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Trial registered on ANZCTR


Registration number
ACTRN12610000924055
Ethics application status
Approved
Date submitted
12/05/2010
Date registered
29/10/2010
Date last updated
1/11/2017
Type of registration
Retrospectively registered

Titles & IDs
Public title
Panobinostat with 5-azacytidine in patients with untreated high risk Myelodysplastic Syndrome (MDS) or Acute Myeloid Leukaemia (AML).
Scientific title
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.
Secondary ID [1] 251738 0
CLBH589B2401 (Panobinostat)
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Previously untreated high risk Myelodysplastic syndrome (MDS) 257346 0
Previously untreated Acute Myeloid Leukaemia (AML) 257865 0
Condition category
Condition code
Cancer 257491 257491 0 0
Leukaemia - Acute leukaemia
Blood 258678 258678 0 0
Haematological diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
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.
Intervention code [1] 256458 0
Treatment: Drugs
Comparator / control treatment
Uncontrolled
Control group
Uncontrolled

Outcomes
Primary outcome [1] 258409 0
To examine the safety and tolerability of panobinostat in combination with 5-azacytidine administered in newly diagnosed acute myeolid leukaemia (AML) patients unsuitable for or unwilling to undergo standard AML-type induction therapy. This will be assessed by adverse event data and dose limiting toxicity of panobinostat combined with 5-azacytidine.
Timepoint [1] 258409 0
Patients are to complete 1 cycle of treatment to be evaluable for maximum tolerated dose and dose limiting toxicity. Patients will be assessed following each cycle of treatment.
Secondary outcome [1] 264161 0
To provide preliminary data that panobinostat may improve outcomes in patients receiving 5-azacytidine. Assessed by bone marrow biopsy and aspirate and blood tests to determine response rates, progression-free survival and cytogenetic response rates and overall survival.
Timepoint [1] 264161 0
Patients will be assessed at the completion of each cycle of treatment.
Secondary outcome [2] 264162 0
To evaluate the role of panobinostat maintenance therapy in patients that have achieved complete remission following induction with panobinostat and 5-azacytidine combination therapy. Assessed by response rates progression-free survival and cytogenetic response rates and overall survival. Tolerability of panobinostat maintenance therapy will also be assessed.
Timepoint [2] 264162 0
Patients will be assessed at the completion of each cycle of treatment.
Secondary outcome [3] 264163 0
To determine the correlation between clinical responses and biomarkers of demethylation and acetylation in leukaemic cells.
Timepoint [3] 264163 0
Patients will be assessed at the completion of each cycle of treatment.
Secondary outcome [4] 266138 0
To assess Quality of Life outcomes for patients receiving the panobinostat/5-azacytidine combination. Patients will complete the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire.
Timepoint [4] 266138 0
Patients will be assessed at the completion of each cycle of treatment.

Eligibility
Key inclusion criteria
1. Age greater than 55 years and/or unsuitable for standard AML-type induction therapy
2. Provision of written informed consent
3. 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)
4. No previous chemotherapy other than hydroxyurea or thioguanaine which was ceased greater than 48 hours preceding commencement of study medication
5. Life expectancy of greater than 3 months in relation to diseases other then AML/MDS
6. Eastern Cooperative Oncology Group (ECOG) performance status 0 – 2
7. Electrolyte levels (potassium, calcium (albumin-adjusted), magnesium, phosphorous) within normal limits (WNL) or easily correctable with supplements
8. 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
9. Adequate renal function, with serum creatinine = 1.5 times the upper limit of normal
10. Patients with no uncontrolled active infection
11. 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.
Minimum age
55 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. 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
2. History of major non-compliance to medication
3. Evidence of central nervous system (CNS) leukemia
4. 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
5. Uncontrolled viral infection with known Human Immunodeficiency virus (HIV) or Hepatitis type B or C
6. 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
7. 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
8. Female patients who are pregnant or breastfeeding and the lack of adequate contraception in females of childbearing potential, or their partners
9. Patients taking any concurrent medications which have a known risk of prolonging the QTc interval or inducing Torsades de Pointes tachycardia

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Each patient in the study will be uniquely identified by a 9 digit patient number that is a combination of a 4-digit centre number and 5-digit subject number. Upon signing the informed consent form the patient will be assigned a patient number by the investigator. Once assigned to a patient, a patient number will not be reused. If the patient fails to commence treatment, for any reason, the reason for not being treated will be entered into the Screening Log and the patient demographics will be recorded on the relevant case record form. This numbering convention will remain the same throughout the study.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Phase 1 / Phase 2
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
18/12/2009
Actual
11/01/2010
Date of last participant enrolment
Anticipated
Actual
12/12/2011
Date of last data collection
Anticipated
1/11/2017
Actual
25/09/2017
Sample size
Target
40
Accrual to date
Final
40
Recruitment in Australia
Recruitment state(s)
VIC

Funding & Sponsors
Funding source category [1] 256950 0
Hospital
Name [1] 256950 0
The Alfred Hospital
Country [1] 256950 0
Australia
Primary sponsor type
Hospital
Name
The Alfred Hospital
Address
Malignant Haematology and Stem Cell Transplantation Service, Ground Floor, South Block, The Alfred Hospital, Commercial Rd, Melbourne, VIC. 3004
Country
Australia
Secondary sponsor category [1] 256212 0
None
Name [1] 256212 0
None
Address [1] 256212 0
None
Country [1] 256212 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 258952 0
The Alfred Hospital Ethics Committee
Ethics committee address [1] 258952 0
Ethics committee country [1] 258952 0
Australia
Date submitted for ethics approval [1] 258952 0
Approval date [1] 258952 0
15/07/2009
Ethics approval number [1] 258952 0
AH189/09

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 31150 0
Prof Andrew Spencer
Address 31150 0
The Alfred Hospital, Malignant Haematology and Stem Cell Transplantation Service, South Block, Commercial Rd, Melbourne VIC 3004
Country 31150 0
Australia
Phone 31150 0
+61390763393
Fax 31150 0
+61390765531
Email 31150 0
aspencer@netspace.net.au
Contact person for public queries
Name 14397 0
Professor Andrew Spencer
Address 14397 0
Malignant Haematology and Stem Cell Transplantation Service, The Alfred Hospital, Commercial Rd, Melbourne, Victoria. 3004
Country 14397 0
Australia
Phone 14397 0
+61 3 9076 3393
Fax 14397 0
+61 3 9076 5531
Email 14397 0
aspencer@netspace.net.au
Contact person for scientific queries
Name 5325 0
Professor Andrew Spencer
Address 5325 0
Malignant Haematology and Stem Cell Transplantation Service, The Alfred Hospital, Commercial Rd, Melbourne, Victoria. 3004
Country 5325 0
Australia
Phone 5325 0
+61 3 9076 3393
Fax 5325 0
+61 3 9076 5531
Email 5325 0
aspencer@netspace.net.au

No information has been provided regarding IPD availability


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
SourceTitleYear of PublicationDOI
Dimensions AIReducing TNF Receptor 2+ Regulatory T Cells via the Combined Action of Azacitidine and the HDAC Inhibitor, Panobinostat for Clinical Benefit in Acute Myeloid Leukemia Patients2014https://doi.org/10.1158/1078-0432.ccr-13-1576
EmbaseEpigenetic regulation of miRNA-124 and multiple downstream targets is associated with treatment response in myeloid malignancies.2016https://dx.doi.org/10.3892/ol.2016.4912
Dimensions AIBeyond the Edge of Hypomethylating Agents: Novel Combination Strategies for Older Adults with Advanced MDS and AML2018https://doi.org/10.3390/cancers10060158
EmbaseEpigenetic treatment-mediated modulation of PD-L1 predicts potential therapy resistance over response markers in myeloid malignancies: A molecular mechanism involving effectors of PD-L1 reverse signaling.2019https://dx.doi.org/10.3892/ol.2018.9841
N.B. These documents automatically identified may not have been verified by the study sponsor.