E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Acute myeloid leukemia (AML) |
Akut myeloid leukæmi (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.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.0 |
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 | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
● To assess the efficacy of azacitidine in combination with low dose venetoclax in patients with AML (ORR=CR/CRi/MLFS rate, composite CR/CRh rate, PR rate). |
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E.2.2 | Secondary objectives of the trial |
● To assess overall survival (OS), duration of response (DOR), event free survival (EFS) in patients with AML. ● To assess the safety |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Written informed consent.
2. Patients who present with one of the following (except acute promyelocytic leukemia). a. De novo or secondary AML unfit for standard induction therapy (see below). b. Relapsed/refractory AML after at least 1 line of prior therapies (see below).
3. Written informed consent to participate in the exploratory research program including biobanking, AML profiling, and ex vivo drug sensitivity testing to assess venetoclax and other drug sensitivities. a. All patients are treated with azacitidine+venetoclax irrespective of the ex vivo screening results.
4. ECOG Performance status ≤ 2 for patients ≥ 75 years of age OR ≤ 3 for patients ≥ 18 to 74 years of age.
5. Leukocyte count < 25 x10E9/l. Hydroxyurea use is permitted to meet this criterion.
6. Adequate renal function as demonstrated by a calculated creatinine clearance ≥ 30 mL/min; determined by the Cockcroft Gault formula.
7. Adequate liver function as demonstrated by a. alanine aminotransferase (ALT) ≤ 4.0 × ULN. b. bilirubin ≤ 1.5 × ULN.
8. Specific inclusion criteria for elderly/unfit AML patients: a. ≥ 70 years of age OR b. ≥ 18 to 69 years of age and ineligible for intensive chemotherapy meeting at least one of the following criteria: • Clinically significant comorbidities, as reflected by at least 1 of the following criteria: o Left ventricular ejection fraction (LVEF) < 50%. o Lung diffusion capacity for carbon monoxide (DLCO) ≤ 65% of expected. o Forced expiratory volume in 1 second (FEV1) ≤ 65% of expected. o Chronic stable angina or congestive heart failure controlled with medication. o Alanine aminotransferase (ALT) 3.0-4.0 × ULN. • Other contraindication(s) to anthracycline therapy (must be documented). • Adverse risk genetics (ELN criteria) associated with poor outcome with standard chemotherapy. • Patient declines intensive chemotherapy. • sAML after previous disease modifying treatment (i.e. HMA/induction chemotherapy and/or allogeneic stem cell transplantation) of clonal myeloid diseases such as MDS, MDS/MPN, or MPN.
9. Specific inclusion criteria for relapsed AML patients: a. ≥ 55 years of age with non-CBF AML relapse OR b. ≥ 18 of age and meeting at least one of the following criteria: • Not candidate for intensive chemotherapy (see criterion 8.) • Relapse after chemotherapy, or monotherapy with HMA, or allogeneic stem cell transplantation. (note: patients with 4th or higher relapse are excluded). • Patient declines intensive chemotherapy.
10. Specific inclusion criteria for refractory AML patients: The patients who fail to achieve a complete or partial remission after previous monotherapy with HMA or induction chemotherapy (at least 1 cycle of chemotherapy containing cytarabine or clofarabine, in combination with a topoisomerase II inhibitor (e.g. anthracycline or mitoxantrone). |
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E.4 | Principal exclusion criteria |
1.Acute promyelocytic leukemia (APL).
2. Patients with 4th or higher AML relapse.
3. The leukemic cell content (blast percentage) in bone marrow/peripheral blood (depending which is used for drug sensitivity testing) is < 10 %.
4. ECOG >3 (see also inclusion criteria 4).
5. Prior venetoclax treatment for myeloid malignancy.
6. Known CNS involvement with AML (note: CSF or radiological investigations are not required without clinical suspicion).
7. Known HIV infection or active hepatitis B virus (HBV), or hepatitis C virus (HCV) infection that is not controlled with antiviral medication with the definition hereof at the discretion of the investigator.
8. Cardiovascular disability status of New York Heart Association Class ≥ 2. Class 2 is defined as cardiac disease in which patients are comfortable at rest but ordinary physical activity results in palpitations, fatigue, dyspnea, or anginal pain.
9. Evidence of clinically significant condition(s), which at the investigator's discretion would adversely affect the patient's participation in this study (including but not limited to): a. Chronic respiratory disease that requires continuous oxygen use. b. Systemic uncontrolled infection requiring therapy (viral, bacterial or fungal). c. Malabsorption syndrome or other condition that precludes enteral route of administration. d. Uncontrolled GVHD.
10. Previous malignancies with the exception of previous malignancy treated successfully with curative intent and indolent/smoldering malignancies (defined at the investigator's discretion).
11. Pregnant women and nursing mothers (a negative pregnancy test is required for all women of childbearing potential within 7 days before start of treatment).
12. Fertile men or women of childbearing potential unless: a. Surgically sterile or ≥ 2 years after the onset of menopause. b. Willing to use two methods of reliable contraception including one highly effective contraceptive method (Pearl Index <1) and one additional effective (barrier) method during study treatment and for 12 months after the end of study treatment.
13. Known hypersensitivity to Venetoclax and Azacitidine. |
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E.5 End points |
E.5.1 | Primary end point(s) |
● Overall response rate (ORR=CR/CRi/MLFS rate, composite CR/CRh rate, PR rate).
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
When relevant data of all patients are available and validated |
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E.5.2 | Secondary end point(s) |
Secondary Endpoints: ● Overall survival (OS), duration of response (DOR), event free survival (EFS). ● Frequency and severity of adverse events (hema-AE grade 3+4, febrile neutropenia, days until neutrophil recovery ≥ 0.5 x 10E9/l and platelet recovery ≥ 50 x 10E9/l, severe AE grade 3+4). |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
When relevant data of all patients are available and validated |
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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 | 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 | No |
E.8.1.1 | Randomised | No |
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 | 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) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 1 |
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 | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 3 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
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 study is defined as the date when the last patient has received 2 years of treatment or been followed-up for at least 2 years after inclusion in the study. |
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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 | 10 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 10 |