| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Previously untreated Acute Myeloid Leukemia (AML) or Myelodysplastic syndromes with excess blasts-2 (MDS-EB2) with FLT3 mutations |
|
| E.1.1.1 | Medical condition in easily understood language |
| Previously untreated Acute Myeloid Leukemia (AML) or Myelodysplastic syndromes with excess blasts-2 (MDS-EB2) with FLT3 mutations |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10001941 |
| E.1.2 | Term | AML |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10068361 |
| E.1.2 | Term | MDS |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 compare overall survival (OS) between gilteritinib and midostaurin in combination with induction therapy and consolidation therapy followed by one-year maintenance therapy in patients with newly diagnosed AML with a FLT3 gene mutation eligible for intensive chemotherapy. |
|
| E.2.2 | Secondary objectives of the trial |
- To determine if treatment with gilteritinib, as compared to midostaurin, prolongs EFS in the AML patient group.
- To compare the CR rate after induction therapy (i.e., CR as best response during or at completion of induction) for treatment including gilteritinib vs. midostaurin in the AML patient group.
- To determine if treatment with gilt, as compared to mido, prolongs EFS with a modified CR by 60 days after the initiation of the last induction cycle (mEFS) in AML patients
- To compare CR and CR with CRi rates after induction cycle 1 and after induction cycle 2 for treatment including gilteritinib vs. midostaurin in the AML patient group.
- To compare RFS, CIR and CID for treatment including gilteritibib vs. midostaurin in the AML patient group.
PLEASE FIND REST OF OBJECTIVES IN PROTOCOL AS BOX IS TOO LIMITED.
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
• Age ≥18 years
• Newly diagnosed AML or MDS with excess of blasts-2 (EB2) defined according to WHO criteria (appendix A), with centrally documented FLT3 gene mutation (either TKD or ITD or both). AML may be secondary to prior hematological disorders, including MDS, and/or therapy-related. Patients may have had previous treatment with erythropoiesis stimulating agents (ESA) for MDS. ESA have to be stopped at least four weeks before registration
• FLT3 mutation as assessed by DNA fragment analysis PCR for FLT3-ITD and FLT3-TKD mutation. Positivity is defined as a FLT3-ITD or FLT3-TKD / FLT3-WT ratio of ≥ 0.05 (5%).
• Considered to be eligible for intensive chemotherapy
• Patient is suitable for oral administration of study drug
• WHO/ECOG performance status ≤ 2
• Adequate hepatic function as evidenced by
o Serum total bilirubin ≤ 2.5 × upper limit of normal (ULN) unless considered due to leukemic involvement following written approval by the (co) Principal Investigator
o Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) ≤ 3.0 × ULN, unless considered due to leukemic involvement following written approval by the (co) Principal Investigator
• Adequate renal function as defined by creatinine clearance > 40 mL/min based on the Cockroft-Gault glomerular filtration rate (GFR)
• Written informed consent
• Patient is capable of giving informed consent
• Female patient must either:
o Be of nonchildbearing potential:
Postmenopausal (defined as at least 1 year without any menses) prior to screening, or
Documented surgically sterile or status posthysterectomy (at least 1 month prior to screening)
o Or, if of childbearing potential,
Agree not to try to become pregnant during the study and for 6 months after the final study drug administration
And have a negative urine or serum pregnancy test at screening
And, if heterosexually active, agree to consistently use highly effective* contraception per locally accepted standards in addition to a barrier method starting at screening and throughout the study period and for 6 months after the final study drug administration.
*Highly effective forms of birth control include:
• Consistent and correct usage of established hormonal contraceptives that inhibit ovulation,
• Established intrauterine device (IUD) or intrauterine system (IUS),
• Bilateral tubal occlusion,
• Vasectomy (A vasectomy is a highly effective contraception method provided the absence of sperm has been confirmed. If not, an additional highly effective method of contraception should be used.)
• Male is sterile due to a bilateral orchiectomy.
• Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual activity during the entire period of risk associated with the study drug. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical study and the preferred and usual lifestyle of the patient.
*List is not all inclusive. Prior to enrollment, the investigator is responsible for confirming patient will utilize highly effective forms of birth control per the requirements of the CTFG Guidance document ‘Recommendations related to
contraception and pregnancy testing in clinical trials’, September 2014 (and any updates thereof) during the protocol defined period.
o Female patient must agree not to breastfeed starting at screening and throughout the study period, and for 2 months and 1 week after the final study drug administration.
o Female patient must not donate ova starting at screening and throughout the study period, and for 6 months after the final study drug administration.
• Male patient and their female partners who are of childbearing potential must be using highly effective contraception per locally accepted standards in addition to a barrier method starting at screening and continue throughout the study period and for 4 months and 1 week after the final study drug administration.
• Male patient must not donate sperm starting at screening and throughout the study period and for 4 months and 1 week after the final study drug administration.
• Patient agrees not to participate in another interventional study while on treatment
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|
| E.4 | Principal exclusion criteria |
• Prior chemotherapy for AML or MDS-EB2, including prior treatment with hypomethylating agents. Hydroxyurea is allowed for the control of peripheral leukemic blasts in patients with leukocytosis (e.g., white blood cell [WBC] counts > 30 x 109/L)
• Acute promyelocytic leukemia (APL) with PML-RARA or one of the other pathognomonic variant fusion genes/chromosome translocations
• Blast crisis after CML
• Known or suspected hypersensitivity to midostaurin or gilteritinib and/or any excipients
• Patient requires treatment with concomitant drugs that are strong inducers of cytochrome P450 (CYP) 3A
• Breast feeding at start of study treatment
• Active infection, including hepatitis B or C or HIV infection that is uncontrolled at randomization. An infection controlled with an approved or closely monitored antibiotic/antiviral/antifungal treatment is allowed.
• Patients with a currently active second malignancy. Patients are not considered to have a currently active malignancy if they have completed therapy and are considered by their physician to be at less than 30% risk of relapse within one year. However, patients with the following history/concurrent conditions are allowed:
o Basal or squamous cell carcinoma of the skin;
o Carcinoma in situ of the cervix;
o Carcinoma in situ of the breast;
o Incidental histologic finding of prostate cancer
• Significant active cardiac disease within 6 months prior to the start of study treatment, including:
o New York Heart Association (NYHA) Class III or IV congestive heart failure;
o Myocardial infarction;
o Unstable angina and/or stroke;
o Left ventricular ejection fraction (LVEF) < 40% by ECHO or MUGA scan obtained within 28 days prior to the start of study treatment
• QTc interval using Fridericia’s formula (QTcF) ≥ 450 msec (average of triplicate determinations) or other factors that increase the risk of QT prolongation or arrhythmic events (e.g., heart failure, family history of long QT interval syndrome). Prolonged QTc interval associated with bundle branch block or pacemaking is permitted with written approval of the (co) Principal Investigator.
• Patient with hypokalemia and/or hypomagnesemia before registration (defined as values below LLN) Note: electrolyte suppletion is allowed to correct LLN values before registration.
• Dysphagia, short-gut syndrome, gastroparesis, or other conditions that limit the ingestion or gastrointestinal absorption of orally administered drugs
• Clinical symptoms suggestive of active central nervous system (CNS) leukemia or known CNS leukemia. Evaluation of cerebrospinal fluid (CSF) during screening is only required if there is a clinical suspicion of CNS involvement by leukemia during screening
• Immediate life-threatening, severe complications of leukemia such as uncontrolled bleeding and/or disseminated intravascular coagulation
• Any other medical or psychological condition deemed by the Investigator to be likely to interfere with a patient’s ability to give informed consent or participate in the study
• Any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Overall survival (OS), defined as the time from date of randomization to the date of death due to any cause. Patients still alive or lost to follow up will be censored at the time they were last known to be alive. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
The primary analysis of the study, with the main purpose to evaluate treatment effect by comparing OS within the AML patients, will be performed at a defined time, provided that all clinical data collected until that time-point are clean, verified and locked according to the data management plan.
PLEASE FIND FURTHER DETAILS IN THE PROTOCOL AS THIS BOX IS TOO LIMITED. |
|
| E.5.2 | Secondary end point(s) |
Key secondary endpoints:
• Event-free survival (EFS), defined as the time from randomization to failure to achieve CR after remission induction, death or relapse after achieving CR, whichever occurs first. A patient is said to have failed to achieve CR after remission induction if his/her best response during or at completion of the induction therapy is less than CR. Patients who achieved CR after remission induction and are not known to have relapsed or died will be censored at the date of last clinical assessment. CR is determined by the Investigator according to the European LeukemiaNet (ELN2017) recommended response criteria.
• Complete remission (CR) rate after remission induction, defined as best response of CR during or at completion of the induction treatment, as determined by the Investigator, based on the European LeukemiaNet (ELN2017) recommended response criteria, where CR is defined as: bone marrow blasts < 5%; absence of circulating blasts and blasts with Auer rods; absence of extramedullary disease; ANC ≥ 1.0 × 10^9/L (1000/µL); platelet count ≥ 100 × 10^9/L (100 000/µL).
• EFS with modified CR (mEFS) is defined similarly to EFS above. It is the time from randomization to failure to achieve CR after remission induction, death or relapse after achieving CR, whichever occurs first.
However, a patient will be considered to have failed to achieve CR after remission induction if CR is not achieved within 60 days after the start of the last induction cycle. CR will be derived programmatically based upon the FDA (FDA 2022) recommended response criteria with the requirement that bone marrow and peripheral blood tests must be within 7 days of each other. Patients who achieve CR within 60 days of the start of the last induction cycle and are not known to have relapsed or died will be censored at the date of last clinical assessment.
Other secondary endpoints:
• CR and CR with incomplete hematologic recovery (CRi) rates after induction cycle 1 and after induction cycle 2, as determined by the Investigator, based on the European LeukemiaNet (ELN2017) recommended response criteria, where CRi is defined as: all CR criteria except for residual neutropenia [<1.0 x 10^9/L (1000/μL)] or thrombocytopenia [<100 x 10^9/L (100 000/μL)].
• Relapse-free survival (RFS) after CR as determined by the Investigator, defined as time from the date of achievement of CR until relapse or death from any cause, whichever comes first. Patients still in first CR and alive or lost to follow up will be censored at the date of last clinical assessment.
• Cumulative incidence of relapse (CIR) after CR as determined by the Investigator , as measured from the date of achievement of CR until the date of relapse. Patients not known to have relapsed will be censored on the date of last clinical assessment. Patients who died without relapse will be counted as a competing cause of failure.
• Cumulative incidence of death (CID) after CR as determined by the Investigator, as measured from the date of achievement of CR until the date of death from any cause. Patients not known to have died will be censored on the date they were last known to be alive. Patients who experienced relapse in CR will be counted as competing cause of failure.
• CR without minimal residual disease (CRMRD-) rate after induction cycle 2, defined as CR as determined by the
Investigator with negativity for a genetic marker by realtime quantitative polymerase chain reaction (RT-qPCR), or CR with negativity by multi-color flow cytometry, if studied pre-treatment.
• CR or CRi without minimal residual disease (CR/CRiMRD-) rate after induction cycle 2, defined as CR/CRi as determined by the Investigator with negativity for a genetic marker by realtime quantitative polymerase chain reaction (RT-qPCR), and with negativity by multi-color flow cytometry, if studied pre-treatment.
• Frequency and severity of adverse events according to CTCAE version 5.0
• Time to hematopoietic recovery (ANC 0.5 and 1.0 x 10^9/L; platelets 50 and 100x 10^9/L) after each chemotherapy treatment cycle, defined as the time from the start of the cycle until recovery.
• Percentage of patients undergoing an allo-SCT.
• Quality of Life (QoL) during maintenance treatment. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| PLEASE FIND DETAILS OF THE TIMEPOINT(S) OF EVALUATION IN THE PROTOCOL AS THIS BOX IS TOO LIMITED. |
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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 | 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) | Yes |
| E.8.2.2 | Placebo | No |
| 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 | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 178 |
| 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 |
| Australia |
| Austria |
| Belgium |
| Finland |
| France |
| Germany |
| Ireland |
| Lithuania |
| Luxembourg |
| Netherlands |
| Norway |
| Spain |
| Sweden |
|
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 13 |
| 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 | 13 |
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