Additional identifiers
EudraCT number
2014-002563-16
ClinicalTrials.gov number
Protocol/serial number
18136
Study information
Scientific title
A phase Ib study to assess the safety and tolerability of oral Ruxolitinib in combination with 5-azacitidine in patients with advanced phase myeloproliferative neoplasms (MPN), including myelodysplastic syndromes (MDS) or acute myeloid leukaemia (AML) arising from MPN.
Acronym
PHAZAR
Study hypothesis
To establish the maximum tolerated dose (MTD) and safety of ruxolitinib in combination with 5-azacitidine
Ethics approval
NRES Committee West Midlands - Edgbaston,19/01/2015, ref: 14/WM/1260
Study design
Non-randomised; Interventional; Design type: Treatment
Primary study design
Interventional
Secondary study design
Non randomised study
Trial setting
Other
Trial type
Treatment
Patient information sheet
Not available in web format, please use contact details to request a patient information shee
Condition
Myeloproliferative neoplasms (MPN), including myelodysplastic syndromes (MDS) or acute myeloid leukaemia (AML) arising from MPN
Intervention
All patients registered to the interventional component will receive treatment with a minimum of 6 cycles (each cycle 28 days) of 5-azacitidine in combination with one of 5 doses of ruxolitinib (5mg bd, 10mg bd, 15mg bd, 20mg bd, 25mg bd). 5-azacitidine will be administered on days 1-5 and 8-9 of each cycle via subcutaneous injection at a dose of 75mg/m2. Ruxolitinib will be taken orally, twice daily. If patients are achieving a clinical benefit at the end of 6 cycles, they can continue treatment for as long as they are benefitting at the discretion of the Chief Investigator. Patients will be followed up for a minimum of 1 year following registration.
The observational component will receive standard care and the trial will collect information on their outcome.
Intervention type
Drug
Phase
Phase I
Drug names
Ruxolitinib
5-azacitidine
Primary outcome measure
To determine the MTD of ruxolitinib in combination with 5-azacitidine; Timepoint(s): Within 1 cycle of treatment
Secondary outcome measures
1. Best response following 3 and 6 cycles of treatment Assessment will be made according to the following criteria: Proposed criteria for response assessment in patients treated in clinical trials for MPNs in blast phase (MPN-BP): Formal recommendations from the post-MPN acute myeloid leukaemia consortium (for patients with >20% blasts at baseline)
2. International Working Group (IWG) response criteria in myelodysplasia (for patients with <20% blasts at baseline)
3. Change in the proportion of patients who require transfusion of red cells or platelets
4. Achievement of red blood cell (RBC) transfusion independence
5. Achievement of platelet transfusion independence
6. Change in palpable splenomegaly or hepatomegaly
7. Duration of Complete Response (CR) or Partial Response (PR)
8. 12 months Progression-free survival (PFS)
9. 12 months Leukaemia-free survival (LFS)
10. 12 months Overall survival (OS)
11. Duration of treatment
12. Clinical improvement in haemoglobin level
13. Clinical improvement in platelet count
14. Quality of life as measured by the MPN SAF; EQ-5D-5L and EORTC QLQ-C30 (Cycles 1, 2, 4 and 6 for interventional patients; at registration, 3 months and 6 months for observational patients)
15. To determine treatment and outcome of Advanced Phase MPN (MPN-AP) and Blast Phase MPN (MPN-BP) patients who enter the observation component.
16. Change in clonal marker (e.g. JAK2 or CALR allele burden) (to be centrally assessed)
Overall trial start date
05/01/2016
Overall trial end date
31/10/2020
Reason abandoned (if study stopped)
Eligibility
Participant inclusion criteria
Current participant inclusion criteria as of 01/08/2018:
For the Interventional component:
1. Age ≥ 16 years old
2. A prior diagnosis of Essential Thrombocythaemia (ET), Polycythaemia Vera (PV) or Myelofibrosis (MF) with one of the following:
2.1. ≥ 10% blasts in blood or bone marrow with or without dysplastic changes (MPN-AP) at baseline
2.2. ≥ 20% blasts in blood or bone marrow (MPN-BP) at baseline
3. In need of treatment in the opinion of the investigator
4. Eastern Cooperative Oncology Group (ECOG) performance status 0-3
5. Adequate liver and renal function, defined as:
5.1. Liver transaminases ≥ 3 × ULN (AST/SGOT and ALT/SGPT)
5.2. Bilirubin <4 x ULN (Patients with elevated bilirubin due to Gilbert’s syndrome are eligible)
5.3. GFR ≥ 40 ml/min
6. Willingness to undergo and ability to tolerate assessments during the study including bone marrow assessments and symptom assessments using patient reported outcome instruments
7. Able to give valid informed consent
For the Observational Component
1. Age ≥ 16 years old
2. A prior diagnosis of ET, PV or MF with one of the following:
2.1. Blasts in blood or marrow 10-19%
with or without dysplastic changes (MPN-AP)
2.2 ≥ 20% Blasts (MPN-BP)
2.3. Patients who are unwilling/unable to enter the interventional component and/or fail the interventional component entry criteria. This can include patients entered into studies with more aggressive therapy such as AML 17/19 as well as those receiving palliation only
Previous participant inclusion criteria:
For the Interventional component:
1. Age ≥ 16 years old
2. A prior diagnosis of Essential Thrombocythaemia (ET), Polycythaemia Vera (PV) or Myelofibrosis (MF) with one of the following:
2.1. Blasts in blood or marrow 10-19%
with or without dysplastic changes (MPN-AP)
2.2. ≥ 20% Blasts (MPN-BP)
3. In need of treatment in the opinion of the investigator
4. Eastern Cooperative Oncology Group (ECOG) performance status 0-3
5. Platelet or red blood cell transfusion-dependent
6. Adequate liver and renal function, defined as:
6.1. Liver transaminases ≥ 3 × ULN (AST/SGOT and ALT/SGPT)
6.2. Bilirubin <4 x ULN (Patients with elevated bilirubin due to Gilbert’s syndrome are eligible)
6.3. GFR ≥ 40 ml/min
7. Willingness to undergo and ability to tolerate assessments during the study including bone marrow assessments and symptom assessments using patient reported outcome instruments
8. Able to give valid informed consent
For the Observational Component
1. Age ≥ 16 years old
2. A prior diagnosis of ET, PV or MF with one of the following:
2.1. Blasts in blood or marrow 10-19%
with or without dysplastic changes (MPN-AP)
2.2 ≥ 20% Blasts (MPN-BP)
2.3. Patients who are unwilling/unable to enter the interventional component and/or fail the interventional component entry criteria. This can include patients entered into studies with more aggressive therapy such as AML 17/19 as well as those receiving palliation only
Participant type
Patient
Age group
Adult
Gender
Both
Target number of participants
Planned Sample Size: 64; UK Sample Size: 64; Description: As this is a phase I study dose-finding study using a 3+3 cohort design, no formal power calculation has been carried out. A maximum of 24 patients and a minimum of 3 patients will be recruited. Once the MTD has been determined, an additional 10 patients will be recruited to the trial and treated at the MTD to gain further information on the safety and activity of the combined treatment. Up to 30 additional patients will be recruited into an observational component.
Participant exclusion criteria
Current participant exclusion criteria as of 01/08/2018:
For the Interventional Component:
1. Any co-morbidity that could limit compliance with the trial or any other condition (including laboratory abnormalities) that in the Investigators opinion will affect the patient’s participation in this trial
2.New York Heart Association Class II, III, or IV congestive heart failure
3. On-going cardiac dysrhythmias of grade 3, QTc prolongation >480 ms, or other factors that increase the risk of QT interval prolongation (e.g. heart failure, hypokalemia defined as serum potassium <3.0 mEq/L, family history of long QT interval syndrome)
4. Erythropoietic agent within 28 days prior to registration
5. Thrombopoietic agent within 14 days prior to registration
6. CYP3A4 inhibitor within 7 days prior to registration
7. Experimental treatment for AML or MPN within 14 days prior to registration (except Ruxolitinib and Hydroxycarbamide which can be taken up until study entry at the prestudy dose. Hydroxycarbamide must be stopped before the first scheduled day of treatment)
8. Previously received 5-azacitidine
9. Known contraindications to receiving azacitidine or ruxolitinib
10. Known HIV seropositivity
11. Known to have active hepatitis A, B, or C
12. Women who are pregnant or lactating. Patients of childbearing potential must have a negative pregnancy test prior to study entry
13. Patients and partners of childbearing potential not willing to use effective contraception for the duration of the study treatment and for three months after the last dose.
14. Active infection ≥ grade 3 (CTCAE criteria) at trial entry
For the Observational Component:
No Exclusions planned.
Previous participant exclusion criteria:
For the Interventional Component:
1. Any co-morbidity that could limit compliance with the trial or any other condition (including laboratory abnormalities) that in the Investigators opinion will affect the patient’s participation in this trial
2.New York Heart Association Class II, III, or IV congestive heart failure
3. On-going cardiac dysrhythmias of grade 3, QTc prolongation >480 ms, or other factors that increase the risk of QT interval prolongation (e.g. heart failure, hypokalemia defined as serum potassium <3.0 mEq/L, family history of long QT interval syndrome)
4. Erythropoietic agent within 28 days prior to registration
5. Thrombopoietic agent within 14 days prior to registration
6. CYP3A4 inhibitor within 7 days prior to registration
7. Experimental treatment for AML or MPN within 14 days prior to registration (except Ruxolitinib and Hydroxycarbamide which can be taken up until study entry at the prestudy dose. Hydroxycarbamide must be stopped before the first scheduled day of treatment)
8. Previously received 5-azacitidine
9. Known contraindications to receiving azacitidine or ruxolitinib
10. Known HIV seropositivity
11. Known to have active hepatitis A, B, or C
12. Women who are pregnant or lactating. Patients of childbearing potential must have a negative pregnancy test prior to study entry
13. Patients and partners of childbearing potential not willing to use effective contraception for the duration of the study treatment and for three months after the last dose.
For the Observational Component:
No Exclusions planned.
Recruitment start date
05/01/2016
Recruitment end date
30/04/2019
Locations
Countries of recruitment
United Kingdom
Trial participating centre
Beatson West of Scotland Cancer Centre
Glasgow
G12 0YN
United Kingdom
Trial participating centre
Belfast City Hospital
Belfast
BT9 7AB
United Kingdom
Trial participating centre
Christie Hospital
Manchester
M20 4BX
United Kingdom
Trial participating centre
Churchill Hospital
Oxford
OX3 7LE
United Kingdom
Trial participating centre
Hammersmith Hospital
London
W12 0HS
United Kingdom
Trial participating centre
Nottingham City Hospital
Nottingham
NG5 1PB
United Kingdom
Trial participating centre
Queen Elizabeth Hospital Birmingham
Birmingham
B15 2TH
United Kingdom
Trial participating centre
Southampton General Hospital
Southampton
SO16 6YD
United Kingdom
Trial participating centre
St James University Hospital
Leeds
LS9 7TF
United Kingdom
Trial participating centre
University Hospital of Wales
Cardiff
CF14 4XW
United Kingdom
Trial participating centre
Bart's and the London Hospital
London
EC1A 7BE
United Kingdom
Trial participating centre
Guy's Hospital
London
SE1 7EH
United Kingdom
Trial participating centre
The Clatterbridge Cancer Centre
Wirral
CH63 4JY
United Kingdom
Trial participating centre
Addenbrooke's Hospital
Cambridge
CB2 0QQ
United Kingdom
Trial participating centre
University College London Hospital
London
NW1 2BU
United Kingdom
Funders
Funder type
Government
Funder name
Bloodwise TAP
Alternative name(s)
Funding Body Type
Funding Body Subtype
Location
Results and Publications
Publication and dissemination plan
The results of the trial will be presented at national/international meetings and published in a peer reviewed journal. The primary outcome will be published once all patients have completed one cycle of combination treatment.
IPD sharing statement
The data sharing plans for the current study are unknown and will be made available at a later date.
Intention to publish date
31/10/2021
Participant level data
To be made available at a later date
Basic results (scientific)
Publication list