Prospective randomized multicenter phase III trial of decitabine and venetoclax administered in combination with all-trans retinoic acid or placebo in patients with acute myeloid leukemia who are ineligible for induction chemotherapy
Organizational Data
- DRKS-ID:
- DRKS00023646
- Recruitment Status:
- Recruiting ongoing
- Date of registration in DRKS:
- 2022-08-23
- Last update in DRKS:
- 2024-03-12
- Registration type:
- Prospective
Acronym/abbreviation of the study
DECIDER-2
URL of the study
No Entry
Brief summary in lay language
The planned clinical trial deals with the improvement of the therapy of AML, which you have been newly diagnosed with. This is a disease of the hematopoietic system in which precursors of so-called myeloid cells degenerate. As a result, these cells divide uncontrollably in the bone marrow, producing "leukemic" cells rather than "normal" and functional mature cells. This leads to a lack of mature cells of the hematopoietic system. Therefore, patients with AML are at risk from infections, anemia and bleeding tendencies, bruising or nosebleeds.
Brief summary in scientific language
Acute myeloid leukemia (AML) is a hematologic malignancy occurring predominantly in the elderly (median patient age at diagnosis >65 years). Until recently, therapeutic options for elderly AML patients were very limited, since intensive chemotherapy often results in unacceptable toxicities, and frequently was not as effective as in younger patients. Better tolerated, less intensive AML therapy is provided by the epigenetically active agents Decitabine and Azacitidine. These closely related DNA- hypomethylating drugs are administered on an outpatient basis, are well tolerated also by elderly patients with comorbidities, and thought to act by "reprogramming" of the leukemia cells. It is therefore thought that this class of drugs has a mechanism of action distinct from conventional chemotherapy, by reactivating "silenced" tumor suppressor genes, immunogenic genes and other genes inactivated in the AML blasts. To enhance the efficacy of this epigenetic AML therapy - by itself not leading to cure - numerous drug combinations have been clinically tested during the last years. Through a collaboration within a trial network of physicians from different German University Hospitals, we could demonstrate in the multicenter clinical phase II randomized trial DECIDER (registered under NCT00867672) that Decitabine infusions in combination with a vitamin A derivative (all-trans retinoic acid, ATRA) led to an increase in overall survival (OS) of elderly AML patients (median age 76 years) compared to treatment with Decitabine alone. Within the planned successor study (DECIDER-2, double-blind randomized phase III) the primary objective is to confirm the extension of patient survival with ATRA add-on compared to treatment without ATRA add-on. Half the patients will receive ATRA in addition to Decitabine, the other half will receive placebo in addition to Decitabine. All patients will receive a third drug (Venetoclax, a BCL-2 inhibitor) with the aim to accelerate apoptosis in the AML cells. The study is planned to accrue 256 patients at approx. 30 German study sites. The primary objective is to test the hypothesis that patients receiving ATRA add-on will have an increase in OS compared to patients receiving placebo. Another important objective is the quantification of quality of life before and during this type of AML therapy. We also hypothesize that patients benefiting from the treatment will also experience an improvement of their quality of life. In accompanying laboratory studies, the mechanism of action of this novel therapy shall be studied using bone marrow and blood cells of the patients, in order to be able to make better predictions about which patient will profit most from this chemotherapy-free treatment.
Health condition or problem studied
- ICD10:
- C92 - Myeloid leukaemia
- Healthy volunteers:
- No
Interventions, Observational Groups
- Arm 1:
- Backbone treatment: • DAC intravenously (i.v.) 20 mg/m2 over 1h, on day 1 to day 5 (total dose 100 mg/m2) and • VEN per os (p.o.) ramp-up (during posaconazole prophylaxis, which is strongly recommended): 10 mg on day 1, 20 mg on day 2, 50 mg on day 3 and 100 mg on days 4-28 in cycle 1, 100 mg on days 1-28, in subsequent cycles and IMP: • ATRA p.o. 45 mg/m2, day 6-28. Cycles are repeated every 28 days.
- Arm 2:
- Backbone treatment: • DAC i.v. 20 mg/m2 over 1h, on day 1 to day 5 (total dose 100 mg/m2) and • VEN p.o. ramp-up (during posaconazole prophylaxis, which is strongly recommended): 10 mg on day 1, 20 mg on day 2, 50 mg on day 3 and 100 mg on days 4-28 in cycle 1, 100 mg on days 1-28, in subsequent cycles and IMP: • Placebo p.o. (45 mg/m2 p.o., day 6-28), Cycles are repeated every 28 days.
Endpoints
- Primary outcome:
- Overall survival (OS) time
- Secondary outcome:
- • Objective best response (CR, CRi, MLFS or PR) • CR with negative MRD (CRMRD-) • OS time with objective best response (CR, CRi, MLFS or PR) • Quality of life (EORTC QLQ-C30) (especially fatigue) and FACIT Fatigue Scale
Study Design
- Purpose:
- Treatment
- Allocation:
- Randomized controlled study
- Control:
-
- Placebo
- Phase:
- III
- Study type:
- Interventional
- Mechanism of allocation concealment:
- No Entry
- Blinding:
- Yes
- Assignment:
- Parallel
- Sequence generation:
- No Entry
- Who is blinded:
-
- Assessor
- Caregiver
- Data analyst
- Investigator/therapist
- Patient/subject
Recruitment
- Recruitment Status:
- Recruiting ongoing
- Reason if recruiting stopped or withdrawn:
- No Entry
Recruitment Locations
- Recruitment countries:
-
- Germany
- Number of study centers:
- Multicenter study
- Recruitment location(s):
-
- University medical center UKF Freiburg im Breisgau
- Medical center Klinikum Konstanz Konstanz
- University medical center Universitätsklinikum Münster Münster
- University medical center Universitätsklinikum Ulm Ulm
- University medical center Universitätsmedizin Mannheim Mannheim
- Medical center St.-Antonius-Hospital Eschweiler gGmbH Eschweiler
- University medical center Medizinische Hochschule Hannover Hannover
- Medical center Asklepios Klinik Altona Hamburg
- Medical center Ortenau Klinikum Lahr mit Ortenau MVZ GmbH Lahr
- Medical center Helios Klinikum Berlin-Buch Berlin
- Medical center Kath. Krankenhaus Hagen gem. GmbH, St. Josef Hospital Hagen
- Medical center Schwarzwald-Baar Klinikum Villingen-Schwenningen Villingen-Schwenningen
- University medical center Uniklinik RWTH Aachen Aachen
- University medical center Universitätsklinikum Düsseldorf Düsseldorf
- Medical center Märkische Kliniken GmbH Klinikum Lüdenscheid Lüdenscheid
- University medical center Universitätsklinikum Augsburg Augsburg
- Medical center Pius-Hospital Oldenburg Oldenburg
- University medical center Universitätsklinikum Jena Jena
- Medical center Katholisches Karl-Leisner-Klinikum gGmbH, Wilhelm-Anton-Hospital Goch Goch
- Medical center Städtisches Klinikum Karlsruhe Karlsruhe
- University medical center Universitätsklinikum Bonn Bonn
- Medical center Augusta-Kranken-Anstalt gGmbH Bochum Bochum
- University medical center Universitätsklinikum Marburg Marburg
- Medical center Städtisches Klinikum Braunschweig gGmbH Braunschweig
- Medical center Krankenhaus der Barmherzigen Brüder Trier Trier
Recruitment period and number of participants
- Planned study start date:
- 2022-09-30
- Actual study start date:
- 2022-10-17
- Planned study completion date:
- No Entry
- Actual Study Completion Date:
- No Entry
- Target Sample Size:
- 256
- Final Sample Size:
- No Entry
Inclusion Criteria
- Sex:
- All
- Minimum Age:
- 18 Years
- Maximum Age:
- 99 Years
- Additional Inclusion Criteria:
- 1. Age ≥ 18 years 2. Previously untreated AML (WHO 2016) 3. ECOG ≤ 2 4. White blood cell count < 25 × 109/L (hydroxyurea or Ara-C are permitted to meet this criterion see section 6.6.2) 5. No standard induction chemotherapy feasible; the following criteria are generally accepted: • age ≥ 75 years • ECOG ≥ 1 • HCT-CI ≥ 3 • patient declines standard aggressive chemotherapy • missing social support system 6. Projected life expectancy of at least 8 weeks 7. Written informed consent obtained according to international guidelines and local laws 8. Ability to understand the nature, significance and consequences of the trial and the trial related procedures and to comply with them
Exclusion Criteria
1. Acute promyelocytic leukemia (APL, FAB M3) 2. Previous treatment with DAC, azacitidine, or other DNA-hypomethylating agents, ATRA, venetoclax and other Bcl-2 inhibitors 3. Previous allogeneic stem cell transplantation or solid organ transplantation 4. Previous induction chemotherapy 5. Previous low-dose chemotherapy (e.g. hydroxyurea, cytosine arabinoside (Ara-C), melphalan etc.) within 4 weeks prior to the first administration of study treatment, except for cytoreduction of leukocytosis ≥ 25,000/µl with hydroxyurea or Ara-C as proscribed by the clinical trial protocol (section 6.6.2); the patient must have recovered from all clinically relevant reversible non-hematologic toxicities 6. Central nervous system (CNS) leukemia 7. Severe congestive heart failure or clinically unstable cardiac disease 8. Known positivity for HIV, Hepatitis B# or Hepatitis C 9. Uncontrolled bacterial, viral or fungal infection 10. Known allergy against soy-beans or peanuts (due to ATRA excipients) 11. Known hypersensitivity to or intolerance of one of the trial drugs or its constituents (e.g. other retinoids or sunset yellow FCF E110) 12. Known rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption 13. Any malignancy requiring chemotherapy for which the patient received chemotherapy within 3 months prior to randomization 14. Participation in any other interventional clinical trial within the last 30 days before randomization 15. Simultaneous participation in other interventional trials which could interfere with this trial; simultaneous participation in registry and diagnostic trials is allowed 16. Patient without legal capacity 17. Known or persistent abuse of medication, drugs or alcohol 18. Active COVID-19-infection or non-compliance with the prevailing hygiene measures regarding the COVID-19 pandemic 19. Person who is in a relationship of dependence/employment with the sponsor or the investigator 20. Current or planned pregnancy, nursing period 21. For fertile patients: failure to use one of the following safe methods of contraception: intra-uterine device or hormonal contraception in combination with a mechanical method of contraception.
Addresses
Primary Sponsor
- Address:
- Universitätsklinikum FreiburgBreisacher Straße 15379110 FreiburgGermany
- Telephone:
- No Entry
- Fax:
- No Entry
- Contact per E-Mail:
- Contact per E-Mail
- URL:
- http://www.uniklinik-freiburg.de
- Investigator Sponsored/Initiated Trial (IST/IIT):
- Yes
Contact for Scientific Queries
- Address:
- Department of Medicine I: Hematology, Oncology, and Stem-Cell TransplantationProf. Michael LübberHugstetter Str. 5579106 FreiburgGermany
- Telephone:
- +49 761 270-32790
- Fax:
- +49 761 270-36970
- Contact per E-Mail:
- Contact per E-Mail
- URL:
- https://www.uniklinik-freiburg.de/medizin1.html
Contact for Public Queries
- Address:
- Universitätsklinikum FreiburgProf. Michael LübbertHugstetter Str. 5579106 FreiburgGermany
- Telephone:
- +49 761 27032790
- Fax:
- +49 761 27036970
- Contact per E-Mail:
- Contact per E-Mail
- URL:
- https://www.uniklinik-freiburg.de/medizin1.html
Principal Investigator
- Address:
- Department of Medicine I: Hematology, Oncology, and Stem-Cell TransplantationProf. Michael LübberHugstetter Str. 5579106 FreiburgGermany
- Telephone:
- +49 761 270-32790
- Fax:
- +49 761 270-36970
- Contact per E-Mail:
- Contact per E-Mail
- URL:
- https://www.uniklinik-freiburg.de/medizin1.html
Sources of Monetary or Material Support
Public funding institutions financed by tax money/Government funding body (German Research Foundation (DFG), Federal Ministry of Education and Research (BMBF), etc.)
- Address:
- Deutsche ForschungsgemeinschaftKennedyallee 4053175 BonnGermany
- Telephone:
- No Entry
- Fax:
- No Entry
- Contact per E-Mail:
- Contact per E-Mail
- URL:
- http://www.dfg.de
Ethics Committee
Address Ethics Committee
- Address:
- Ethik-Kommission der Albert-Ludwigs-Universität FreiburgEngelberger Str. 2179106 FreiburgGermany
- Telephone:
- +49-761-27072600
- Fax:
- +49-761-27072630
- Contact per E-Mail:
- Contact per E-Mail
- URL:
- No Entry
Vote of leading Ethics Committee
- Vote of leading Ethics Committee
- Date of ethics committee application:
- 2022-01-18
- Ethics committee number:
- 22-1020-AMG-ff multi
- Vote of the Ethics Committee:
- Approved
- Date of the vote:
- 2022-06-14
Further identification numbers
- Other primary registry ID:
- No Entry
- EudraCT Number:
- 2020-005495-36
IPD - Individual Participant Data
- Do you plan to make participant-related data (IPD) available to other researchers in an anonymized form?:
- No
- IPD Sharing Plan:
- No Entry
Study protocol and other study documents
- Study protocols:
- Clinical Trial Protocol DECIDER-2
- Study abstract:
- No Entry
- Other study documents:
- No Entry
- Background literature:
- No Entry
- Related DRKS studies:
- DRKS00000733 - DECIDER
Publication of study results
- Planned publication:
- No Entry
- Publikationen/Studienergebnisse:
- No Entry
- Date of first publication of study results:
- No Entry
- DRKS entry published for the first time with results:
- No Entry
Basic reporting
- Basic Reporting / Results tables:
- No Entry
- Brief summary of results:
- No Entry