| 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] - Blood and lymphatic diseases [C15] |
| 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 |
To assess clinical efficacy of sequential or one-dose gemtuzumab ozogamicin as adjunct to induction therapy in older patients with newly diagnosed AML. Clinical efficacy is determined by MRD-negativity after induction therapy.
To assess clinical efficacy of glasdegib as adjunct to 2 months consolidation and as single agent 6 months maintenance therapy in older patients with newly diagnosed AML. Clinical efficacy is determined by event-free survival (EFS) defined as the time from randomization to time until one of the following events, whichever occurs first: a) failure to obtain complete remission (CR) or complete remission with incomplete hematological recovery (CRi), b) relapse from complete remission for patients with induction success or c) death from any cause. Patients without an applicable event are censored on the last date of follow-up.
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| E.2.2 | Secondary objectives of the trial |
Complete remission rate (CRR) and overall survival (OS).
Relapse-free survival (RFS), defined as the time from achievement of a CR/CRi after randomization to time of recurrence of the disease or death from any cause, whatever occurs first.
Assessment of patient reported outcomes.
Evaluation of safety based on duration of neutropenia and leukopenia, incidence of infection, duration of initial hospitalization.
Cost-effectiveness analysis of the four different treatment schedules from health care payer´s perspective.
Budget impact analysis of introducing effective treatment schedule(s) in everyday clinical practice.
Mapping the EORTC QLQ-C30 cancer specific instrument to the SF-36 generic instrument for older patients with newly diagnosed AML in Germany.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
• Patients with newly diagnosed CD33 positive acute myeloid leukemia according to the 2016 WHO classification
• Genetic and immunophenotypic assessment in the central laboratory
• No prior chemotherapy for leukemia except hydroxyurea to control hyperleukocytosis (≤7 days) *
• Age ≥60 years, no upper age limit
• Eastern Cooperative Oncology Group performance status (ECOG PS) ≤2. See appendix 19.1
• Signed written informed consent
• Ability of patient to understand character and consequences of the clinical trial
• Non-pregnant and non-nursing women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test within a sensitivity of at least 25 mIU/mL within 72 hours prior to start of study treatment. A woman is considered of childbearing potential, i.e. fertile, following menarche and until becoming post-menopausal unless permanently sterile.
• WOCBP must be using an effective method of birth control to avoid pregnancy throughout the study and for 7 months after the last dose of the IMP. This includes effective contraception methods that can achieve a failure rate of less than 1% per year (e.g. hormonal contraceptive and condom, IUD/IUS and condom) or sterilization, resulting in a failure rate less than 1% per year.
• Fertile men must be willing and able to use an effective method of birth control (i.e. latex condoms) throughout the study for up to 7 months after the last dose of the IMP, if their sexual partners are WOCBP (acceptable methods see above). A man is considered fertile after puberty unless permanently sterile by bilateral orchidectomy.
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| E.4 | Principal exclusion criteria |
• AML with PML-RARA or BCR-ABL1
• Patients with known active central nervous system (CNS) leukemia (assessed clinically).
• Prior treatment with a smoothened inhibitor (SMOi) and/or hypomethylating agent (HMA) for AML. (treatment of a preceding myelodysplastic syndrome (MDS) with HMA is not an exclusion criterion.)
• Inadequate renal function: creatinine >1.5 x upper normal serum level; estimated creatinine clearance ≤30 mL/min (calculated using the standard method for the institution).
• Inadequate liver function: ALT and AST ≥2.5 x ULN), total bilirubin ≥1.5 x ULN; Alkaline phosphatase ≥2.5 x ULN. Known liver cirrhosis or history of sinusoidal obstruction syndrome (SOS), also known as hepatic veno-occlusive disease (VOD)
• Uncontrolled hypertension; severe obstructive or restrictive ventilation disorder
• Any one of the following ongoing or in the previous 6 months: myocardial infarction, congenital long QT syndrome, Torsades de pointes, arrhythmias (including sustained ventricular tachyarrhythmia), right or left bundle branch block and bifascicular block, unstable angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure (CHF NYHA III/IV), cerebrovascular accident, transient ischemic attack or symptomatic pulmonary embolism; as well as bradycardia defined as <50 bpms
• QTc interval >470 msec using the Fridericia correction (QTcF).
• Uncontrolled infection
• Patients known to be refractory to platelet or packed red cell transfusions as per institutional guidelines, or who are known to refuse or who are likely to refuse blood product support.
• Patients with a “currently active” second malignancy other than non-melanoma skin cancer. Patients are not considered to have a “currently active” malignancy if they have completed therapy for more than one year and are considered by their physician to be at less than 30% risk of relapse within one year.
• Severe neurologic or psychiatric disorder interfering with ability of giving informed consent
• Known or suspected active alcohol or drug abuse
• Known positivity for human immunodeficiency virus (HIV), active hepatitis B virus (HBV), hepatitis C virus (HCV), or hepatitis A infection
• Evidence or history of severe non-leukemia associated bleeding diathesis or coagulopathy
• No consent for biobanking and for registration, storage and processing of the individual disease-characteristics and course as well as information of the family physician about study participation.
• Pregnancy and lactation
• History of hypersensitivity to the investigational medicinal product or to any drug with similar chemical structure or to any excipient present in the pharmaceutical form of the investigational medicinal product
• Participation in a clinical study involving an investigational drug(s) (Phases 1-4) within 4 weeks prior to study entry. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
For the gemtuzumab ozogamicin primary objective, the primary estimand according to the ICH-E9 (R1) [40] addendum is defined as:
Treatment: GO-147 (experimental arm) compared to GO-1 (control arm)
Population: all patients fulfilling the in- and exclusion criteria
Variable: MRD-negativity (MRD) defined as absence of leukemic cells at the end of the induction therapy assessed by flow-cytometry.
Post-randomisation events: if MRD-negativity cannot be measured, the outcome will be imputed (hypothetical strategy; see also Section 10.5.3), the outcome of patients who drop out of the study before MRD measurement will be imputed (hypothetical strategy; see also Section 10.5.3), changes in treatment, or discontinuation of treatment will be ignored (treatment policy strategy), any-cause death before MRD measurement will be regarded as MRD-positive (composite strategy).
Summary measure: Odds ratio for the endpoint MRD-negativity between the two treatment arms
For the glasdegib primary objective, the primary estimand is defined as:
Treatment: HiDAC + glasdegib (experimental arm) compared to HiDAC + placebo (control arm)
Population: all patients fulfilling the in- and exclusion criteria
Variable: Event-free survival (EFS) defined as the time from randomization to time until one of the following events, whichever occurs first: a) failure to obtain complete remission (CR) or complete remission with incomplete hematological recovery (CRi), b) relapse from complete remission for patients with induction success or c) death from any cause.
Post-randomisation events: death from any cause is incorporated into the variable definition (composite strategy); changes in treatment and termination of treatment will be ignored (treatment policy strategy); event-free patients at the end of the follow-up period will be censored and patients who were lost to follow up or dropped out of the trial will be censored at the last observation (hypothetical strategy).
Summary measure: Hazard ratio for the endpoint disease-free survival between the two treatment arms
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
• Complete remission rate (CRR), defined as the proportion of patients experiencing CR/CRi after induction therapy
• Relapse-free survival (RFS), defined as the time from achievement of CR/CRi after randomization to time of recurrence of the disease or death from any cause, whatever occurs first. Patients without an applicable event are censored on the last date of follow-up. [time frame: up to LPLV]
• Overall survival (OS), defined as the time from randomization to time of death from any cause. Patients without an applicable event are censored on the last date of follow-up. [time frame: up to LPLV]
• Patient-Reported Outcomes including Quality of Life:
o Health-related quality of life (QoL) is calculated as the new EORTC QLQ-C30 Summary Score recommended by the EORTC Quality of Life Group, which has been recently developed and evaluated [41]. In addition, the EORTC QLQ function and symptom scores is calculated according to the actual EORTC Scoring Manual [42].
o Fatigue is calculated from the EORTC QLQ-FA12 according to the EORTC Scoring Manual [42].
o Sleep problems is calculated from the PSQI according to the corresponding scoring guidelines [43].
o Perceived cognitive impairments and impact of cognitive changes is calculated from the FACT-cog according to the corresponding scoring manual.
o Anxiety is calculated from the PHQ-4 according to the corresponding scoring manual [44].
o Depression is calculated from the PHQ-4 according to the corresponding scoring manual [44].
o Health state utilities are calculated based on the SF-36 generic instrument [45].
• Effectiveness of the investigational treatment is measured using the SF-36 generic instrument. A preference based single index is calculated using the SF-6D measure that facilitates obtaining health utilities and quality adjusted life years (QALYs).
• Health care resource utilization and costs are measured through the treatment course. Resource units and unit costs are collected separately by self-administered questionnaires at the end of each cycle and 3-monthly during maintenance therapy, as well as using relevant data from the eCRF and German reimbursement database.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | 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 | Yes |
| 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 | 4 |
| 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 | 25 |
| E.8.5 | The trial involves multiple Member States | No |
| 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 | 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 | 4 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
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