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

Phase 2

Completed

• Conditions: Acute Myeloid Leukemia
• Interventions: Drug: Decitabine; Drug: ATRA; Drug: VPA

• Registration Number: NCT00867672
• Lead Sponsor: University Hospital Freiburg

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).

Study Timeline

• Study First Submitted: 2009-03-23
• Study First Submitted QC: 2009-03-23
• Study First Posted: 2009-03-24
• Study Start: 2011-08
• Primary Completion: 2015-02
• Study Completion: 2016-02
• Status Verified: 2016-08
• Last Update Submitted: 2016-08-30
• Last Update Posted: 2016-08-31

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 204

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

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

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

Primary Outcome Measures

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

Secondary Outcome Measures

Name	Time	Method
quality of life	until 4 weeks after study drug intake
safety and toxicity	until 4 weeks after study drug intake
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

Trial Locations

Locations (27)

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, Germany

Universität Frankfurt; 🇩🇪 Frankfurt, Germany

Medizinische Universitätsklinik Freiburg; 🇩🇪 Freiburg, Germany

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