HOVON HO156 AML

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Main info

Identificatie:
HOVON 156 AML / AMLSG 28-18
Sponsor:
HOVON
Working group party:
Leukemia
Age:
>= 18
Stadium:
1st lijn
Echelon:
Level C-HIC&C-SCT
Included patients:
207
(of 768)
Active sites:
126
(of 200)
66 sites are pending
Title:

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.

Timeline

Scheduled
Actual
2017
11 sep.
Opportunity
2017
31 okt.
Development
2017
20 dec.
Development
2018
28 feb.
Submission in Progress
2018
01 apr.
EC Approval
2018
30 jun.
Activated
2018
02 aug.
Submission in Progress
2019
02 aug.
EC Approval
2019
31 okt.
First Site
2019
18 nov.
Activated
2019
18 nov.
First Site
2019
30 nov.
FPI
2019
20 dec.
FPI
2022
31 dec.
Endpoint Analysis
2022
31 dec.
ClosedForInclusionScheduledStart
2032
31 dec.
Closeout in Progress
2033
31 dec.
Archived

News

19MAY2021 Correction on the EC approval
With regards to the EC approval, in their list of approved documents the EC had by accident not copied down the correct IB midostaurin version 24 date. This was mentioned as 24-7-2019. They have now updated it to the correct date: 2-4-2020. The updated EC aproval can be found in the downloads section.

19MAY2021 Usage of Addendum
For the Netherlands we received the question if the Addendum should be used for all patients, or just the Arm B (Gilteritinib) patients, as the updates are only relevant for them. We have requested this to our central EC, and indeed they approve that only patients that signed the previous ICF (02APR2019) and were randomized to Arm B need to sign the addendum.

16DEC2020 Update site lab manual
We have send out the site labmanual to all active sites, this document can also be found in the study documents at the bottom of this page.

04MAR2020 IF update
The IF has been updated to add a very small update of the assessment instructions that incorrectly indicated page 1 of 2 in to the top right corner, while it only existed out of 1 page. As this update is so minor it was not send out to the sites separately.

14JAN2020 IF update
The IF has been update to add the latest version of the lab manual.

20DEC2019 First study site activation
Very first study site (NL-Rotterdam-ERASMUSMC) has been activated.

02DEC2019 IF update
The IF has been update to add the eCRF instructions as well.

27NOV2019 IF update
The IF has been updated to add the new pharmacy manual.

18NOV2019 Study activation
Study has been activated

01NOV2019 IF update
The ITF has been updated as we received a new IB for Midosaturin (v23). We have updated the IF accordingly. Please download the latest IF. Also the site document checklist has been updated as the CV of the independent physician is also needed for site activation.

30OCT2019 IF update
The IF has been updated as we received a new QP declaration and a new IB for Gilteritinib. We have updated the IF accordingly. Please download the latest IF.

12SEP2019 (Investigator File uploaded)
All Dutch sites have received by email a link to the IF that contains all documents required to receive local approval. This IF contains documents like: Protocol, ICFs (both study ICF and screenings ICF), ABR form, EC correspondence and Central EC approval form, CA approval, Patient card (which you will also receive by regular post), Patient Diaries (for both Midostaurin and Gilteritinib), eCRF instructions, SAE forms, etc.

Below - in section Downloads you can download the entire zip file as well. You can also find an excel sheet (HO156_Overview folders and files_ddMONyyyy) that lists the exact documents that are within the ZIP file and indicate the section in which they are filed. If there are updates, these will be emailed to the sites, the latest version of the ZIP file can always be downloaded below.

Flow

Flow

Details

Phase:
Prospective Phase III study
Monitoring Type:
Study Specific
Objectives:

Primary study objective

  • To compare event-free survival (EFS) between gilteritinib and midostaurin 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 eligible for intensive chemotherapy.

Key secondary study objectives

  • To determine if treatment with gilteritinib, as compared to midostaurin, prolongs overall survival (OS) in the AML patient group.
  • 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.

Other secondary study objectives

  • 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.
  • 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.
  • 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.
  • To assess the safety and tolerability of treatment including gilteritinib vs. midostaurin in the AML patient group.
  • 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.
  • To assess the percentage of patients undergoing an allogeneic stem cell transplant (allo-SCT) in the AML patient group.
  • To determine quality of life (QoL) during maintenance treatment with gilteritinib vs. midostaurin in the AML patient group.

Exporatory objectives

  • 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 oneyear maintenance therapy in subjects with Myelodysplastic Syndromes (MDS) with excess blasts-2 (EB2) with a FLT3 gene mutation eligible for intensive chemotherapy.

Eligibility

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) and/or hypomethylating agents (HMAs) for 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 sequencing for FLT3-TKD. FLT3-ITD positivity is defined as a FLT3-ITD / FLT3-WT ratio of ≥ 0.05 (5%). FLT3-TKD positivity is defined as a variant allelele frequency (VAF = FLT3 TKD / (FLT3 WT + FLT3 TKD)) ≥ 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
    • Serum total bilirubin ≤ 2.5 × upper limit of normal (ULN) unless considered due to leukemic involvement following written approval by the (co) Principal Investigator
    • 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:
    • 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)
    • 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 locally accepted standards during the protocol defined period.
    • 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.
  • 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
Exclusion Criteria:
  • Prior chemotherapy for AML or MDS-EB2 (with the exception of ESA and HMA). 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
  • Patient requires treatment with concomitant drugs that are strong inducers of cytochrome P450 (CYP) 3A (Appendix I)
  • Breast feeding as of the 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:
    • Basal or squamous cell carcinoma of the skin;
    • Carcinoma in situ of the cervix;
    • Carcinoma in situ of the breast;
    • Incidental histologic finding of prostate cancer
  • Significant active cardiac disease within 6 months prior to the start of study treatment, including:
    • New York Heart Association (NYHA) Class III or IV congestive heart failure;
    • Myocardial infarction;
    • Unstable angina and/or stroke;
    • 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 hypomagnesemia at screening (defined as values below LLN)
  • 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

Registration Details

Patients who are possibly eligible for this trial should first be screened to determine the FLT3 mutation status. This can only be done after the patient has provided a written informed consent for the screening. Screening is done through a separate screening database. There are two screening databases for this trial, one managed by HOVON and one managed by AMLSG. Each group/institute that is participating in this trial is assigned one of the two screening databases.

Eligible patients should be registered before start of treatment. Patients need to be registered at the HOVON Data Center by one of the following options:

  • By ALEA; Use goto eCRF button > select the [Patient tab] and click the [Add new patient] button. Complete all items and click the [Submit] button
  • By faxing the completed registration/randomization CRF +31 (0)10 704 1028 Monday through Friday, from 09:00 to 17:00 CET
  • By phone +31 (0)10 704 1560 Monday through Friday, from 09:00 to 17:00 CET
Go to eCRF

Participating Sites

Ziekenhuizen die deelnemen aan het onderzoek staan benoemd op de HOVON website bij het onderzoek. Het kan zijn dat uw ziekenhuis niet genoemd wordt, maar wel aan het onderzoek deelneemt. Informeer hiernaar bij uw arts.

Site
192 results
Order by
Accrual rate
Activation date
NL-Rotterdam-ERASMUSMC
14
20 dec. 2019
DE-Ulm-UNIKLINKULM
14
21 jul. 2020
FR-Marseille-IPC
10
20 nov. 2020
NL-Groningen-UMCG
10
16 mei 2020
FR-Pessac Cedex-CHUBORDEAUX
8
21 jul. 2020
NL-Nieuwegein-ANTONIUS
7
10 feb. 2020
FR-Toulouse-CHUTOULOUSE
7
09 sep. 2020
LT-Vilnius-SANTA
6
26 feb. 2020
NL-Breda-AMPHIA
6
06 feb. 2020
NL-Dordrecht-ASZ
4
27 feb. 2020
NO-Oslo-OSLOUH
4
22 jul. 2020
NL-Amsterdam-VUMC
4
07 feb. 2020
CH-Bern-INSEL
4
26 okt. 2020
NL-Zwolle-ISALA
4
01 mei 2020
FR-Le Chesnay cedex-CHVERSAILLES
4
13 jan. 2021
FR-Grenoble cedex 9-CHUGRENOBLE
4
29 jul. 2020
FR-Nice-LARCHET
4
08 sep. 2020
FR-Paris cedex 10-SAINTLOUIS
4
14 jul. 2020
CH-Zürich-USZ
3
23 okt. 2020
BE-Haine-Saint-Paul-JOLIMONT
3
28 okt. 2020
DE-Oldenburg-KLINIKUMOLDENBURG
3
10 mrt. 2021
DE-Bremen-KBM
3
20 apr. 2021
FR-Rennes cedex 9-CHURENNES
3
17 jul. 2020
FR-Angers-CHUANGERS
3
31 jul. 2020
NL-Eindhoven-MAXIMAMC
3
04 mrt. 2020
FR-Lyon Pierre Benite cedex-LYONSUD
3
15 okt. 2020
AU-Melbourne-ALFRED
3
19 mrt. 2021
DE-Karlsruhe-KLINIKUMKARLSRUHE
2
15 dec. 2020
SE-Uppsala-UPPSALAUH
2
10 sep. 2020
FR-Rouen cedex-BECQUEREL
2
05 okt. 2020
DE-Passau-KLINIKUMPASSAU
2
28 jan. 2021
FR-Nantes-CHUNANTES
2
20 jul. 2020
FR-Nice-CAL
2
16 sep. 2020
DE-Mainz-UNIMEDIZINMAINZ
2
31 mrt. 2021
NO-Stavanger-HELSESTAVANGER
2
09 sep. 2020
BE-Liege-CHULIEGE
2
15 sep. 2020
FR-Vandoeuvre Les Nancy-CHRUNANCY
2
07 aug. 2020
FR-Villejuif-GUSTAVEROUSSY
2
08 jan. 2021
FR-Bobigny-AVICENNE
2
09 sep. 2020
DE-Bonn-UNIBONN
2
07 apr. 2021
NL-Nijmegen-RADBOUDUMC
2
26 feb. 2020
NL-Leeuwarden-MCL
2
24 apr. 2020
NL-Den Haag-HAGA
2
30 jul. 2020
DE-Bochum-RUB
2
15 dec. 2020
BE-Leuven-UZLEUVEN
2
30 okt. 2020
NL-Utrecht-UMCUTRECHT
2
30 mrt. 2020
NL-Maastricht-MUMC
1
25 sep. 2020
NL-Arnhem-RIJNSTATE
1
10 mrt. 2020
NL-Amersfoort-MEANDERMC
1
10 mrt. 2020
FR-Lille-CHULILLE
1
03 dec. 2020
DE-Saarbrücken-CARITASKLINIKUM
1
23 feb. 2021
FR-Paris cedex 15-NECKER
1
04 sep. 2020
NL-Leiden-LUMC
1
30 jul. 2020
NL-Den Bosch-JBZ
1
04 mrt. 2020
BE-Roeselare-AZDELTA
1
18 sep. 2020
FR-Limoges-CHULIMOGES
1
12 okt. 2020
FR-Bayonne-CHCOTEBASQUE
1
25 jun. 2021
FI-Helsinki-HUS
1
03 feb. 2021
BE-Antwerpen-ZNASTUIVENBERG
1
21 okt. 2020
NL-Amsterdam-AMC
1
19 jun. 2020
FR-Strasbourg cedex-HAUTEPIERRE
1
02 sep. 2020
CH-Basel-USB
1
03 feb. 2021
DE-Bad Saarow-HELIOSBADSAAROW
1
28 mei 2021
DE-Flensburg-MALTESER
1
22 dec. 2020
DE-Hamburg-ASKLEPIOS
1
17 feb. 2021
BE-Gent-UZGENT
1
25 feb. 2021
CH-Luzern-LUKS
1
18 jan. 2021
DE-Hamburg-UKE
1
09 jun. 2021
CH-Geneve (14)-HCUGE
1
18 jan. 2021
CH-Bellinzona-IOSI
1
03 feb. 2021
FR-Montpellier-STELOI
AU-Sydney-WSAH
AU-Adelaide-RAH
FR-Clermont Ferrand-ESTAING
ES-Barcelona-CLINICUB
ES-Palma-SSIB
30 jun. 2021
ES-Barcelona-MUTUATERRASSA
30 jun. 2021
ES-Barcelona-GERMANTRIALS
06 jul. 2021
AU-Brisbane-PAH
AU-Camperdown-RPA
ES-Palma-HSLL
14 mei 2021
FR-Reims-CHREIMS
AU-Perth-SCGH
AU-Melbourne-AUSTIN
FR-Besançon Cedex-JEANMINJOZ
11 jun. 2021
FR-Lyon-LEONBERARD
AU-Melbourne-RMELBOURNE
AU-Sydney-CONCORD
NO-Trondheim-STOLAV
23 sep. 2020
AU-Hobart TAS-RHOBART
SE-Lund-SUH
23 jul. 2021
BE-Brussel-BORDET
DE-Aschaffenburg-KLINIKUMAB
DE-Berlin-CAMPUSVIRCHOW
DE-Berlin-CAMPUSBENFRANKLIN
DE-Berlin-VIVANTESURBAN
DE-Berlin-VIVANTESNEUKOLLN
23 dec. 2020
DE-Dortmund-JOHODORTMUND
07 jan. 2021
DE-Düsseldorf-MEDUNIDUESSELDORF
DE-Essen-KEM
18 nov. 2020
SE-Stockholm-KAROLINSKAHUDDINGE
FR-Tours cedex-BRETONNEAU
FR-Saint-Priest-en-Jarez-ICLOIRE
IE-Limerick-UHL
25 mei 2021
DE-Greifswald-UNIGREIFSWALD
AU-Sydney-STGEORGE
AU-Sydney-NEPEAN
AT-Vienna-HANUSCH
AT-Linz-ORDENSKLINIKUM
DE-Trier-MUTTERHAUS
DE-Tübingen-MEDUNITUEBINGEN
18 mei 2021
FI-Tampere-TAYS
19 mei 2021
ES-Barcelona-ICODURANREYNALS
ES-Madrid-CSGREGORIOMARANON
CH-St. Gallen-KSSG
12 mrt. 2021
BE-Mons-AMBROISE
06 nov. 2020
CH-Fribourg-HFR
16 nov. 2020
DE-Magdeburg-OVGU
24 jun. 2021
LU-Luxembourg-CHL
23 mrt. 2021
AU-Canberra-CANBERRAHOSPITAL
AT-Graz-MEDUNIGRAZ
AT-Innsbruck-IMED
DE-Frankfurt-KLINIKUMFRANKFURT
DE-Berlin-CAMPUSMITTE
BE-Bruxelles-STLUC
22 okt. 2020
DE-Giessen-UKGM
DE-Goch-KKLE
23 jun. 2021
DE-Hannover-MHHANNOVER
29 jul. 2021
DE-Luedenscheid-KLINIKUMLUEDENSCHEID
09 feb. 2021
DE-München-IRZTUM
DE-Offenburg-ORTENAUKLINIKUM
18 nov. 2020
DE-Regensburg-UKR
DE-Stuttgart-DIAKSTUTTGART
25 feb. 2021
DE-Stuttgart-KLINIKUMSTUTTGART
30 apr. 2021
ES-Barcelona-PARCDESALUTMAR
ES-Barcelona-SANTPAU
21 jun. 2021
ES-Barcelona-VHEBRON
ES-Girona-ICSTRUETA
ES-Lleida-ICSVILANOVA
ES-Malaga-HUVV
DE-Ludwigshafen-KLILU
07 apr. 2021
DE-Minden-MUEHLENKREISKLINKEN
13 jul. 2021
BE-Liege-CHRCITADELLE
29 jun. 2021
NL-Enschede-MST
13 jan. 2021
NL-Amsterdam-OLVG
03 feb. 2020
BE-Brugge-AZBRUGGE
20 mei 2021
BE-Yvoir-MONTGODINNE
NL-Delft-RDGG
29 jul. 2020
NO-Bergen-HELSEBERGEN
16 jun. 2020
CH-Lausanne-CHUV
05 jan. 2021
CH-Aarau-KSA
11 mei 2021
BE-Hasselt-VIRGAJESSE
DE-Hamm-EVKHAMM
DE-Hannover-SILOAHKRH
24 jun. 2021
DE-Homburg-UNIKLINIKSAARLAND
08 apr. 2021
DE-Lemgo-KLINIKUMLIPPE
28 jun. 2021
NO-Tromsø-NORTHNOORWEGEN
10 sep. 2020
ES-Tarragona-JOAN
ES-Valencia-MALVARROSA
AU-Douglas-TOWNSVILLE
AU-Brisbane-RBWH
AU-Melbourne-MONASH
AU-Melbourne-SVHM
AU-Perth-FSH
AU-Perth-RPH
AU-Sydney-RNSH
AU-Waratah-CALVARYMATER
IE-Dublin 4-SVUH
AU-Launceston TAS-LAUNCESTON
AU-Geelong VIC-BARWONHEALTH
AU-Gosford NSW-GOSFORDHOSPITAL
DE-Esslingen-KLINIKUMESSLINGEN
20 jan. 2021
DE-Hamburg-ASKLEPIOSSTGEORG
10 mrt. 2021
DE-Lübeck-UKSHLUBECK
AU-Adelaide-FLINDERS
DE-Villingen-Schwenningen-SBKVS
19 mei 2021
FR-Amiens-CHUAMIENS
24 sep. 2020
FR-Argenteuil-CHARGENTEUIL
06 jan. 2021
FR-Poitiers-CHUPOITERS
20 jan. 2021
IE-Cork-CUH
30 jun. 2021
IE-Dublin 24-TUH
IE-Dublin 7-MATER
09 jun. 2021
IE-Dublin 8-STJAMES
19 mei 2021
IE-Galway-UHGALWAY
DE-Heilbronn-SLK
07 jan. 2021
FR-Clamart-HIAPERCY
31 dec. 2020
IE-Dublin 9-BEAUMONT
01 jun. 2021
DE-Braunschweig-KLINIKUMBRAUNSCHWEIG
12 apr. 2021
DE-Darmstadt-KLINIKUMDARMSTADT
24 feb. 2021
DE-Wuppertal-HELIOSGESUNDHEIT
DE-Herne-MARIENHOSPITALHERNE
18 feb. 2021
DE-Meschede-HOCHSAUERLAND
07 okt. 2020
= Active hospitals
= Inactive hospitals

Participating Parties

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