| 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 | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
To compare the efficacy of magrolimab + venetoclax + azacitidine versus placebo + venetoclax + azacitidine in patients with previously untreated acute myeloid leukemia (AML) who are ineligible for intensive chemotherapy as measured by complete remission (CR) rate within 6 cycles of treatment
To compare the efficacy of magrolimab + venetoclax + azacitidine versus placebo + venetoclax + azacitidine in patients with previously untreated AML who are ineligible for intensive chemotherapy as measured by overall survival (OS) |
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| E.2.2 | Secondary objectives of the trial |
To compare the efficacy of magrolimab (M) + venetoclax (V) + azacitidine (A) versus placebo (P) + V + A as measured by rate of CR without minimal residual disease (CRMRD-) within 6 cycles
To compare the efficacy of M+V+A vs P+V+A as measured by the rate of CR + complete remission with partial hematologic recovery (CRh) within 6 cycles
To evaluate the duration of complete remission (DCR) in patients who achieved CR within 6 cycles
To evaluate the duration of CR + CRh in patients who achieved CR or CRh within 6 cycles
To compare the efficacy of M+V+A vs P+V+A as measured by conversion rate of transfusion dependence to transfusion independence
To compare the efficacy of M+V+A vs P+V+A as measured by EFS
To compare the efficacy of M+V+A vs P+V+A as measured by time until meaningful definitive deterioration (TUDD) on the GHS/QoL and the physical functioning scales of the EORTC QLQC30
To assess the safety and tolerability of M+V+A vs P+V+A
To evaluate the PK and immunogenicity of M |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1) Previously untreated patients with histological confirmation of AML by World Health Organization criteria who are ineligible for treatment with a standard cytarabine and anthracycline induction regimen due to age, or comorbidity. Patients must be considered ineligible for intensive chemotherapy, defined by the following:
a) ≥ 75 years of age;
Or
b) ≥ 18 to 74 years of age with at least 1 of the following comorbidities:
i) Eastern Cooperative Oncology Group (ECOG) performance status of 2 or 3,
ii) Diffusing capacity of the lung of carbon monoxide ≤ 65% or forced expiratory volume in 1 second ≤ 65%,
iii) Left ventricular ejection fraction ≤ 50%,
iv) Baseline creatinine clearance ≥ 30 mL/min to < 45 mL/min calculated by the Cockcroft Gault formula or measured by 24-hour urine collection,
v) Hepatic disorder with total bilirubin > 1.5 x upper limit of normal (ULN)
vi) Any other comorbidity that the investigator judges to be incompatible with intensive chemotherapy that must be approved by the sponsor’s medical monitor before study enrollment
2) ECOG performance status:
a) Of 0 to 2 for subjects ≥ 75 years of age
Or
b) Of 0 to 3 for subjects ≥ 18 to 74 years of age
3) Patients with white blood cell (WBC) count ≤ 20 x 10^3/μL prior to randomization. If the patient’s WBC is > 20 x10^3/μL prior to randomization, the patient can be enrolled, assuming all other eligibility criteria are met. However, the WBC should be ≤ 20 x 10^3/μL prior to the first dose of study treatment and prior to each magrolimab/placebo dose during Cycle 1.
NOTE: Patients can be treated with hydroxyurea and/or leukapheresis prior to randomization and throughout the study to reduce the WBC to ≤ 20 x 103/μL to enable eligibility for study drug dosing.
4) Hemoglobin must be ≥ 9 g/dL prior to initial dose of study treatment.
NOTE: Transfusions are allowed to meet hemoglobin eligibility.
5) Patient has provided informed consent.
6) Patient is willing and able to comply with clinic visits and procedures outlined in the study protocol.
7) Male or female, ≥ 18 years of age
8) Patients must have 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.
9) Adequate liver function as demonstrated by:
a) aspartate aminotransferase ≤ 3.0 x upper limit of normal (ULN)
b) alanine aminotransferase ≤ 3.0 x ULN
c) total bilirubin ≤ 1.5 x ULN, or primary unconjugated bilirubin ≤ 3.0 x ULN if patient has a documented history of Gilbert’s syndrome or genetic equivalent. Patients ≥ 18 to 74 years of age may have total bilirubin ≤ 3.0 x ULN
10) Pretreatment blood cross-match completed
11) Male and female patients of childbearing potential who engage in heterosexual intercourse must agree to use protocol-specified method(s) of contraception.
12) Patients must be willing to consent to mandatory pretreatment and on-treatment bone marrow assessments (aspirate and trephines). |
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| E.4 | Principal exclusion criteria |
1) Positive serum pregnancy test
2) Breastfeeding female
3) Known hypersensitivity to any of the study drugs, the metabolites, or formulation excipient
4) Patients receiving any live virus vaccine within 4 weeks prior to initiation of study treatments.
5) Prior treatment with any of the following:
a) CD47 or signal regulatory protein alpha-targeting agents
b) Antileukemic therapy for the treatment of AML (eg, hypomethylating agents (HMAs), low-dose cytarabine, and/or venetoclax), excluding hydroxyurea
NOTE: Patients with prior myelodysplastic syndrome (MDS) who have not received prior HMAs or venetoclax or chemotherapeutic agents for MDS may be enrolled in the study. Prior treatment with MDS therapies including, but not limited to lenalidomide, erythroid-stimulating agents, or similar red blood cell (RBC-), WBC-, or platelet-direct therapies or growth factors is allowed for these patients.
6) Current participation in another interventional clinical study
7) Known inherited or acquired bleeding disorders
8) Patients who have received treatment with strong and/or moderate CYP3A inducers (eg, preparations containing St. John’s wort) within 7 days prior to the initiation of study treatments
9) Patients who have consumed grapefruit, grapefruit products, Seville oranges (including marmalade containing Seville oranges) or starfruit within 3 days prior to the initiation of study treatment and are unwilling to discontinue consumption of these throughout the
receipt of study drug
10) Patients who have malabsorption syndrome or other conditions that preclude enteral route of administration
11) Clinical suspicion of or documented active central nervous system (CNS) involvement with AML
12) Patients who have acute promyelocytic leukemia
13) Significant disease or medical conditions, as assessed by the investigator and sponsor, that would substantially increase the risk-benefit ratio of participating in the study. This includes, but is not limited to, acute myocardial infarction within the last 6 months, unstable angina, uncontrolled diabetes mellitus, significant active infections, and congestive heart failure New York Heart Association Class III to IV.
14) Known history, diagnosis, or suspicion of Hemophagocytic Lymphohistiocytosis (HLH) syndrome.
15) Second malignancy, except MDS, treated basal cell or localized squamous skin carcinomas, localized prostate cancer, or other malignancies for which patients are not on active anticancer therapies and have had no evidence of active malignancy for at least 1 year
NOTE: Patients on maintenance therapy alone who have no evidence of active malignancy for at least ≥ 1 year are eligible.
NOTE: Localized non-CNS radiotherapy, erythroid and/or myeloid growth factors, hormonal therapy with luteinizing hormone-releasing hormone agonists for prostate cancer, hormonal therapy or maintenance for breast cancer, and treatment with bisphosphonates and receptor activator of nuclear factor kappa-B ligand inhibitors are also not criteria for exclusion.
16) Known medical history of active human immunodeficiency virus infection or medical history of active active or chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infection or HIV infection in medical history within 3 months of study entry.
Active HBV, and/or active HCV, and/or HIV following testing at screening:
a) Patients who test positive for hepatitis B surface antigen. Patients who test positive for hepatitis B core antibody will require HBV DNA by quantitative polymerase chain reaction (PCR) for confirmation of active disease.
b) Patients who test positive for HCV antibody. These patients will require HCV RNA quantitative PCR for confirmation of active disease.
c) Patients who test positive for HIV antibody.
d) Patients not currently receiving antiviral therapy and who have an undetectable viral load in the prior 3 months may be eligible for the study |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
CR rate within 6 cycles of treatment, defined as the proportion of patients who achieve CR within 6 cycles of treatment as determined by the investigator.
OS, measured from the date of randomization to the date of death from any cause. Those whose deaths are not observed during the study will be censored at their last known alive date. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
CR rate within 6 cycles of treatment.
OS from date of randomization to the date of death from any cause. Those whose deaths are not observed during the study will be censored at their last known alive date. |
|
| E.5.2 | Secondary end point(s) |
- Rate of CRMRD- within 6 cycles of treatment
- Rate of CR + CRh within 6 cycles of treatment
- DCR in patients who achieved CR within 6 cycles of treatment
- Duration of CR + CRh in patients who achieved CR or CRh within 6 cycles of treatment
- Transfusion independence conversion rate
- EFS
- TUDD on the GHS/QoL and the physical functioning scales of the EORTC QLQC30
- Incidence of treatment-emergent adverse events (AEs) and clinical laboratory abnormalities during the study
- Magrolimab serum concentrations over time
- Incidence/prevalence rate and magnitude of anti-magrolimab antibodies in serum |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Rate of CRMRD-, CR + CRh, DCR in patients who achieved CR, duration of CR + CRh in patients who achieved CR or CRh, evaluated within 6 cycles of treatment.
Please see protocol for extensive Schedule of assessments. |
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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 | Yes |
| 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) | 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 | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| 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 | 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 75 |
| 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 |
| Hong Kong |
| Austria |
| Belgium |
| Canada |
| Czechia |
| Germany |
| Hungary |
| Israel |
| Italy |
| Korea, Republic of |
| Netherlands |
| Poland |
| Russian Federation |
| Spain |
| Taiwan |
| United Kingdom |
| United States |
| France |
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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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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| 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 | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 7 |
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