HOVON 156 AML: Treatment for acute myeloid leukemia (AML) or myelodysplastic syndrome with a FLT3 mutation with gilteritinib or midostaurin in combination with chemotherapy.

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Hemato-Oncologie voor Volwassenen Nederland (Hovon) Stichting

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

20 Dec 2019 → ongoing

Decision date (initial)

2024-08-22

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

External identifiers

EU CT number

2022-502478-18-00

EudraCT number

2018-000624-33

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety, Therapy

To compare EFS 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.

Secondary objectives 11

1. To determine if treatment with gilteritinib, as compared to midostaurin, prolongs overall survival (OS) in the AML patient group.
2. To compare complete remission (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.
3. To compare CR and CR with incomplete hematologic recovery (CRi) rates after induction cycle 1 and after induction cycle 2 for treatment including gilteritinib vs. midostaurin in the AML patient group.
4. To compare relapse-free survival (RFS), cumulative incidence of relapse (CIR) and death (CID) after CR for treatment including gilteritinib vs. midostaurin in the AML patient group.
5. To evaluate minimal residual disease (MRD) status at sequential time points throughout treatment and CRMRD- rates between treatment including gilteritinib vs. midostaurin, using molecular and/or flow cytometric techniques in the AML patient group.
6. To assess the safety and tolerability of treatment including gilteritinib vs. midostaurin in the AML patient group.
7. To assess the time to hematopoietic recovery (ANC 0.5 and 1.0 x 109/L; platelets 50 and 100 x 109/L) after each chemotherapy treatment cycle in the AML patient group.
8. To assess the percentage of patients undergoing an allogeneic stem cell transplant (allo-SCT) in the AML patient group.
9. To determine quality of life (QoL) during maintenance treatment with gilteritinib vs. midostaurin in the AML patient group.
10. To evaluate the above mentioned endpoints (section 6.1, 6.2 and 6.3) 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.
11. To determine 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) in the AML patient group

Conditions and MedDRA coding

Acute Myeloid Leukemia (AML)

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 16

1. Age ≥18 years
2. Patient is capable of giving informed consent
3. 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.
4. 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.
5. 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.
6. Patient agrees not to participate in another interventional study while on treatment
7. 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.
8. 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%).
9. Considered to be eligible for intensive chemotherapy
10. Patient is suitable for oral administration of study drug
11. WHO/ECOG performance status ≤ 2
12. 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
13. Adequate renal function as defined by creatinine clearance > 40 mL/min based on the Cockroft-Gault glomerular filtration rate (GFR)
14. Written informed consent
15. 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.
16. 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 16

1. 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)
2. Acute promyelocytic leukemia (APL) with PML-RARA or one of the other pathognomonic variant fusion genes/chromosome translocations
3. Blast crisis after CML
4. Known or suspected hypersensitivity to midostaurin or gilteritinib and/or any excipients
5. Patient requires treatment with concomitant drugs that are strong inducers of cytochrome P450 (CYP) 3A
6. Breast feeding at start of study treatment
7. 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.
8. 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
9. 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
10. 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.
11. Patient with hypokalemia and/or hypomagnesemia before registration (defined as values below LLN) Note: electrolyte suppletion is allowed to correct LLN values before registration.
12. Dysphagia, short-gut syndrome, gastroparesis, or other conditions that limit the ingestion or gastrointestinal absorption of orally administered drugs
13. 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
14. Immediate life-threatening, severe complications of leukemia such as uncontrolled bleeding and/or disseminated intravascular coagulation
15. 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
16. Any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. 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.

Secondary endpoints 13

1. 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... (please find details in the protocol as this box is to limited)
2. Complete remission (CR) rate after remission induction, defined as CR as best response during or at completion of the induction treatment, as determined by the Investigator, based on the European LeukemiaNet (ELN2017) recommended response criteria18, 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 × 109/L (1000/μL); platelet count ≥ 100 × 109/L (100 000/μL) (see also Appendix B).
3. 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... (please find details in the protocol as this textfield is too limited)
4. CR and CR with incomplete hematologic recovery (CRi) rates after induction cycle 1 andafter induction cycle 2, as determined by the Investigator, based on the European LeukemiaNet (ELN2017) recommended response criteria18, where CRi is defined as: all CR criteria except for residual neutropenia [<1.0 x 109/L (1000/μL)] or thrombocytopenia [<100 x 109/L (100 000/μL)] (See also Appendix B).
5. 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.
6. 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.
7. 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.
8. 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), and with negativity by multi-color flow cytometry, if studied pre-treatment.
9. 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.
10. Frequency and severity of adverse events according to CTCAE version 5.0
11. Time to hematopoietic recovery (ANC 0.5 and 1.0 x 109/L; platelets 50 and 100x 109/L) after each chemotherapy treatment cycle, defined as the time from the start of the cycle until recovery.
12. Percentage of patients undergoing an allo-SCT.
13. Quality of Life (QoL) during maintenance treatment.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 3

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Hemato-Oncologie voor Volwassenen Nederland (Hovon) Stichting

Sponsor organisation

Hemato-Oncologie voor Volwassenen Nederland (Hovon) Stichting

Address

Dr. Molewaterplein 40

City

Rotterdam

Postcode

3015GD

Country

Netherlands

Scientific contact point

Organisation

Haemato Oncology Foundation For Adults Netherlands (HOVON)

Contact name

H.G.P. Raaijmakers

Public contact point

Organisation

Haemato Oncology Foundation For Adults Netherlands (HOVON)

Contact name

H.G.P. Raaijmakers

Third parties 3

Locations

11 EU/EEA countries · 141 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Oversight and notifications

Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77

Serious breaches 2 · Art. 52 CTR

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 51 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

16 submissions — initial application plus substantial / non-substantial modifications