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

Acute Myeloid Leukemia Clinical Trial

— DECIDER  

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00867672
• Other study ID #: 00332/AMLSG14-09
• Status: Completed
• Phase: Phase 2
• First received: March 23, 2009
• Last updated: August 30, 2016
• Start date: August 2011
• Est. completion date: February 2016

Study information

• Verified date: August 2016
• Source: University Hospital Freiburg
• Contact: n/a
• Is FDA regulated: No
• Health authority: Germany: Federal Institute for Drugs and Medical Devices
• Study type: Interventional

Clinical Trial 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.

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).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 204
• Est. completion date: February 2016
• Est. primary completion date: February 2015
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 60 Years and older

Eligibility

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.

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Acute Myeloid Leukemia
• Leukemia
• Leukemia, Myeloid
• Leukemia, Myeloid, Acute

Intervention

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

Locations

Country	Name	City	State
Germany	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	Marien Hospital Düsseldorf	Düsseldorf
Germany	Universitätsklinikum Düsseldorf	Düsseldorf
Germany	Klinikum Esslingen GmbH	Esslingen
Germany	Universität Frankfurt	Frankfurt
Germany	Medizinische Universitätsklinik Freiburg	Freiburg
Germany	St. Marien-Hospital Hagen	Hagen
Germany	Universitätsklinikum Halle	Halle
Germany	Evangelisches Krankenhaus Hamm gGmbH	Hamm
Germany	Med. Hochschule Hannover	Hannover
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

Sponsors (1)

Lead Sponsor	Collaborator
University Hospital Freiburg

Country where clinical trial is conducted

Germany, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Objective best response rate (complete remission (CR) and partial remission (PR))		12 months after randomization of the last patient	No
Secondary	Overall best response rate (CR, PR and antileukemic effect (ALE))		12 months after randomization of the last patient	No
Secondary	progression-free survival (PFS)		12 months after randomization of the last patient	No
Secondary	overall survival (OS)		12 months after randomization of the last patient	No
Secondary	quality of life		until 4 weeks after study drug intake	No
Secondary	safety and toxicity		until 4 weeks after study drug intake	Yes

External Links

•   Study protocol publication