant. Post-transplant count recovery (within 7 days prior to Cycle 1 Day 1) criteria: ANC measured twice at least 2 days apart and within one week from Cycle 1 Day 1. S ubjects should not have granulocyte-colony stimulating factor (G-CSF) treatment for 7 days before first ANC count. (ANC value for Part 1 ≥ 1,500/µL and ≥ 1,000/µL for Part 2); Platelets should be measured twice at least 2 days apart and within 1 week from Cycle 1 Day 1. Subjects should not have a platelet transfusion for 7 days before first platelet count. (value for Part 1 ≥ 80,000/µL and ≥ 50,000/µL for Part 2). Adequate renal function as demonstrated by a creatinine clearance >30 mL/min; calculated by the Cockcroft Gault formula or measured by 24-hour urine collection and subjects 12-17 years old must have the equivalent as calculated by the Schwartz formula. Subjects ≥ 17 years old must have a Karnofsky Performance Scale (KPS) score > 50 and subjects 12 - ≤ 16 years old must have a Lansky Play Performance Scale score > 40.
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E.4 | Principal exclusion criteria |
History of disease progression during prior treatment with venetoclax. History of any other malignancy within 2 years prior to study entry, except for: Adequately treated in situ carcinoma of the cervix uteri or carcinoma in situ of breast; Basal cell carcinoma of the skin or localized squamous cell carcinoma of the skin; Previous malignancy confined and surgically resected (or treated with other modalities) with curative intent; Myelodysplastic Syndrome. Known infection with HIV or history of being positive for hepatitis B virus (HBV) or hepatitis C virus (HCV) infection. Presence of clinical or laboratory symptoms/signs of extramedullary myeloid malignancy. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Part I: The primary endpoint is the frequency of DLTs of venetoclax in combination with azacitidine Part II: Relapse-Free Survival (RFS)
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Part I: the first treatment cycle (28 days). Part II:The time from randomization to the date of relapse or the date of death from any cause, whichever occurs first.
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E.5.2 | Secondary end point(s) |
• Overall Survival (OS) • GvHD-free, relapse free survival (GRFS). • Time to deterioration in Global Health Status (GHS)/QoL • GvHD rate at 90 days after randomization • Fatigue Change in adult subjects • Patient Reported Outcome (PRO) using Patient Reported Outcomes • Minimal residual disease (MRD) response rate |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Overall Survival (OS)-time from randomization to death(any reason) GvHD-free,relapse free survival(GRFS)-time from randomization to a) disease relapse, b)occurrence or worsening of GvHD, or c)death(any reason) Time to deterioration using GHS/QoL in adult subjects-randomization to either deterioration of ≥5 points based on EORTC QLQ-C30(v3)or death (any cause) GvHD rate at 90 days after randomization-Grade 2 or higher for aGvHD and moderate/severe for cGvHD per investigator Fatigue Change in adult subjects-using Patient Reported Outcomes Measurement Information System (PROMIS) Cancer Fatigue SF 7a. Difference between randomization and 6 months of treatment MRD response rate-only among subjects with MRD > 10-3 at study start; response is MRD conversion to < 10-3 after treatment start.
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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) | 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 | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
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 | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
Best Supportive Care (BSC) |
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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 | 7 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 57 |
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 |
Brazil |
Canada |
China |
Israel |
Japan |
Korea, Republic of |
Russian Federation |
Switzerland |
Taiwan |
United States |
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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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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 | 3 |
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 |