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

• Overall best response rate (CR, PR and antileukemic effect (ALE)) [ Time Frame: 12 months after randomization of the last patient ] [ Designated as safety issue: No ]
• progression-free survival (PFS) [ Time Frame: 12 months after randomization of the last patient ] [ Designated as safety issue: No ]
• overall survival (OS) [ Time Frame: 12 months after randomization of the last patient ] [ Designated as safety issue: No ]
• quality of life [ Time Frame: until 4 weeks after study drug intake ] [ Designated as safety issue: No ]
• safety and toxicity [ Time Frame: until 4 weeks after study drug intake ] [ Designated as safety issue: Yes ]

• Overall survival [ Time Frame: after 12 month ] [ Designated as safety issue: No ]
• Toxicity [ Time Frame: after 3-6 months ] [ Designated as safety issue: Yes ]
• Quality of life [ Time Frame: 3-6 ] [ Designated as safety issue: No ]

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.

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).

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

• Experimental: Decitabine
  i.v. Decitabine 20 mg/m² over 1h, 5 days (total dose 100 mg/m²), repeated every 4 weeks
  Intervention: Drug: Decitabine
• 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
  Interventions:

  • Drug: Decitabine
  • Drug: VPA
• 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
  Interventions:

  • Drug: Decitabine
  • Drug: ATRA
• 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
  Interventions:

  • Drug: Decitabine
  • Drug: VPA
  • Drug: ATRA

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% BM blasts) 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. Age-adjusted normal cardiac and kidney function (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 auto-/allografting;
3. Previous treatment with DAC, 5-azacytidine, VPA or another HDAC inhibitor, or ATRA;
4. "Low-dose" chemotherapy (e.g. hydroxyurea, cytosine arabinoside, melphalan, clofarabine etc.) within 8 weeks prior to DAC treatment, except for cytoreduction of leukocytosis ≥ 30 000/µl with hydroxyurea, as proscribed by the study protocol (section 7.3 and 7.4);
5. Treatment with tyrosine kinase Inhibitors, immunomodulating agents (IMIDS) and other investigational AML treatments within previous 8 weeks;
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));
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. Hepatitis B or C;
16. 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;
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.