Treating leukaemia patients with chemotherapy and 2 repurposed drugs
Randomised phase II trial with safety run-in phase evaluating low-dose azacitidine, all-trans retinoic acid (ATRA) and pioglitazone versus standard dose azacitidine in patients ≥60 years of age with acute myeloid leukaemia (AML) who are refractory to standard induction chemotherapy (AML-ViVA).
- Blood cancer
Why this trial?
Acute myeloid leukaemias (AML) are a group of heterogeneous disorders. Outcome is influenced by various factors, including patient features (e.g. age, other illnesses present) and disease characteristics. While responses can be achieved in 70-80% of younger adult patients with a 5-year survival rate of 40-45%, only about 40-60% of older patients achieve remission. The vast majority will relapse, with about 10% surviving more than 5 years.
For patients with AML that don’t respond to chemotherapy, the only option is stem cell transplantation. If no donor is available, or if the procedure is not feasible due to advanced age or other medical reasons, patients with this chemo-refractory AML have a median survival of only 62 days.
This number clearly demonstrates the need for effective treatment options in patients with refractory disease who are not eligible for stem cell transplantation.
Why this intervention?
The most striking improvement in AML therapy has been achieved with all-trans retinoic acid (ATRA), which is a drug currently on the market for the treatment of acne. Several clinical trials have studied the role of ATRA in AML when given in combination with intensive chemotherapy. One study showed that the addition of ATRA to induction chemotherapy in AML patients >60 years of age resulted in a survival benefit.
Pioglitazone is currently on the market for the treatment of diabetes. Studies have shown that the drug is able to regulate cell growth and death. For AML specifically, preclinical data have demonstrated that PPARγ ligands (the drug group of pioglitazone) suppressed growth of AML cells, and, combined with ATRA, induced the development of normal cells instead of AML cells.
Azacitidine impacts cell differentiation, gene expression, and DNA synthesis and metabolism, and causes (tumour) cell death. Since the early 1970s, azacitidine continues to be investigated for the treatment of various types of leukaemia.
Taken together, it is reasonable and attractive to combine low-dose azacitidine, ATRA and pioglitazone in older patients with refractory AML to evaluate whether this combinatorial improves survival.
The main trial is a randomised, phase II, open label, multi-centre trial in 76 adult patients with AML refractory to standard induction chemotherapy.
An initial safety run-in study will be performed administering the study drugs azacitidine, all-trans retinoic-acid (ATRA) and pioglitazone in 9-18 patients. After completion of this run-in phase, toxicity and response data will be analysed, and it will be decided at which doses the main trial study will be conducted. The trial is performed in 13 German centres.
The first results of this trial have been presented in December 2019 at the major haematology conference ASH, Orlando USA. The treatment is safe in this very fragile population and 3 out of 10 patients had a complete response. One additional patient had a stabilisation of his disease for 14 months.
The second part of the trial was supposed to compare the ViVA regimen to the standard dose azacytidine but it won’t happen because of issues with the company providing the azacytidine (and some funding) for the trial.
The investigators are looking for alternative solutions to explore further the ‘ViVA’ regimen in AML. The Anticancer Fund is helping them in this endeavour.
- Dr. Simone Thomas, University Hospital Regensburg, Regensburg, Germany (Coordinating Investigator)
- Prof. A. Reichle, University Hospital Regensburg, Regensburg, Germany (Principal Investigator)
- University Hospital Regensburg, Regensburg, Germany
- Deutsch-Österreichische Studiengruppe Akute Myeloische Leukämie (AMLSG)
More info on trial: NCT02942758
Hui, H., et al. (2014). Oroxylin A has therapeutic potential in acute myelogenous leukemia by dual effects targeting PPARγ and RXRα. Int J Cancer, 134, 1195-1206. doi:10.1002/ijc.28435
Schlenk, R.F., et al. (2016). All-trans retinoic acid as adjunct to intensive treatment in younger adult patients with acute myeloid leukemia: results of the randomized AMLSG 07-04 study. Annals of Hematology, 95(12), 1931–1942. doi:10.1007/s00277-016-2810-z
Nagel, G., et al. (2017). Epidemiological, genetic, and clinical characterization by age of newly diagnosed acute myeloid leukemia based on an academic population-based registry study (AMLSG BiO). Annals of Hematology, 96(12), 1993–2003. doi:10.1007/s00277-017-3150-3
Schlenk, R.F., et al. (2014). Phase III study of all-trans retinoic acid in previously untreated patients 61 years or older with acute myeloid leukemia. Leukemia, 18, 1798-1803. doi:10.1038/sj.leu.2403528
Tabe, Y., et al. (2012). Effects of PPARgamma Ligands on Leukemia. PPAR Research, 2012, 483656. doi:10.1155/2012/483656
Author: Kristine Beckers (Trial Manager)
Last updated: October 2020