Study of Decitabine Alone or in Combination With Valproic Acid and All-trans Retinoic Acid in Acute Myeloid Leukemia

NCT ID: NCT00867672

Last Updated: 2016-08-31

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 204 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2011-08-31
• Study Completion Date: 2016-02-29

Brief Summary

AML of the older patient constitutes a major unmet clinical need since the large majority will not be found eligible for induction chemotherapy. Reasons for this decision include host factors (comorbidities, reduced performance status, functional limitations due to age), leading to often poor tolerance of repeated chemotherapy courses and the unfavorable biology underlying this disease in older patients. Low dose Decitabine has shown very promising efficacy in high-risk MDS and is therefore a very promising approach also in older AML patients. Preliminary results from several centres have demonstrated excellent feasibility and good efficacy of this treatment. Therefore the investigators intend to investigate the effects of two drugs added onto low-dose Decitabine which have shown very promising synergistic effects in vitro and for which preliminary results indicate that the combination with low-dose Decitabine is very feasible.

Detailed Description

By employing a 2x2 factorial design, this phase II study will address the possible added efficacy of addition of one or even both of these agents to low-dose Decitabine. The primary endpoint of this study will be objective response rate (complete and partial remissions).

Conditions

Acute Myeloid Leukemia

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Decitabine

i.v. Decitabine 20 mg/m² over 1h, 5 days (total dose 100 mg/m²), repeated every 4 weeks

Group Type: EXPERIMENTAL

Decitabine

Intervention Type: DRUG

i.v. Decitabine 20 mg/m² over 1h, 5 days (total dose 100 mg/m²), repeated every 4 weeks

Decitabine+VPA

i.v. Decitabine 20 mg/m² over 1h, 5 days (total dose 100 mg/m²), repeated every 4 weeks, and VPA (p.o.) from day 6 of first cycle continuously throughout all treatment cycles

Group Type: EXPERIMENTAL

Decitabine

Intervention Type: DRUG

i.v. Decitabine 20 mg/m² over 1h, 5 days (total dose 100 mg/m²), repeated every 4 weeks

VPA

Intervention Type: DRUG

VPA starting on day 6 of first cycle continuously throughout all treatment cycles

Decitabine+ATRA

i.v. Decitabine 20 mg/m² over 1h, 5 days (total dose 100 mg/m²), repeated every 4 weeks and ATRA (45 mg/m² p.o.) from day 6 to day 28 of each treatment cycle

Group Type: EXPERIMENTAL

Decitabine

Intervention Type: DRUG

i.v. Decitabine 20 mg/m² over 1h, 5 days (total dose 100 mg/m²), repeated every 4 weeks

ATRA

Intervention Type: DRUG

ATRA (45 mg/m² p.o.) from day 6 to day 28 of each treatment cycle

Decitabine+VPA+ATRA

i.v. Decitabine 20 mg/m² over 1h, 5 days (total dose 100 mg/m²), repeated every 4 weeks and VPA (p.o.) from day 6 continuously throughout all treatment cycles and ATRA (45 mg/m² p.o.), from day 6 to day 28 of each treatment cycle

Group Type: EXPERIMENTAL

Decitabine

Intervention Type: DRUG

i.v. Decitabine 20 mg/m² over 1h, 5 days (total dose 100 mg/m²), repeated every 4 weeks

VPA

Intervention Type: DRUG

VPA starting on day 6 of first cycle continuously throughout all treatment cycles

ATRA

Intervention Type: DRUG

ATRA (45 mg/m² p.o.) from day 6 to day 28 of each treatment cycle

Interventions

Decitabine

i.v. Decitabine 20 mg/m² over 1h, 5 days (total dose 100 mg/m²), repeated every 4 weeks

Intervention Type: DRUG

VPA

VPA starting on day 6 of first cycle continuously throughout all treatment cycles

Intervention Type: DRUG

ATRA

ATRA (45 mg/m² p.o.) from day 6 to day 28 of each treatment cycle

Intervention Type: DRUG

Other Intervention Names

Dacogen; Valproic acid; All-trans retinoic acid

Eligibility Criteria

Inclusion Criteria

1. Written informed consent obtained according to international guidelines and local law;

2. Male or female patients aged > 60 years without upper age limit;

3. Patients with primary or secondary AML according to WHO (≥ 20% blasts in the peripheral blood (pB) or bone marrow (BM)) who are not expected to benefit from standard remission-induction chemotherapy;

4. Patients with < 30 000 leukocytes/μl;

5. Performance status ECOG 0, 1, 2;

6. Creatinine < 2.0 mg/dl (unless leukemia-related);

7. Ability to understand the nature of the study and the study related procedures and to comply with them.

Exclusion Criteria

1. AML of FAB subtype M3;

2. Previous remission-induction chemotherapy for MDS or AML, previous allografting;

3. Previous treatment with DAC, 5-azacytidine, VPA or another HDAC inhibitor, or ATRA;

4. "Low-dose" chemotherapy (e.g. hydroxyurea, cytosine arabinoside (Ara-C), melphalan, clofarabine etc.) within 4 weeks prior to DAC treatment, except for cytoreduction of leukocytosis ≥ 30 000/μl with hydroxyurea or Ara-C as proscribed by the study protocol (section 7.3 and 7.4); the patient must have recovered from all clinically relevant reversible non-hematologic toxicities;

5. Treatment with tyrosine kinase inhibitors, immunomodulating agents (IMIDS) or other investigational AML treatment within the last 4 weeks or in a time period of drug half-life x 5 (whatever is shorter) before the first administration of DAC;

6. Treatment with cytokines within previous 4 weeks;

7. Concomitant therapy which is considered relevant for the evaluation of efficacy or safety of the trial drug (i.e. other chemo- or immunotherapy);

9. Cardiac insufficiency NYHA IV;

10. Insufficient hepatic function (bilirubin, AST or ALT > = 2.5 x Upper Limit of Normal (ULN)) (unless leukemia-related);

11. Fatal hepatic function disorder during treatment with valproic acid in siblings;

12. Hepatic porphyria;

13. Manifest serious pancreatic function disorder;

14. Plasmatic coagulation disorder not related to AML;

15. Known active hepatitis B or C;

16. Known HIV infection;

17. Other uncontrolled active infections;

18. Known allergy against soy beans or peanuts;

19. Psychiatric disorder that interferes with treatment;

20. Patient without legal capacity who is unable to understand the nature, significance and consequences of the study;

21. Known hypersensitivity to, or intolerance of, one of the trial drugs, another retinoid or the excipients of the trial drugs;

22. Concomitant use of any other investigational drug or participation in a clinical trial within the last thirty days before the start of this study; simultaneous participation in registry and diagnostic trials is allowed;

23. Female patients who are pregnant or breast feeding;

24. Fertile patients refusing to use safe contraceptive methods during the study (for details see clinical trial protocol section 5.3);

25. Known or persistent abuse of medication, drugs or alcohol.

• Minimum Eligible Age: 60 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

University Hospital Freiburg

OTHER

Sponsor Role: lead

Responsible Party

Michael Luebbert

Professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Michael Lübbert, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Department of Hematology/Oncology, University of Freiburg Medical Center

Locations

Klinikum der Technischen Universität Aachen

Aachen, , Germany

Vivantes Klinikum Neukölln

Berlin, , Germany

Augusta-Kranken-Anstalt gGmbH

Bochum, , Germany

Klinikum Braunschweig

Braunschweig, , Germany

DIAKO Ev. Diakonie-Krankenhaus gGmbH

Bremen, , Germany

Universitätsklinikum Düsseldorf

Düsseldorf, , Germany

Marien Hospital Düsseldorf

Düsseldorf, , Germany

Klinikum Esslingen GmbH

Esslingen am Neckar, , Germany

Universität Frankfurt

Frankfurt, , Germany

Medizinische Universitätsklinik Freiburg

Freiburg im Breisgau, , Germany

St. Marien-Hospital Hagen

Hagen, , Germany

Universitätsklinikum Halle

Halle, , Germany

Evangelisches Krankenhaus Hamm gGmbH

Hamm, , Germany

Med. Hochschule Hannover

Hanover, , Germany

Universitätsklinikum Jena

Jena, , Germany

Ortenau Klinikum Lahr-Ettenheim

Lahr, , Germany

Caritas Krankenhaus Lebach

Lebach, , Germany

Universitätsklinikum Leipzig AöR

Leipzig, , Germany

Klinikum Lüdenscheid

Lüdenscheid, , Germany

Philipps-Universität Marburg

Marburg, , Germany

TU München

München, , Germany

University of Münster Medical Center

Münster, , Germany

Ortenau Klinikum

Offenburg, , Germany

Studienzentrum Onkologie Ravensburg

Ravensburg, , Germany

Eberhard Karls Universität Tübingen

Tübingen, , Germany

Universitätsklinikum Ulm

Ulm, , Germany

Klinikum Villingen-Schwenningen

Villingen-Schwenningen, , Germany

Countries

Germany

References

Bresser H, Schmoor C, Grishina O, Pfeifer D, Thomas J, Rehman UU, Crysandt M, Jost E, Thol F, Heuser M, Gotze KS, Schlenk RF, Salih HR, Schittenhelm MM, Heil G, Schwaenen C, Muller-Tidow C, Brugger W, Kundgen A, de Wit M, Giagounidis A, Scholl S, Neubauer A, Krauter J, Bug G, May AM, Wasch R, Duyster J, Dohner K, Ganser A, Dohner H, Hackanson B, Becker H, Lubbert M. Impact of TP53 Mutation Status in Elderly AML Patients When Adding All-Trans Retinoic Acid or Valproic Acid to Decitabine. Eur J Haematol. 2025 Feb;114(2):231-237. doi: 10.1111/ejh.14304. Epub 2024 Oct 13.

Reference Type: DERIVED

PMID: 39400388 (View on PubMed)

Thomas J, Rehman UU, Bresser H, Grishina O, Pfeifer D, Sollier E, Dohner K, Plass C, Becker H, Schmoor C, de Wit M, Lubbert M. Continued decitabine/all-trans retinoic acid treatment: extended complete remission in an elderly AML patient with multi-hit TP53 lesions and complex-monosomal karyotype. Clin Epigenetics. 2024 Sep 11;16(1):126. doi: 10.1186/s13148-024-01737-4.

Reference Type: DERIVED

PMID: 39261919 (View on PubMed)

Javorniczky NR, Grishina O, Hund I, Pantic M, Pfeifer D, Schmoor C, Thomas J, Duyster J, Becker H, Lubbert M. Long-term decitabine/retinoic acid maintenance treatment in an elderly sAML patient with high-risk genetics. Clin Epigenetics. 2023 Nov 28;15(1):185. doi: 10.1186/s13148-023-01596-5.

Reference Type: DERIVED

PMID: 38012682 (View on PubMed)

Lubbert M, Grishina O, Schmoor C, Schlenk RF, Jost E, Crysandt M, Heuser M, Thol F, Salih HR, Schittenhelm MM, Germing U, Kuendgen A, Gotze KS, Lindemann HW, Muller-Tidow C, Heil G, Scholl S, Bug G, Schwaenen C, Giagounidis A, Neubauer A, Krauter J, Brugger W, De Wit M, Wasch R, Becker H, May AM, Duyster J, Dohner K, Ganser A, Hackanson B, Dohner H; DECIDER Study Team. Valproate and Retinoic Acid in Combination With Decitabine in Elderly Nonfit Patients With Acute Myeloid Leukemia: Results of a Multicenter, Randomized, 2 x 2, Phase II Trial. J Clin Oncol. 2020 Jan 20;38(3):257-270. doi: 10.1200/JCO.19.01053. Epub 2019 Dec 3.

Reference Type: DERIVED

PMID: 31794324 (View on PubMed)

Grishina O, Schmoor C, Dohner K, Hackanson B, Lubrich B, May AM, Cieslik C, Muller MJ, Lubbert M. DECIDER: prospective randomized multicenter phase II trial of low-dose decitabine (DAC) administered alone or in combination with the histone deacetylase inhibitor valproic acid (VPA) and all-trans retinoic acid (ATRA) in patients >60 years with acute myeloid leukemia who are ineligible for induction chemotherapy. BMC Cancer. 2015 May 26;15:430. doi: 10.1186/s12885-015-1432-5.

Reference Type: DERIVED

PMID: 26008690 (View on PubMed)

Related Links

https://bmccancer.biomedcentral.com/articles/10.1186/s12885-015-1432-5

Study protocol publication

Other Identifiers

00332/AMLSG14-09

Identifier Type: -

Identifier Source: org_study_id