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

Study Overview
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Brief Summary
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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
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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).

Official Title
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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

Conditions
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Acute Myeloid Leukemia

Intervention / Treatment
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* Drug: Decitabine
* Drug: VPA
* Drug: ATRA


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

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

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective best response rate (complete remission (CR) and partial remission (PR)) |  | 12 months after randomization of the last patient | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Acute Myeloid Leukemia, Low-dose Decitabine, Valproic acid, All-trans retinoic acid, Older Patients