Acute Myeloid Leukemia
Conditions
Keywords
Acute Myeloid Leukemia, Low-dose Decitabine, Valproic acid, All-trans retinoic acid, Older Patients
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).
Interventions
DRUGDecitabine
i.v. Decitabine 20 mg/m² over 1h, 5 days (total dose 100 mg/m²), repeated every 4 weeks
DRUGVPA
VPA starting on day 6 of first cycle continuously throughout all treatment cycles
DRUGATRA
ATRA (45 mg/m² p.o.) from day 6 to day 28 of each treatment cycle
Sponsors
University Hospital Freiburg
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
60 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Objective best response rate (complete remission (CR) and partial remission (PR)) | 12 months after randomization of the last patient |
Secondary
| Measure | 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 |
Countries
Germany
Outcome results
None listed