Panobinostat with 5-azacytidine in patients with untreated high risk Myelodysplastic Syndrome (MDS) or Acute Myeloid Leukaemia (AML).
A Phase Ib/II clinical evaluation of the safety and efficacy of combining panobinostat with 5-azacytidine in patients with high-risk Myelodysplastic Syndrome (MDS) or Acute Myeloid Leukaemia (AML) that are unsuitable for standard induction chemotherapy.
The Alfred Hospital
40 participants
Jan 11, 2010
Interventional
Conditions
Summary
This study looks at the effectiveness of the drug panobinostat in combination with 5-azacytidine in treating people who have recently been diagnosed with myelodysplastic syndrome (MDS) or acute myeloid leukaemia (AML). Who is it for? You can join this study if you are aged 55 or greater and have recently been diagnosed with high risk myelodysplastic syndrome or acute myeloid leukaemia, and you are unsuitable for or unwilling to undergo standard therapy. Trial details Participants will receive treatment with the anti-cancer drugs panobinostat (taken orally) and 5-azazytidine (administered via injection) over six 28 day cycles, On completion of this initial treatment, all patients not experiencing disease progression will receive further combination therapy with panobinostat and 5-azazytidine based on their degree of disease response. This will be followed by maintenance therapy with panobinostat alone. The study aims to determine the safety, tolerability and efficacy of treatment.
Eligibility
Inclusion Criteria11
- Age greater than 55 years and/or unsuitable for standard AML-type induction therapy
- Provision of written informed consent
- Patients with de novo (except Acute Promyelocytic Leukaemia) or secondary AML (including therapy-related) as defined by the World Health Organisation Classification (WHO) or poor risk myelodysplasia (International Prognostic Scoring System for MDS score Int-2 or High)
- No previous chemotherapy other than hydroxyurea or thioguanaine which was ceased greater than 48 hours preceding commencement of study medication
- Life expectancy of greater than 3 months in relation to diseases other then AML/MDS
- Eastern Cooperative Oncology Group (ECOG) performance status 0 – 2
- Electrolyte levels (potassium, calcium (albumin-adjusted), magnesium, phosphorous) within normal limits (WNL) or easily correctable with supplements
- Adequate hepatic function as defined by bilirubin = 2 times the upper limit of normal and aspartate aminotransferase (AST) and alanine aminotransferase (ALT) = 3 times the upper limit of normal
- Adequate renal function, with serum creatinine = 1.5 times the upper limit of normal
- Patients with no uncontrolled active infection
- Female patients who are amenorrhoeic for one year or have a negative pregnancy test within one day before commencing the trial. All patients of reproductive potential, and their partners, must agree to use at least two effective contraceptive methods throughout the study and for 30 days following the date of the last dose.
Exclusion Criteria16
- Any serious medical or psychiatric conditions which the investigator feels may interfere with the patient’s ability to give informed consent or participate in the procedures or evaluations of the study
- History of major non-compliance to medication
- Evidence of central nervous system (CNS) leukemia
- Impaired cardiac function or clinically significant cardiac disease as follows:
- Left ventricular ejection fraction (LVEF) <45% as determined by Multi Gated Acquisition scan (MUGA) scan or echocardiogram
- Complete left bundle branch block or right bundle branch block and left anterior hemiblock (bifascicular block)
- Obligate use of a cardiac pacemaker
- Congenital long QT syndrome or QTc > 480 msec on the screening ECG
- Clinically significant resting bradycardia (< 50 bpm)
- Angina pectoris or acute myocardial infarction 3 months prior to starting study drug
- Unstable angina, congestive cardiac failure (CCF) or acute myocardial infarction (AMI) within the last 6 months
- Uncontrolled viral infection with known Human Immunodeficiency virus (HIV) or Hepatitis type B or C
- Currently active gastrointestinal disease (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhoea, malabsorption syndrome, or small bowel resection), or other disease, that prevents the patient from absorbing or taking oral medication
- Any other concurrent severe and/or uncontrolled medical conditions (eg. acute or chronic liver disease, infection, pulmonary disease) that in the opinion of the investigator could potentiate unacceptable safety risks or jeopardise compliance with the protocol
- Female patients who are pregnant or breastfeeding and the lack of adequate contraception in females of childbearing potential, or their partners
- Patients taking any concurrent medications which have a known risk of prolonging the QTc interval or inducing Torsades de Pointes tachycardia
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Interventions
Patients will receive induction therapy with 6 cycles of 5-azacytidine in combination with panobinostat. All patients will receive azacitidine at a dose of 75mg/m2 administered subcutaneously. Azacitidine will be given days 1-5 of each 28 day cycle. Panobinostat will commence at a dose of 10mg for Cohort 1 and will increase by 10mg for each subsequent Cohort. Panobinostat will be given orally on Days 5, 8, 10, 12, 15, 17 and 19 of each 28 days cycle. All patients not experiencing disease progression and completing 6 cycles of induction therapy with evidence of disease response (HI: haematological improvement; PR: partial remission; or, CR: complete remission) and without unacceptable toxicity will continue treatment with 5-azacytidine and panobinostat for a further period dependent on their level of response to induction therapy. Patients achieving a CR during induction will receive a further 3 cycles of combination therapy with 5-azacytidine and panobinostat (CR + 3 cycles) before continuing on panobinostat maintenance therapy. Patients achieving HI or PR with induction will continue on combination therapy with 5-azacytidine and panobinostat as long as they exhibit no evidence of disease progression. If with further therapy they subsequently achieve a CR they will receive a further 3 cycles of combination therapy with 5-azacytidine and panobinostat (CR + 3 cycles) before continuing on panobinostat maintenance therapy. All patients may remain on therapy until they experience unacceptable toxicity that precludes further treatment, disease progression, and/or at the discretion of the investigator.
Locations(1)
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ACTRN12610000924055