HOVON 156 AML: A phase 3, multicenter, open-label, randomized, study of gilteritinib versus midostaurin in combination with induction and consolidation therapy followed by one-year maintenance in patients with newly diagnosed Acute Myeloid Leukemia (AML) or Myelodysplastic syndromes with excess blasts-2 (MDS-EB2) with FLT3 mutations eligible for intensive chemotherapy.
- Trial ID
- 2022-502478-18-00
- Protocol
- HO156
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to compare **event-free survival (EFS)** between gilteritinib and midostaurin when used in combination with induction and consolidation therapy, followed by one-year maintenance therapy in patients with newly diagnosed **Acute Myeloid Leukemia (AML)** with a **FLT3 gene mutation** who are eligible for intensive chemotherapy. This objective is clinically relevant as it aims to determine the efficacy of gilteritinib in prolonging the period during which patients remain free from events such as disease progression or relapse, which is crucial for improving long-term outcomes in AML treatment.
Secondary objectives include:
- Determining if treatment with gilteritinib, as compared to midostaurin, prolongs overall survival (OS) in the AML patient group.
- Comparing complete remission (CR) rate after induction therapy for treatment including gilteritinib vs. midostaurin.
- Comparing CR and CR with incomplete hematologic recovery (CRi) rates after induction cycles for treatment including gilteritinib vs. midostaurin.
- Comparing relapse-free survival (RFS), cumulative incidence of relapse (CIR), and death (CID) after CR for treatment including gilteritinib vs. midostaurin.
- Evaluating minimal residual disease (MRD) status at sequential time points throughout treatment and CRMRD- rates between treatments.
- Assessing the safety and tolerability of treatment including gilteritinib vs. midostaurin.
- Assessing the time to hematopoietic recovery after each chemotherapy treatment cycle.
- Assessing the percentage of patients undergoing an allogeneic stem cell transplant (allo-SCT).
- Determining quality of life (QoL) during maintenance treatment with gilteritinib vs. midostaurin.
- Evaluating the above-mentioned endpoints between gilteritinib and midostaurin in combination with induction and consolidation therapy followed by one-year maintenance therapy in subjects with Myelodysplastic Syndromes (MDS) with excess blasts-2 (EB2) with a FLT3 gene mutation eligible for intensive chemotherapy.
- Determining if treatment with gilteritinib, as compared to midostaurin, prolongs EFS with a modified CR by 60 days after the initiation of the last induction cycle (mEFS).
Participants
The clinical trial involves a total of **80 participants** diagnosed with **Acute Myeloid Leukemia (AML)** or MDS-EB2, specifically those with a FLT3 gene mutation. The study population includes both male and female subjects, aged **18 years and older**, who are eligible for intensive chemotherapy. Participants were selected based on their ability to undergo oral administration of the study drug and their adequate hepatic and renal function. The trial includes individuals with a WHO/ECOG performance status of 2 or lower. Participants are required to adhere to specific lifestyle considerations, such as the use of highly effective contraception methods and abstaining from donating ova or sperm during and after the study period. The trial population is considered vulnerable, and all participants have provided written informed consent. The study does not specify any particular dietary or physical activity requirements.
Plans and Procedures
The clinical trial is a **randomized**, open-label, phase III study designed to compare the efficacy of **gilteritinib** versus **midostaurin** in combination with induction and consolidation therapy, followed by one-year maintenance therapy in patients with newly diagnosed **Acute Myeloid Leukemia (AML)** or **Myelodysplastic Syndromes with Excess Blasts-2 (MDS-EB2)** with **FLT3** mutations. The trial aims to evaluate event-free survival (EFS) as the primary endpoint, with secondary endpoints including overall survival (OS), complete remission (CR) rates, and quality of life (QoL) during maintenance treatment. The study is expected to run from October 2018 to October 2031, with participant involvement lasting up to 422 days, depending on individual response and treatment adherence.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age, performance status, and organ function. Following randomization, participants will receive either gilteritinib or midostaurin orally, with the treatment regimen including induction, consolidation, and maintenance phases. Regular follow-up visits will be conducted to monitor treatment response, adverse events, and overall health status. The end-of-study visit will occur after the completion of the maintenance phase or upon early termination from the study.
Early termination from the study may occur due to reasons such as disease progression, unacceptable toxicity, withdrawal of consent, or non-compliance with study procedures. Participants are required to adhere to specific contraceptive measures and agree not to participate in other interventional studies during the trial period. The trial is conducted under strict ethical guidelines, ensuring informed consent and the safety of all participants throughout the study duration.
Treatment
The clinical trial involves the administration of **Rydapt** (midostaurin) 25 mg soft capsules, which are provided by Novartis Europharm Limited. The pharmaceutical form of this medication is a soft capsule, and it is administered orally. The maximum daily dose is 100 mg, with a total maximum dose of 42,200 mg over a treatment period of 422 days. Midostaurin is a chemical substance, and its use in this trial is designated as an orphan drug. The medication is not formulated for pediatric use.
Another treatment used in the trial is **Xospata** (gilteritinib) 40 mg film-coated tablets, manufactured by Astellas Pharma Europe B.V. This medication is also administered orally, with a maximum daily dose of 120 mg and a total maximum dose of 50,640 mg over the same treatment period of 422 days. Gilteritinib is a chemical substance and is not designated as an orphan drug in this study. Similar to Rydapt, Xospata is not formulated for pediatric use.
Both medications are used in combination with induction and consolidation therapy, followed by a one-year maintenance therapy in patients with newly diagnosed **Acute Myeloid Leukemia** (AML) or Myelodysplastic syndromes with excess blasts-2 (MDS-EB2) with FLT3 mutations. The trial aims to compare the event-free survival (EFS) between the two treatments. Participant compliance with the dosing schedule is monitored throughout the study to ensure adherence to the prescribed regimen.
Efficacy
The efficacy of the clinical trial will be assessed using several primary and secondary endpoints. The primary endpoint is **Overall Survival (OS)**, defined as the time from the date of randomization to the date of death from any cause. Patients who are still alive or lost to follow-up will be censored at the last time they were known to be alive.
Secondary endpoints include **Event-Free Survival (EFS)**, which is defined as the time from randomization to failure to achieve complete remission (CR) after remission induction, death, or relapse after achieving CR, whichever occurs first. The **Complete Remission (CR) rate** after remission induction will also be evaluated, based on the European LeukemiaNet (ELN2017) recommended response criteria, where CR is defined as bone marrow blasts less than 5%, absence of circulating blasts and blasts with Auer rods, absence of extramedullary disease, absolute neutrophil count (ANC) ≥ 1.0 × 109/L, and platelet count ≥ 100 × 109/L.
Additional secondary endpoints include **Relapse-Free Survival (RFS)** after CR, **Cumulative Incidence of Relapse (CIR)**, **Cumulative Incidence of Death (CID)** after CR, and **CR without Minimal Residual Disease (CRMRD-) rate** after induction cycle 2. The frequency and severity of adverse events will be assessed according to CTCAE version 5.0. The trial will also measure the time to hematopoietic recovery after each chemotherapy treatment cycle and the percentage of patients undergoing an allogeneic stem cell transplant (allo-SCT). Quality of Life (QoL) during maintenance treatment will be evaluated as well.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Age ≥18 years
- 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
- 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) or hypomethylating agents (HMAs) for an antecedent phase of MDS. ESA and HMAs 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
- 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.
- Female patient must not donate ova starting at screening and throughout the study period, and for 6 months after the final study drug administration
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
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Austria | Not Recruiting | 05 Oct 2018 | 10 |
 Belgium | Not Recruiting | 05 Oct 2018 | 45 |
 Finland | Not Recruiting | 05 Oct 2018 | 10 |
 France | Not Recruiting | 05 Oct 2018 | 230 |
 Germany | Not Recruiting | 05 Oct 2018 | 190 |
 Ireland | Not Recruiting | 05 Oct 2018 | 15 |
 Lithuania | Not Recruiting | 05 Oct 2018 | 10 |
 The Netherlands | Not Recruiting | 05 Oct 2018 | — |
 Norway | Not Recruiting | 05 Oct 2018 | 25 |
 Spain | Not Recruiting | 05 Oct 2018 | 20 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Rydapt 25 mg soft capsules | Test | SOFT CAPSULES | ORAL | 100 | 422 | PRD5414155 |
Xospata 40 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL USE | 120 | 422 | PRD8022659 |
Rydapt 25 mg soft capsules | Test | SOFT CAPSULES | ORAL | 100 | 422 | PRD5589815 |