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NCT03839771 | SNCTP000003541

HOVON 150
Behandlung mit Ivosidenib oder Enasidenib in Kombination mit intensiver Chemotherapie für Patienten mit bislang unbehandelter akuter myeloischer Leukämie (AML) oder bislang unbehandeltem vorangeschrittenem myelodysplastischem Syndrom (MDS-EB2) mit IDH1- oder IDH2-Mutation.

Data source: BASEC (Imported from 10.12.2019), WHO (Imported from 01.12.2019)
Changed: 03.12.2019
Disease category: Leukämie

Brief description of trial (Source of data: BASEC)

Ziel dieser Studie ist eine Verbesserung des Behandlungsergebnisses der Therapie bei AML und MDS-EB2, beides bösartige Erkrankungen des Knochenmarks. Die Standardbehandlung gegen diese Erkrankungen ist eine Chemotherapie. Diese Patienten haben eine besondere Unter-Form der Erkrankung des Knochenmarks, weil in ihren Leukämiezellen im genetischen Material (DNA) ein spezifischer Fehler aufgetreten ist. Diesen Fehler bezeichnen wir als IDH1 oder IDH2 Mutation (Mutation = Veränderung der DNA), die zu Veränderungen bestimmter Stoffe in den Leukämiezellen führt. Diese veränderten Stoffe spielen bei der Entstehung von Leukämie und für das Überleben von Leukämiezellen eine wichtige Rolle.
Ivosidenib ist ein Medikament, welches die veränderte Form von IDH1 in den Zellen hemmt. Enasidenib ist ein Medikament, welches die veränderte Form von IDH2 in den Zellen hemmt. Studien haben gezeigt, dass Ivosidenib und Enasidenib bei Patienten mit AML und MDS mit einer IDH1- oder einer IDH2-Mutation, bei denen die Krankheit nach vorheriger Chemotherapie zurückgekehrt ist, sicher sind. Bei einigen dieser Patienten konnte die Leukämie durch die Behandlung kontrolliert werden. Aufgrund der Ergebnisse dieser Studien wurden beide Medikamente in den USA für die Behandlung von Patienten mit AML und einer IDH1- oder einer IDH2-Mutation bereits zugelassen, bei denen die Krankheit nach vorheriger Behandlung mit Standardmedikamenten zurückgekehrt ist oder bei denen die Krankheit auf Standardmedikamente nicht angesprochen hat.
Ivosidenib und Enasidenib sind in der Schweiz noch nicht zugelassen.
Wir möchten nun die Wirksamkeit und Sicherheit von Ivosidenib und Enasidenib bei Patienten mit AML oder MDS-EB2 und einer IDH1- oder einer IDH2-Mutation untersuchen, die für diese Erkrankung bislang noch nicht behandelt wurden. Dabei möchten wir herausfinden, ob sich die Krankheit durch die Gabe des neuen Medikaments zusätzlich zur Standardbehandlung mit Chemotherapie wirksamer und länger kontrollieren lässt.

Health conditions investigated (Source of data: BASEC)

unbehandelte akute myeloische Leukämie (AML) oder bislang unbehandelte vorangeschrittenes myelodysplastisches Syndrom (MDS-EB2) mit IDH1- oder IDH2-Mutation

Health conditions (Source of data: WHO)

Acute Myeloid Leukemia
Myelodysplastic Syndrome With Excess Blasts-2

Rare disease (Source of data: BASEC)

Yes

Intervention investigated (e.g. drug, therapy or campaign) (Source of data: BASEC)

- Die individuelle Behandlung dauert insgesamt etwa 2,5 Jahre. Im Rahmen dieser Studie werden die Patienten über einen Zeitraum von 10 Jahren nach Beginn der Behandlung nachbeobachtet.
- Die erste Phase der Behandlung, die Induktionstherapie, besteht aus zwei aufeinanderfolgenden Zyklen mit verschiedenen Formen der Chemotherapie. Während der Induktionszyklen wird die Chemotherapie entweder mit Ivosidenib oder einem Placebo (bei einer IDH1-Mutation) oder mit Enasidenib oder einem Placebo (bei einer IDH2-Mutation) kombiniert.
- Nach Abschluss der ersten Phase wird beurteilt, ob der Patient für die zweite Phase (Konsolidierungstherapie) in Frage kommt. Es gibt drei mögliche Behandlungen:
• Chemotherapie in Kombination mit Ivosidenib oder Placebo (bei einer IDH1-Mutation) oder mit Enasidenib oder Placebo (bei einer IDH2-Mutation).
• Chemotherapie mit Stammzelltransplantation mit Ihren eigenen Stammzellen.
• Chemotherapie mit Stammzelltransplantation mit Stammzellen eines Spenders.
- In der dritten Phase der Behandlung, die Erhaltungstherapie, erhalten die Patienten über zwei Jahre Ivosidenib oder Placebo (bei einer IDH1-Mutation) oder Enasidenib oder Placebo (bei einer IDH2-Mutation) als Tabletten ein.

Interventions (Source of data: WHO)

Drug: AG-120
Drug: AG-221
Drug: Placebo for AG-120
Drug: Placebo for AG-221

Criteria for participation in trial (Source of data: BASEC)

Es können alle Personen teilnehmen, die an einer neudiagnostizierten AML oder MDS-EB2 leiden, und welche die IDH1- oder IDH2-Mutation in den Leukämiezellen haben. Ausserdem müssen diese mindestens 18 Jahre alt sein.

Exclusion criteria (Source of data: BASEC)

Nicht teilnehmen dürfen Patienten, die bereits eine andere Therapie hatten, mit Ausnahme von Hydroxyurea.

Inclusion/Exclusion Criteria (Source of data: WHO)


Inclusion Criteria:

- Age =18 years

- Newly diagnosed AML or MDS-EB2 defined according to WHO criteria, with a documented
IDH1 or IDH2 gene mutation (as determined by the clinical trial assay) at a specific
site (IDH1 R132, IDH2 R140, IDH2 R172). AML may be secondary to prior hematological
disorders, including MDS, and/or therapy-related (in which prior disease should have
been documented to have existed for at least 3 months). Patients may have had previous
treatment with hypomethylating agents (HMAs) for MDS. HMAs have to be stopped at least
four weeks before registration

- Patients with dual mutant FLT3 and IDH1 or IDH2 mutations may be enrolled only if, for
medical or other reasons, treatment with a FLT3 inhibitor is not considered.

- Considered to be eligible for intensive chemotherapy.

- ECOG/WHO performance status = 2

- Adequate hepatic function as evidenced by:

- Serum total bilirubin = 2.5 × upper limit of normal (ULN) unless considered due
to Gilbert's disease (e.g. a mutation in UGT1A1) (only for patients in IDH2
cohort), or leukemic involvement of the liver - 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 of
the liver, following written approval by the Principal Investigator.

- Adequate renal function as evidenced by creatinine clearance > 40 mL/min based on the
Cockroft-Gault formula for glomerular filtration rate (GFR).

- Able to understand and willing to sign an informed consent form (ICF).

- Written informed consent

- Female patients of reproductive potential must undergo a pregnancy test prior to
starting study drug and this test must have a negative result. The first pregnancy
test will be performed at entry (within 7 days prior to first study drug
administration). A pregnancy test should also be repeated within 72 hours before the
first study drug administration and confirmed negative prior to dosing. Patients with
reproductive potential are defined as sexually mature women who have not undergone a
hysterectomy, bilateral oophorectomy or tubal occlusion or who have not been naturally
postmenopausal for at least 24 consecutive months.

- Females of reproductive potential as well as fertile men and their partners who are
females of reproductive potential must agree to abstain from sexual intercourse or to
use a highly effective form of contraception from the time of giving informed consent,
during the study, and for 4 months (females and males) following the last dose of
ivosidenib/enasidenib or placebo. A highly effective form of contraception is defined
as hormonal oral contraceptives, injectables, patches, intrauterine devices,
double-barrier method (e.g., synthetic condoms, diaphragm or cervical cap with
spermicidal foam, cream, or gel) or male partner sterilization.

- Subject agrees not to participate in another interventional study while on treatment

Exclusion Criteria:

- Prior chemotherapy for AML or MDS-EB2 (with the exception of HMA). Hydroxyurea is
allowed for the control of peripheral leukemic blasts in patients with leukocytosis
(e.g., white blood cell [WBC] counts > 30x109/L).

- Dual IDH1 and IDH2 mutations.

- Acute promyelocytic leukemia (APL) with PML-RARA or one of the other pathognomonic
variant fusion genes/chromosome translocations.

- Blast crisis after chronic myeloid leukemia (CML).

- Taking medications with narrow therapeutic windows with potential interaction with
investigational medication (see Appendix I), unless the patient can be transferred to
other medications prior to enrolling or unless the medications can be properly
monitored during the study.

- Taking P-glycoprotein (P-gp) or breast cancer resistance protein (BCRP)
transporter-sensitive substrate medications (see Appendix J) unless the patient can be
transferred to other medications within = 5 half-lives prior to administration of
ivosidenib or enasidenib, or unless the medications can be properly monitored during
the study.

- Breast feeding at 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 < 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 (appendix G); myocardial infarction, unstable angina and/or stroke; or
left ventricular ejection fraction (LVEF) < 40% by ultrasound or MUGA scan obtained
within 28 days prior to the start of study treatment.

- QTc interval using Fridericia's formula (QTcF) = 450 msec or other factors that
increase the risk of QT prolongation or arrhythmic events (e.g., heart failure,
hypokalemia, family history of long QT interval syndrome). Prolonged QTc interval
associated with bundle branch block or pacemaking is permitted with written approval
of the Principal Investigator.

- Taking medications that are known to prolong the QT interval (see Appendix K), unless
the patient can be transferred to other medications within = 5 half-lives prior to
dosing or unless the medications can be properly monitored during the study.

- 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.

- A known medical history of progressive multifocal leukoencephalopathy (PML
Minimum age: 18 Years
Maximum age: N/A
Sex: All

Further information on the trial in WHO primary registry

http://www.who.int/trialsearch/Trial2.aspx?TrialID=NCT03839771

Further information on the trial from WHO database (ICTRP)

http://apps.who.int/trialsearch/Trial2.aspx?TrialID=NCT03839771

Further information on trial

Date trial registered

06.02.2019

Incorporation of the first participant

01.03.2019

Recruitment status

Recruiting

Academic title (Source of data: WHO)

A Phase 3, Multicenter, Double-blind, Randomized, Placebo-controlled Study of Ivosidenib or Enasidenib in Combination With Induction Therapy and Consolidation Therapy Followed by Maintenance Therapy in Patients With Newly Diagnosed Acute Myeloid Leukemia or Myelodysplastic Syndrome With Excess Blasts-2, With an IDH1 or IDH2 Mutation, Respectively, Eligible for Intensive Chemotherapy.

Type of trial (Source of data: WHO)

Interventional

Design of the trial (Source of data: WHO)

Allocation: Randomized. Intervention model: Parallel Assignment. Primary purpose: Treatment. Masking: Triple (Participant, Care Provider, Investigator).

Phase (Source of data: WHO)

Phase 3

Primary end point (Source of data: WHO)

Event-free survival (EFS)

Secundary end point (Source of data: WHO)

Complete remission without minimal residual disease (CRMRD-) rate after induction cycle 2
CR/CRi rate after remission induction (i.e., CR or CRi as best response during or at completion of induction therapy)
CR/CRi rates after induction cycle 1 and 2
Cumulative incidence of death (CID) after CR/CRi
Cumulative incidence of relapse (CIR) after CR/CRi
EORTC-QLQ-C30 global health status/QoL scale.
EQ-5D-5L visual analogue scale (VAS)
Frequency and severity of adverse events according to CTCAE version 5.0
Overall survival (OS)
Relapse-free survival (RFS) after CR/CRi
Time to hematopoietic recovery after each chemotherapy treatment cycle

Contact information (Source of data: WHO)

Please refer to primary and secondary sponsors

Trial sites

Trial sites in Switzerland (Source of data: BASEC)

Basel, Bellinzona, Bern, Freiburg, Genf, Lausanne, Luzern, St Gallen, Zürich

Countries (Source of data: WHO)

Netherlands

Contact for further information on the trial

Details of contact in Switzerland (Source of data: BASEC)

SAKK, Zuzanna Maniecka
+41 31 389 91 91
trials@sakk.ch

Contact for general information (Source of data: WHO)

B. Wouters

Contact for scientific information (Source of data: WHO)

B.J. Wouters
Erasmus MC / HOVON

Principal Sponsor/Investigator

Principal sponsor (Source of data: WHO)

Stichting Hemato-Oncologie voor Volwassenen Nederland

Additional sponsors (Source of data : WHO)

Deutsch-Österreichische Studiengruppe Akute Myeloische Leukämie (AMLSG)

Further trial identification numbers

BASEC ID (Source of data: BASEC)

2019-01281

Secondary ID (Source of data: WHO)

2018-000451-41;HO150