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JOURNAL ONKOLOGIE – STUDIE

Treatment of MDS/AML Patients With an Impending Hematological Relapse With AZA or ATA and Pevonedistat

Noch nicht rekrutierend

NCT-Nummer:
NCT04712942

Studienbeginn:
Februar 2021

Letztes Update:
19.01.2021

Wirkstoff:
Pevonedistat, azacitidine

Indikation (Clinical Trials):
Neoplasm, Residual, Myelodysplastic Syndromes

Geschlecht:
Alle

Altersgruppe:
Erwachsene (18+)

Phase:
Phase 2

Sponsor:
University of Leipzig

Collaborator:
Millennium Pharmaceuticals, Inc.

Studienleiter

Uwe Platzbecker, Prof. Dr.
Principal Investigator
University Leipzig

Kontakt

Uwe Platzbecker, Prof. Dr.
Kontakt:
Phone: +49 341 97 13050
E-Mail: uwe.platzbecker@medizin.uni-leipzig.de
» Kontaktdaten anzeigen

Studienlocations
(3 von 14)

Klinik für Innere Medizin III, Hämatologie, Onkologie, Stammzelltransplantation, Klinikum Chemnitz gGmbH
09113 Chemnitz
(Sachsen)
Germany» Google-Maps
Ansprechpartner:
Mathias Hänel, PD Dr.
» Ansprechpartner anzeigen
Medizinischen Klinik und Poliklinik I / Hämatologie, Universitätsklinikum Carl Gustav Carus an der Technischen Universität Dresden
01304 Dresden
(Sachsen)
Germany» Google-Maps
Ansprechpartner:
Jan Moritz Middeke, Dr.
» Ansprechpartner anzeigen
Universitätsklinik und Poliklinik für Innere Medizin IV, Onkologie, Hämatologie, Universitätsklinikum Halle (Saale)
06120 Halle (Saale)
(Sachsen-Anhalt)
Germany» Google-Maps
Ansprechpartner:
Judith Schaffrath, Dr.
» Ansprechpartner anzeigen
Klinik für Innere Medizin II/ Hämatologie und Onkologie, Univ.Klinikum Schleswig-Holstein/Campus Kiel
24105 Kiel
(Schleswig-Holstein)
Germany» Google-Maps
Ansprechpartner:
Lars Fransecky, Dr.
» Ansprechpartner anzeigen
Medizinische Klinik und Poliklinik I - Hämatologie und Zelltherapie, Hämostaseologie, Leipzig University
04103 Leipzig
(Sachsen)
Germany» Google-Maps
Ansprechpartner:
Uwe Platzbecker, Prof. Dr.


E-Mail: uwe.platzbecker@medizin.uni-leipzig.de
» Ansprechpartner anzeigen
Innere Medizin A/Hämatologie-Onkologie, Universitätsklinik Münster
48149 Münster
(Nordrhein-Westfalen)
Germany» Google-Maps
Klinik für Hämatologie, Onkologie & Stammzelltherapie, Helios-Klinikum Schwerin
19049 Schwerin
(Mecklenburg-Vorpommern)
Germany» Google-Maps
Klinik Innere Medizin III - Onko-, Häma- u. Palliativmedizin, Diakonie-Klinikum Schwäbisch Hall gGmbH
74523 Schwäbisch Hall
(Baden-Württemberg)
Germany» Google-Maps
Ansprechpartner:
Thomas Geer, Dr.
» Ansprechpartner anzeigen
Abteilung für Hämatologie, Onkologie und Palliativmedizin, Robert-Bosch-Krankenhaus Stuttgart
70376 Stuttgart
(Baden-Württemberg)
Germany» Google-Maps
Ansprechpartner:
Martin Kaufmann, Dr.
» Ansprechpartner anzeigen
Alle anzeigen

Studien-Informationen

Detailed Description:

Experimental arm: pevonedistat in combination with azacitidine Control arm: azacitidine alone

With the following modifications:

- Patients on the azacitidine arm and still MRD+ at 3 months but without hematological

relapse can cross over to the combination arm

- Cross over into the combination arm is possible any time up to 9 months of study

treatment if initially responding patients (at 3 months) on AZA monotherapy become MRD

positive again

- Maximum treatment duration of 1 year

- Patients receive pevonedistat at 20 mg/m2 i.v. (d1,3,5, q4w); azacitidine is given at a

standard dose of 75 mg/m² i.v. or s.c. (d1-7 or 1-5,8,9, q4w)

Ein-/Ausschlusskriterien

Inclusion Criteria:

- AML or MDS

- continuing first CR after conventional intensive chemotherapy OR continuing CR after

alloSCT

- Confirmed MRD positivity (assessed by central lab) as defined by:

- NPM1mut status >1% in peripheral blood or bone marrow in NPM1 mutated patients at

diagnosis or

- Patients after allogeneic transplantation, who were NPM1 unmutated at diagnosis

and have a blood or marrow CD34/CD117 chimerism <80%

Exclusion Criteria:

Compliance with major study procedures

- Patient does not accept bone marrow sampling during screening, primary end point visit

and after the treatment.

- Patient does not accept several blood sampling during screening, treatment (up to

bi-daily) and after the treatment.

Safety

- Inadequate organ function as defined in the list below:

- White blood cell (WBC) count > 50 Gpt/L before administration of pevonedistat on

Cycle 1 Day 1

- Absolute neutrophil count (ANC) < 1.5 Gpt/L

- Platelets < 100 Gpt/L

- Albumin < 2.7 g/dL

- Creatinine clearance < 30 mL/min (Cockcroft und Gault formula)

- Total bilirubin > 1.5xupper limit of normal (ULN) except in patients with

Gilbert's syndrome. Patients with Gilbert's syndrome may be enrolled if direct

bilirubin > 1.5x ULN of the direct bilirubin.

- Both Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) > 3.0

ULN

- ECOG performance status of ≥2

Concomitant Diseases

- Hematological relapse

- Liver cirrhosis or severe pre-existing hepatic impairment

- Known severe cardiopulmonary disease (e.g. unstable angina, congestive heart failure

NYHA III or IV, myocardial infarction within 6 months prior to screening, symptomatic

cardiomyopathy, clinically significant arrhythmia, clinically significant pulmonary

hypertension requiring pharmacologic therapy)

- Uncontrolled high blood pressure (i.e. systolic blood pressure > 180 mm Hg, diastolic

blood pressure > 95 mm Hg)

- Confirmed prolonged rate corrected QT interval ≥ 500 msec, calculated according to

institutional guidelines (Screening ECG)

- Confirmed left ventricular ejection fraction < 50% as assessed by echocardiogram or

radionuclide angiography (Screening TTE)

- Known moderate to severe symptomatic chronic obstructive pulmonary disease,

interstitial lung disease, or pulmonary fibrosis

- Active uncontrolled infection or severe infectious disease, such as severe pneumonia,

meningitis, or septicemia

- Known psychiatric or substance abuse disorders that would interfere with cooperation

with the requirements of the trial.

- Known Human Immunodeficiency Virus (HIV 1/2 antibodies)

- Known active Hepatitis B (i.e. HBsAg reactive) or Hepatitis C (i.e., HCV RNA

[qualitative] is detected). NOTE: Patients who have isolated positive hepatitis B core

antibody (i.e. in the setting of negative hepatitis B surface antigen and negative

hepatitis B surface antibody) must have an undetectable hepatitis B viral load.

Patients who have positive hepatitis C antibody may be included if they have an

undetectable hepatitis C viral load.

- Major surgery within 14 days of randomization or a scheduled surgery during study

period

- Known central nervous system (CNS) involvement

- Diagnosis or treatment for another malignancy within 2 years before randomization.

(NOTE: Patients with non-melanoma skin cancer or carcinoma in situ of any type are not

excluded if they have undergone resection. Prior diagnosis of myelodysplasia,

myeloproliferative neoplasm, or aplastic anemia and treatment for that diagnosis does

not lead to exclusion)

- Any evidence of residual disease of another malignancy

- Patients with uncontrolled coagulopathy or bleeding disorder

- History or current evidence of any condition, therapy, or laboratory abnormality that

might confound the results of the trial, interfere with the subject's participation

for the full duration of the trial, or is not in the best interest of the subject to

participate, in the opinion of the treating investigator

Unexpected effect of HMA monotherapy

- Prior HMA failure

- Prior HMA treatment without subsequent allogeneic transplantation

Interfering Treatments

- Any ongoing therapy with investigational agents or chemotherapeutic agents active

against MDS or AML

- BCRP inhibitors (for exceptions, see section 5.7.5) are not permitted during the study

and should be stopped 14 days before first dose of the study drug

Exclusion criteria regarding special restrictions for females of childbearing potential

- Current or planned pregnancy or nursing women (negative urine or serum pregnancy test

within 3 days prior to receiving study treatment is needed. If the urine test is

positive or cannot be confirmed as negative, a serum pregnancy test needs to be

required.)

- Female patients of childbearing potential, who are not using or not willing to use 1

highly effective method and 1 additional effective (barrier) method of contraception,

at the same time, from the time of signing the informed consent through 4 months after

the last dose of study drug. Note: Abstinence is acceptable if this is the usual

lifestyle and preferred contraception for the subject.

- Female patients who intend to donate eggs (ova) during the course of this study or 4

months after receiving their last dose of study drug(s).

Exclusion criteria regarding special restrictions for males, even if surgically sterilized

(i.e. status post vasectomy)

- Male patients, who do not agree to use an adequate method of contraception, starting

with the first dose of study therapy during the entire study treatment period and

through 4 months after the last dose of study drug. Note: Abstinence is acceptable if

this is the usual lifestyle and preferred contraception for the subject.

- Male patients who intend to donate sperm during the course of this study or 4 months

after receiving their last dose of study drug(s).

Regulatory requirements

- Age under 18 years at registration

- Inability to provide written informed consent

- Subject without legal capacity who is unable to understand the nature, scope,

significance and consequences of this clinical trial

- Simultaneous participation in another interventional clinical trial or participation

in any clinical trial involving administration of an investigational medicinal product

within 30 days prior to SHAPE trial beginning

Studien-Rationale

Primary outcome:

1. Measurable residual disease (MRD) status after 3 months of treatment (Time Frame - 3 months after start of treatment):
To show that pevonedistat and azacitidine are more effective compared to azacitidine alone with regard to achievement of MRD negativity after 3 months of treatment. MRD assessment is carried out as determination of the NPM1mut status or as CD34/CD117 chimerism analysis.



Secondary outcome:

1. Overall Survival (Time Frame - From date of randomization until the date of death from any cause, assessed up to 25 months):
To describe and compare outcome measures between two strategies: pevonedistat and azacitidine in combination versus azacitidine alone with cross over option.

2. Relapse Free Survival (Time Frame - Time from randomization until hematological relapse or death from any cause (whichever comes first), assessed up to 25 Months.):
To describe and compare outcome measures between two strategies: pevonedistat and azacitidine in combination versus azacitidine alone with cross over option.

3. Impact of treatment assessed by using the validated questionnaires EORTC QLQ-C30. (Time Frame - Time from randomization until hematological relapse or death from any cause (whichever comes first)):
To describe and compare outcome measures between two strategies: pevonedistat and azacitidine in combination versus azacitidine alone with cross over option.

4. Impact of treatment assessed by using the validated questionnaires EQ-5D-5L. (Time Frame - Time from randomization until hematological relapse or death from any cause (whichever comes first), assessed up to 25 months.):
To describe and compare outcome measures between two strategies: pevonedistat and azacitidine in combination versus azacitidine alone with cross over option.

Studien-Arme

  • Experimental: pevonedistat + azacitidine
    pevonedistat in combination with azacitidine
  • Other: azacitidine monotherapy
    administration of azacitidine monotherapy

Geprüfte Regime

  • Pevonedistat:
    Patients receive pevonedistat at 20 mg/m2 i.v. (d1,3,5, q4w) up to 12 cycles
  • Azacitidine:
    azacitidine is given at a standard dose of 75 mg/m² (d1-7 or 1-5,8,9, q4w) up to 12 cycles

Quelle: ClinicalTrials.gov


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