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 SCT.
Part II:To evaluate the efficacy of venetoclax in combination with azacitidine to improve OS 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 |
Part 2: *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 as measured by RFS. *To determine the efficacy 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). *To determine the effect of venetoclax in combination with azacitidine on minimal residual disease levels. |
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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 60 days. Blast percentage in bone marrow prior to pre-transplant conditioning must be < 10%. Blast count in peripheral blood must be “0” and malignant Blast percentage in bone marrow must be < 5% after transplant within 7 days prior to Cycle 1 Day 1. Bilirubin ≤3 × ULN* within 7 days prior to Cycle 1 Day 1 For Part 1: ANC ≥1,500/µL, measured twice at least 2 days apart (approximately 48 hours) and within 1 week prior to Cycle 1 Day 1. Subjects should not have granulocyte-colony stimulating factor (G-CSF) treatment for 7 days before first ANC count. For Part 2: ANC ≥1,000/µL, measured twice at least 2 days apart (approximately 48 hours) and within 1 week prior to Cycle 1 Day 1 or prior to dosing on Cycle 1 Day 1. Subjects should not have granulocyte-colony stimulating factor (G-CSF) treatment for 7 days before first ANC count. Part 1: Platelet count ≥80,000/µL measured twice at least 2 days apart (approximately 48 hours) and within 1 week prior to Cycle 1 Day 1. Subjects should not have supportive treatment (e.g., transfusions and/or growth factors) for 7 days before first platelet count. Part 2: Platelet count ≥50,000/µL measured twice at least 2 days apart (approximately 48 hours) and within 1 week prior to Cycle 1 Day 1 or prior to dosing on Cycle 1 Day 1. Subjects should not have supportive treatment (e.g., transfusions and/or growth factors) for 7 days before first platelet count. 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.
Subjects ≥17 years old must have a Karnofsky Performance Scale (KPS) score > 50 and Subjects 12 to 16 years old must have a Lansky Play-Performance Scale (LPPS) score > 40. Part 2: If a subject is 12 to 16 at the time of screening and turns 17 during the study, the subject will continue with the LPPS. Cycle 1 Day 1 administration of 1st dose of the study drug(s) must occur within 28 to 100 days after transplant. Subjects may enter into Screening upon the first instance of meeting the count recovery criteria without the need for supportive care (e.g., growth factors and/or platelet transfusions) for at least 7 days prior. Upon entering screening, subjects must maintain count thresholds on at least 2 occasions (approximately 48 hours apart) in the absence of supportive care (platelet transfusion/G-CSF within 7 days). If graft failure occurs during the registration period and a subsequent transplant is planned, the subject can be reconsented for the study. (Notes a - b): a) C1D1 must occur within 28 to 100 days of this subsequent transplant date. b) If there is a subsequent (second) graft failure after reconsent during the registration period, the subject will not be permitted to enroll into the study.
No known active severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. |
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E.4 | Principal exclusion criteria |
Subjects with favorable cytogenetic risk per NCCN 2016 criteria and in first complete remission prior to transplant are not eligible to enroll in this study. 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; Myeloproliferative neoplasm (only allowed if it transformed to AML and AML should be the indication for marrow transplantation). Known infection with HIV or subjects with active hepatitis B virus (HBV) or hepatitis C virus (HCV) with high viral titers. 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: OS defined as the time from randomization to death from any cause |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Part I: The primary endpoint is the frequency of DLTs of venetoclax in combination with azacitidine Part II: OS defined as the time from randomization to death from any cause
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E.5.2 | Secondary end point(s) |
• IRC-assessed morphologic RFS • IRC-assessed composite relapse-free survival
• GvHD-free, relapse free survival (GRFS). • GvHD rate at 90 days after randomization (Arm B) or initiation of treatment (Arm A) "Higher grade GvHD" is defined as Grade 2 or higher for aGvHD and moderate or severe for cGvHD as defined by the investigator following National Institutes of Health (NIH) criteria. - Change from baseline (Cycle 1 Day 1 [predose]) at 6 months in physical functioning after randomization (Arm B) or initiation of study treatment (Arm A) in adult subjects, as measured by the EORTC QLQ-C30 physical functioning domain • Fatigue Change from baseline at 6 months after randomization (Arm B) or initiation of study treatment (Arm A) in adult subjects - defined as Fatigue measured as Patient Reported Outcome (PRO) using Patient Reported Outcomes Measurement Information System (PROMIS) Cancer Fatigue SF 7a - Measurable residual disease conversion rate - The rate will be calculated only among subjects with MRD ≥10-3 at baseline (Cycle 1 Day 1 [predose]). The MRD conversion rate will be defined as proportion of subjects who convert to MRD < 10-3 after randomization (Arm B) or initiation of treatment (Arm A) - Time to deterioration in Global Health Status (GHS)/QoL in adult subjects - defined as time from randomization to death from any cause, or the first-time deterioration of ≥10 points from baseline (Cycle 1 Day 1 [predose]) in GHS/QoL score as measured by the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Version 3, whichever occurs first. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
IRC-assessed morphologic RFS (morphologic relapse or death) IRC-assessed composite relapse-free survival (morphologic relapse from AML, non-morphologic relapse,or death) GvHD-free,relapse free survival(GRFS)-time from randomization to disease relapse, incidence of GvHD, or death(any reason) 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 after randomization (Arm B) or initiation of study treatment (Arm A) Measurable residual disease conversion rate measured as described in Secondary Endpoints
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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 | 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 | 36 |
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 |
Switzerland |
Taiwan |
Australia |
Brazil |
Canada |
China |
Czechia |
France |
Germany |
Greece |
Hungary |
Israel |
Italy |
Japan |
Korea, Republic of |
Spain |
United Kingdom |
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 | 6 |
E.8.9.1 | In the Member State concerned days | |
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 |