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

Sponsor

University Hospital Freiburg (Other)

Overall Status

Completed

CT.gov ID

NCT00867672

Collaborator

(none)

204

Enrollment

Locations

Arms

Duration (Months)

7.6

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Acute Myeloid Leukemia	Drug: Decitabine Drug: VPA Drug: ATRA	Phase 2

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).

Study Design

Study Type:

Interventional

Actual Enrollment :

204 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

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 Start Date :

Aug 1, 2011

Actual Primary Completion Date :

Feb 1, 2015

Actual Study Completion Date :

Feb 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Decitabine i.v. Decitabine 20 mg/m² over 1h, 5 days (total dose 100 mg/m²), repeated every 4 weeks	Drug: Decitabine i.v. Decitabine 20 mg/m² over 1h, 5 days (total dose 100 mg/m²), repeated every 4 weeks Other Names: Dacogen
Experimental: 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	Drug: Decitabine i.v. Decitabine 20 mg/m² over 1h, 5 days (total dose 100 mg/m²), repeated every 4 weeks Other Names: Dacogen Drug: VPA VPA starting on day 6 of first cycle continuously throughout all treatment cycles Other Names: Valproic acid
Experimental: 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	Drug: Decitabine i.v. Decitabine 20 mg/m² over 1h, 5 days (total dose 100 mg/m²), repeated every 4 weeks Other Names: Dacogen Drug: ATRA ATRA (45 mg/m² p.o.) from day 6 to day 28 of each treatment cycle Other Names: All-trans retinoic acid
Experimental: 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	Drug: Decitabine i.v. Decitabine 20 mg/m² over 1h, 5 days (total dose 100 mg/m²), repeated every 4 weeks Other Names: Dacogen Drug: VPA VPA starting on day 6 of first cycle continuously throughout all treatment cycles Other Names: Valproic acid Drug: ATRA ATRA (45 mg/m² p.o.) from day 6 to day 28 of each treatment cycle Other Names: All-trans retinoic acid

Outcome Measures

Primary Outcome Measures

Objective best response rate (complete remission (CR) and partial remission (PR)) [12 months after randomization of the last patient]

Secondary Outcome Measures

Overall best response rate (CR, PR and antileukemic effect (ALE)) [12 months after randomization of the last patient]
progression-free survival (PFS) [12 months after randomization of the last patient]
overall survival (OS) [12 months after randomization of the last patient]
quality of life [until 4 weeks after study drug intake]
safety and toxicity [until 4 weeks after study drug intake]

Eligibility Criteria

Criteria

Ages Eligible for Study:

60 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Written informed consent obtained according to international guidelines and local law;
Male or female patients aged > 60 years without upper age limit;
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;
Patients with < 30 000 leukocytes/μl;
Performance status ECOG 0, 1, 2;
Creatinine < 2.0 mg/dl (unless leukemia-related);
Ability to understand the nature of the study and the study related procedures and to comply with them.

Exclusion Criteria:

AML of FAB subtype M3;
Previous remission-induction chemotherapy for MDS or AML, previous allografting;
Previous treatment with DAC, 5-azacytidine, VPA or another HDAC inhibitor, or ATRA;
"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;
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;
Treatment with cytokines within previous 4 weeks;
Concomitant therapy which is considered relevant for the evaluation of efficacy or safety of the trial drug (i.e. other chemo- or immunotherapy);
Other malignancy requiring treatment (previous chemotherapy for other malignancies is not an exclusion criteria);
Cardiac insufficiency NYHA IV;
Insufficient hepatic function (bilirubin, AST or ALT > = 2.5 x Upper Limit of Normal (ULN)) (unless leukemia-related);
Fatal hepatic function disorder during treatment with valproic acid in siblings;
Hepatic porphyria;
Manifest serious pancreatic function disorder;
Plasmatic coagulation disorder not related to AML;
Known active hepatitis B or C;
Known HIV infection;
Other uncontrolled active infections;
Known allergy against soy beans or peanuts;
Psychiatric disorder that interferes with treatment;
Patient without legal capacity who is unable to understand the nature, significance and consequences of the study;
Known hypersensitivity to, or intolerance of, one of the trial drugs, another retinoid or the excipients of the trial drugs;
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;
Female patients who are pregnant or breast feeding;
Fertile patients refusing to use safe contraceptive methods during the study (for details see clinical trial protocol section 5.3);
Known or persistent abuse of medication, drugs or alcohol.

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	Klinikum der Technischen Universität Aachen	Aachen	Germany	52074
2	Vivantes Klinikum Neukölln	Berlin	Germany	12351
3	Augusta-Kranken-Anstalt gGmbH	Bochum	Germany	44791
4	Klinikum Braunschweig	Braunschweig	Germany	38126
5	DIAKO Ev. Diakonie-Krankenhaus gGmbH	Bremen	Germany	28239
6	Universitätsklinikum Düsseldorf	Düsseldorf	Germany	40225
7	Marien Hospital Düsseldorf	Düsseldorf	Germany	40479
8	Klinikum Esslingen GmbH	Esslingen	Germany	73730
9	Universität Frankfurt	Frankfurt	Germany
10	Medizinische Universitätsklinik Freiburg	Freiburg	Germany	79106
11	St. Marien-Hospital Hagen	Hagen	Germany	58095
12	Universitätsklinikum Halle	Halle	Germany	06120
13	Evangelisches Krankenhaus Hamm gGmbH	Hamm	Germany	59063
14	Med. Hochschule Hannover	Hannover	Germany	30625
15	Universitätsklinikum Jena	Jena	Germany	07747
16	Ortenau Klinikum Lahr-Ettenheim	Lahr	Germany	77933
17	Caritas Krankenhaus Lebach	Lebach	Germany	66822
18	Universitätsklinikum Leipzig AöR	Leipzig	Germany	04103
19	Klinikum Lüdenscheid	Lüdenscheid	Germany	58515
20	Philipps-Universität Marburg	Marburg	Germany	35032
21	TU München	München	Germany	86175
22	University of Münster Medical Center	Münster	Germany	48149
23	Ortenau Klinikum	Offenburg	Germany	77654
24	Studienzentrum Onkologie Ravensburg	Ravensburg	Germany	88212
25	Eberhard Karls Universität Tübingen	Tübingen	Germany	72076
26	Universitätsklinikum Ulm	Ulm	Germany	89081
27	Klinikum Villingen-Schwenningen	Villingen-Schwenningen	Germany	78050