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

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).

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.