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JOURNAL ONKOLOGIE – STUDIE
HOVON150AML

A 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 Myedysplastic Syndrome EB2, With an IDH1 or IDH2 Mutation, Respectively, Eligible for Intensive Chemotherapy

Rekrutierend

NCT-Nummer:
NCT03839771

Studienbeginn:
März 2019

Letztes Update:
01.09.2021

Wirkstoff:
AG-120, Placebo for AG-120, AG-221, Placebo for AG-221

Indikation (Clinical Trials):
Leukemia, Leukemia, Myeloid, Leukemia, Myeloid, Acute, Preleukemia, Myelodysplastic Syndromes, Anemia, Refractory, with Excess of Blasts, Syndrome

Geschlecht:
Alle

Altersgruppe:
Erwachsene (18+)

Phase:
Phase 3

Sponsor:
Stichting Hemato-Oncologie voor Volwassenen Nederland

Collaborator:
Deutsch-Österreichische Studiengruppe Akute Myeloische Leukämie (AMLSG)

Studienleiter

B.J. Wouters
Principal Investigator
Erasmus MC / HOVON

Kontakt

Studienlocations
(3 von 182)

DE-Bad Saarow-HELIOSBADSAAROW
Bad Saarow
(Brandenburg)
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DE-Berlin-CAMPUSBENFRANKLIN
Berlin
(Berlin)
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DE-Berlin-VIVANTESURBAN
Berlin
(Berlin)
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DE-Braunschweig-KLINIKUMBRAUNSCHWEIG
Braunschweig
(Niedersachsen)
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DE-Dortmund-JOHODORTMUND
Dortmund
(Nordrhein-Westfalen)
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DE-Düsseldorf-MEDUNIDUESSELDORF
Düsseldorf
(Nordrhein-Westfalen)
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DE-Esslingen-KLINIKUMESSLINGEN
Esslingen
(Baden-Württemberg)
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DE-Flensburg-MALTESER
Flensburg
(Schleswig-Holstein)
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DE-Giessen-UKGM
Gießen
(Hessen)
GermanyNoch nicht rekrutierend» Google-Maps
DE-Hamburg-ASKLEPIOSSTGEORG
Hamburg
(Hamburg)
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DE-Hamburg-UKE
Hamburg
(Hamburg)
GermanyNoch nicht rekrutierend» Google-Maps
DE-Hanau-KLINIKUMHANAU
Hanau
(Hessen)
GermanyNoch nicht rekrutierend» Google-Maps
DE-Hannover-MHHANNOVER
Hannover
(Niedersachsen)
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DE-Hannover-SILOAHKRH
Hannover
(Niedersachsen)
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DE-Herne-MARIENHOSPITALHERNE
Herne
(Nordrhein-Westfalen)
GermanyRekrutierend» Google-Maps
DE-Homburg-UNIKLINIKSAARLAND
Homburg
(Saarland)
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DE-Karlsruhe-KLINIKUMKARLSRUHE
Karlsruhe
(Baden-Württemberg)
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DE-Lebach-CARITASKHLEBACH
Lebach
(Saarland)
GermanyNoch nicht rekrutierend» Google-Maps
DE-Lemgo-KLINIKUMLIPPE
Lemgo
(Nordrhein-Westfalen)
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DE-Ludwigshafen-KLILU
Ludwigshafen
(Rheinland-Pfalz)
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DE-Luedenscheid-KLINIKUMLUEDENSCHEID
Lüdenscheid
(Nordrhein-Westfalen)
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DE-Magdeburg-OVGU
Magdeburg
(Sachsen-Anhalt)
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DE-Mainz-KLINKUNIMAINZ
Mainz
(Rheinland-Pfalz)
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DE-Mainz-UNIMEDIZINMAINZ
Mainz
(Rheinland-Pfalz)
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DE-Meschede-HOCHSAUERLAND
Meschede
(Nordrhein-Westfalen)
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DE-Minden-MUEHLENKREISKLINKEN
Minden
(Nordrhein-Westfalen)
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DE-München-MEDUNIMUNCHIN
München
(Bayern)
GermanyNoch nicht rekrutierend» Google-Maps
DE-Offenburg-ORTENAUKLINIKUM
Offenburg
(Baden-Württemberg)
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DE-Oldenburg-KLINIKUMOLDENBURG
Oldenburg
(Niedersachsen)
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DE-Stuttgart-DIAKSTUTTGART
Stuttgart
(Baden-Württemberg)
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DE-Stuttgart-KLINIKUMSTUTTGART
Stuttgart
(Baden-Württemberg)
GermanyNoch nicht rekrutierend» Google-Maps
DE-Trier-MUTTERHAUS
Trier
(Rheinland-Pfalz)
GermanyNoch nicht rekrutierend» Google-Maps
DE-Tübingen-MEDUNITUEBINGEN
Tübingen
(Baden-Württemberg)
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DE-Ulm-UNIKLINKULM
Ulm
(Baden-Württemberg)
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DE-Villingen-Schwenningen-SBKVS
Villingen-Schwenningen
(Baden-Württemberg)
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DE-Wuppertal-HELIOSGESUNDHEIT
Wuppertal
(Nordrhein-Westfalen)
GermanyNoch nicht rekrutierend» Google-Maps
AU-Canberra-CANBERRAHOSPITAL
Canberra
AustraliaNoch nicht rekrutierend» Google-Maps
AU-Launceston TAS-LAUNCESTON
Launceston
AustraliaNoch nicht rekrutierend» Google-Maps
AU-Waratah-CALVARYMATER
Waratah
AustraliaNoch nicht rekrutierend» Google-Maps
BE-Haine-Saint-Paul-JOLIMONT
Haine-Saint-Paul
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FR-Clermont-Ferrand-ESTAING
Clermont-Ferrand
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FR-Grenoble cedex 9-CHUGRENOBLE
Grenoble cedex 9
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FR-Vandoeuvre Les Nancy-CHRUNANCY
Vandœuvre-lès-Nancy
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LU-Luxembourg-CHL
Luxembourg
LuxembourgNoch nicht rekrutierend» Google-Maps
ES-Barcelona-ICODURANREYNALS
Barcelona
SpainNoch nicht rekrutierend» Google-Maps
ES-Barcelona-MUTUATERRASSA
Barcelona
SpainNoch nicht rekrutierend» Google-Maps
ES-Barcelona-PARCDESALUTMAR
Barcelona
SpainNoch nicht rekrutierend» Google-Maps
ES-Madrid-CSGREGORIOMARANON
Madrid
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Alle anzeigen

Studien-Informationen

Brief Summary:

AML and MDS-EB2 are malignancies of the bone marrow. The standard treatment for these

diseases is chemotherapy. Patients participating have a special type of this disease because

the leukemia cells (blasts) have developed an error in the genetic material (DNA). This error

is called an IDH1 mutation or an IDH2 mutation (a mutation is a change in the DNA), which

leads to changes in specific substances in the leukemia cells. This trial will investigate

whether the addition of the new drugs Ivosidenib (for patients with IDH1 mutation) or

Enasidenib (for patients with IDH2 mutation) to the standard treatment of chemotherapy

controle the disease more effectively and for a longer period.

Ein-/Ausschlusskriterien

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 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.

- 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.

- 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).

- Known allergy or suspected hypersensitivity to Ivosidenib or Enasidenib and/or any

exipients.

- 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,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

deemed critical and without a suitable alternative. In those cases, they may be

administered, but with proper monitoring (see section 10.2, Table 13).

- 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).

- Immediately life-threatening, severe complications of leukemia such as uncontrolled

bleeding, pneumonia with hypoxia or shock, and/or severe disseminated intravascular

coagulation

- Any other medical 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.

Studien-Rationale

Primary outcome:

1. Event-free survival (EFS) (Time Frame - Approximately up to 60 months following first patient enrollment):
EFS is defined as the time from randomization to failure to achieve CR or CRi after remission induction, death after achieving CR or CRi or relapse after achieving CR or CRi, whichever occurs first. A patient is said to have failed to achieve CR or CRi after induction therapy, if his/her best response during or at completion of the induction treatment is less than CRi. Patients who achieved CR/CRi after remission induction and are not known to have relapsed or died will be censored at the date of last clinical assessment.



Secondary outcome:

1. Overall survival (OS) (Time Frame - Approximately up to 84 months following first patient enrollment):
OS is defined as the time from date of randomization to 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.

2. Relapse-free survival (RFS) after CR/CRi (Time Frame - Approximately up to 60 months following first patient enrollment):
RFS is defined as time from the date of achievement of CR/CRi until relapse or death from any cause, whichever comes first. Patients still in first CR/CRi and alive or lost to follow up will be censored at the date of last clinical assessment.

3. Cumulative incidence of relapse (CIR) after CR/CRi (Time Frame - Approximately up to 60 months following first patient enrollment):
CIR is measured from the date of achievement of CR/CRi 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.

4. Cumulative incidence of death (CID) after CR/CRi (Time Frame - Approximately up to 60 months following first patient enrollment):
CID is measured from the date of achievement of CR/CRi 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/CRi will be counted as competing cause of failure.

5. Complete remission without minimal residual disease (CRMRD-) rate after induction cycle 2 (Time Frame - Approximately up to 60 months following first patient enrollment):
CRMRD- rate is defined as the percentage of patients who achieved CR or CRi with no evidence of MRD in bone marrow

6. Frequency and severity of adverse events according to CTCAE version 5.0 (Time Frame - Continuously throughout the study, starting from informed consent until 30 days following the last administration of any study drug):
Adverse events will be evaluated using the National Cancer Institute's Common Terminology Criteria for AEs (CTCAE) version 5.0

7. CR/CRi rates after induction cycle 1 and 2 (Time Frame - Approximately up to 60 months following first patient enrollment):
CR and CRi are determined by the Investigator based on the European LeukemiaNet (ELN2017) recommended response criteria

8. CR/CRi rate after remission induction (i.e., CR or CRi as best response during or at completion of induction therapy) (Time Frame - Approximately up to 60 months following first patient enrollment):
CR+CRi rate after remission induction is defined as the percentage of patients with best response of CR or CRi during or at completion of induction therapy

9. Time to hematopoietic recovery after each chemotherapy treatment cycle (Time Frame - Approximately up to 60 months following first patient enrollment):
Time to hematopoietic recovery is defined as the time from the start of the cycle until recovery

10. EQ-5D-5L visual analogue scale (VAS) (Time Frame - At entry, 1st day of maintenance, every 3 months during the first year of maintenance, every 6 months during the second year of maintenance until relapse or treatment discontinuation (approximately up to 84 months following first patient enrollment)):
The EQ-5D-5L is a 5 item questionnaire that assesses 5 domains including mobility, self-care, usual activities, pain/discomfort and anxiety/depression plus a visual analog scale rating "health today". Each domain has 5 levels. Each level has a 1 digit number expressing the level selected for that dimension. These levels are summed up and the self-rated health is recorded on a 20 cm vertical, visual analogue scale, with endpoints labelled 'the best health you can imagine' and 'the worst health you can imagine'.

11. EORTC-QLQ-C30 global health status/QoL scale. (Time Frame - At entry, 1st day of maintenance, every 3 months during the first year of maintenance, every 6 months during the second year of maintenance until relapse or treatment discontinuation (approximately up to 84 months following first patient enrollment)):
The EORTC QLQ-C30 is a 30-item questionnaire that assesses 5 functional subdomains (physical functioning, role functioning, emotional functioning, cognitive functioning and social functioning), 1 global health status, 3 symptom subdomains (fatigue, nausea and vomiting and pain) and 6 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). All of the scales and single-item measures range in score from 0 to 100. A high scale score represents a higher response level. Estimate the average of the items that contribute to the scale; this is the raw score. a higher score represents a higher ("better") level of functioning, or a higher ("worse") level of symptoms.

Studien-Arme

  • Placebo Comparator: Arm A: Placebo
    Cycle 1: day 1-start cycle 2 | Cycle 2: day 1 - start consolidation treatment | Consolidation treatment: day 1 - start maintenance | Maintenance treatment: day 1- day 730 (2 years) | The dosage for Placebo for AG-120 (IDH1): 500 mg dose/day The dosage for Placebo for AG-221 (IDH2): 100mg dose/day
  • Experimental: Arm B: Ivosidenib (IDH1) or Enasidenib (IDH2)
    Cycle 1: day 1-start cycle 2 | Cycle 2: day 1 - start consolidation treatment | Consolidation treatment: day 1 - start maintenance | Maintenance treatment: day 1- day 730 (2 years) | The dosage for AG-120 (IDH1): 500 mg dose/day The dosage for AG-221 (IDH2): 100mg dose/day

Geprüfte Regime

  • AG-120 (Ivosidenib):
    250mg tablets
  • Placebo for AG-120:
    250mg tablets
  • AG-221 (Enasidenib):
    100mg tablets
  • Placebo for AG-221:
    100mg tablets

Quelle: ClinicalTrials.gov


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"A 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 Myedysplastic Syndrome EB2, With an IDH1 or IDH2 Mutation, Respectively, Eligible for Intensive Chemotherapy"

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