Clinical trial NCT00867672: Study of Decitabine Alone or in Combination With Valproic Acid and All-trans Retinoic Acid in Acute Myeloid Leukemia
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Acute Myeloid Leukemia
Keywords: Acute Myeloid Leukemia
Low-dose Decitabine
Valproic acid
All-trans retinoic acid
Older Patients
Lead sponsor: University Hospital Freiburg
Sponsor class: OTHER
First posted: 2009-03-24
Enrollment: 204
Sex: ALL
Minimum age (years): 60
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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).

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);
8. Other malignancy requiring treatment (previous chemotherapy for other malignancies is not an exclusion criteria);
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.

Primary outcomes:
measure: Objective best response rate (complete remission (CR) and partial remission (PR))
timeFrame: 12 months after randomization of the last patient
Secondary outcomes:
measure: Overall best response rate (CR, PR and antileukemic effect (ALE))
timeFrame: 12 months after randomization of the last patient
measure: progression-free survival (PFS)
timeFrame: 12 months after randomization of the last patient
measure: overall survival (OS)
timeFrame: 12 months after randomization of the last patient
measure: quality of life
timeFrame: until 4 weeks after study drug intake
measure: safety and toxicity
timeFrame: until 4 weeks after study drug intake
Other outcomes:
Locations:
city: Aachen
country: Germany
facility: Klinikum der Technischen Universität Aachen
city: Berlin
country: Germany
facility: Vivantes Klinikum Neukölln
city: Bochum
country: Germany
facility: Augusta-Kranken-Anstalt gGmbH
city: Braunschweig
country: Germany
facility: Klinikum Braunschweig
city: Bremen
country: Germany
facility: DIAKO Ev. Diakonie-Krankenhaus gGmbH
city: Düsseldorf
country: Germany
facility: Universitätsklinikum Düsseldorf
city: Düsseldorf
country: Germany
facility: Marien Hospital Düsseldorf
city: Esslingen
country: Germany
facility: Klinikum Esslingen GmbH
city: Frankfurt
country: Germany
facility: Universität Frankfurt
city: Freiburg
country: Germany
facility: Medizinische Universitätsklinik Freiburg
city: Hagen
country: Germany
facility: St. Marien-Hospital Hagen
city: Halle
country: Germany
facility: Universitätsklinikum Halle
city: Hamm
country: Germany
facility: Evangelisches Krankenhaus Hamm gGmbH
city: Hannover
country: Germany
facility: Med. Hochschule Hannover
city: Jena
country: Germany
facility: Universitätsklinikum Jena
city: Lahr
country: Germany
facility: Ortenau Klinikum Lahr-Ettenheim
city: Lebach
country: Germany
facility: Caritas Krankenhaus Lebach
city: Leipzig
country: Germany
facility: Universitätsklinikum Leipzig AöR
city: Lüdenscheid
country: Germany
facility: Klinikum Lüdenscheid
city: Marburg
country: Germany
facility: Philipps-Universität Marburg
city: München
country: Germany
facility: TU München
city: Münster
country: Germany
facility: University of Münster Medical Center
city: Offenburg
country: Germany
facility: Ortenau Klinikum
city: Ravensburg
country: Germany
facility: Studienzentrum Onkologie Ravensburg
city: Tübingen
country: Germany
facility: Eberhard Karls Universität Tübingen
city: Ulm
country: Germany
facility: Universitätsklinikum Ulm
city: Villingen-Schwenningen
country: Germany
facility: Klinikum Villingen-Schwenningen
Study officials:
affiliation: Department of Hematology/Oncology, University of Freiburg Medical Center
name: Michael Lübbert, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.