Assessing 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.

ISRCTN	ISRCTN16783472
DOI	https://doi.org/10.1186/ISRCTN16783472
EudraCT/CTIS number	2014-002563-16
Secondary identifying numbers	18136

Submission date: 18/03/2015
Registration date: 19/03/2015
Last edited: 17/08/2023

Recruitment status: No longer recruiting
Overall study status: Completed
Condition category: Cancer

Prospectively registered

Protocol

Statistical analysis plan

Results

Individual participant data

Plain English summary of protocol

http://www.cancerresearchuk.org/about-cancer/find-a-clinical-trial/a-trial-of-azacitidine-and-ruxolitinib-for-blood-disorders-called-myeloproliferative-neoplasms

Contact information

Mrs Sonia Fox
Scientific

University of Birmingham
Edgbaston
Birmingham
B15 2TT
United Kingdom

Study information

Study design	Non-randomised; Interventional; Design type: Treatment
Primary study design	Interventional
Secondary study design	Non randomised study
Study setting(s)	Other
Study type	Treatment
Participant information sheet	Not available in web format, please use contact details to request a patient information shee
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
Study acronym	PHAZAR
Study objectives	To establish the maximum tolerated dose (MTD) and safety of ruxolitinib in combination with 5-azacitidine
Ethics approval(s)	NRES Committee West Midlands - Edgbaston,19/01/2015, ref: 14/WM/1260
Health condition(s) or problem(s) studied	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
Pharmaceutical study type(s)
Phase	Phase I
Drug / device / biological / vaccine name(s)	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 study start date	05/01/2016
Completion date	18/08/2022

Eligibility

Participant type(s)	Patient
Age group	Adult
Lower age limit	18 Years
Sex	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.
Total final enrolment	58
Key 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
Key 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.
Date of first enrolment	05/01/2016
Date of final enrolment	30/04/2019

Locations

Countries of recruitment

England
Northern Ireland
Scotland
United Kingdom
Wales

Study participating centres

Beatson West of Scotland Cancer Centre

Glasgow
G12 0YN
United Kingdom

Belfast City Hospital

Belfast
BT9 7AB
United Kingdom

Christie Hospital

Manchester
M20 4BX
United Kingdom

Churchill Hospital

Oxford
OX3 7LE
United Kingdom

Hammersmith Hospital

London
W12 0HS
United Kingdom

Nottingham City Hospital

Nottingham
NG5 1PB
United Kingdom

Queen Elizabeth Hospital Birmingham

Birmingham
B15 2TH
United Kingdom

Southampton General Hospital

Southampton
SO16 6YD
United Kingdom

St James University Hospital

Leeds
LS9 7TF
United Kingdom

University Hospital of Wales

Cardiff
CF14 4XW
United Kingdom

Bart's and the London Hospital

London
EC1A 7BE
United Kingdom

Guy's Hospital

London
SE1 7EH
United Kingdom

The Clatterbridge Cancer Centre

Wirral
CH63 4JY
United Kingdom

Addenbrooke's Hospital

Cambridge
CB2 0QQ
United Kingdom

University College London Hospital

London
NW1 2BU
United Kingdom

Sponsor information

The University of Birmingham (UK)
University/education

Haematology Team
Cancer Research UK Clinical Trials Unit
School of Cancer Science
Edgbaston
Birmingham
B15 2TT
England
United Kingdom

"ROR"	https://ror.org/03angcq70

Funders

Funder type

Government

Bloodwise TAP

No information available

Results and Publications

Intention to publish date	15/08/2023
Individual participant data (IPD) Intention to share	Yes
IPD sharing plan summary	Available on request
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 plan	The datasets generated during the current study will be available upon request from the CRCTU’s Director’s Committee (CRCTU-General@adf.bham.ac.uk) within 6 months after the publication of the outcome measures unless the trial results are to be used as part of a regulatory submission where the release of the data may be delayed or be subject to the approval of a third party. Only scientifically sound proposals from appropriately qualified research groups will be considered for data and/or sample sharing. A data-sharing agreement will cover the terms and conditions of the release of trial data and will include publication requirements, authorship and acknowledgements and obligations for the responsible use of data. An anonymised encrypted dataset will be transferred directly using a secure method and in accordance with the University of Birmingham’s IT guidance on the encryption of datasets.

Study outputs

Output type	Details	Date created	Date added	Peer reviewed?	Patient-facing?
Protocol file	version 5.0	15/08/2018	18/08/2022	No	No
HRA research summary			26/07/2023	No	No
Basic results	version 1.0	17/08/2023	17/08/2023	No	No

Additional files

30472 Phazar Protocol v5.0a 15Aug2018.pdf
ISRCTN16783472_BasicResults_V1.0_17Aug23.pdf

Editorial Notes

17/08/2023: Basic results, total final enrolment and IPD sharing statement added.
15/03/2023: The overall end date was changed from 31/12/2021 to 18/08/2022.
07/12/2022: The intention to publish date was changed from 31/12/2022 to 15/08/2023.
18/08/2022: Uploaded protocol (not peer-reviewed) as an additional file.
11/04/2022: The intention to publish date has been changed from 31/03/2022 to 31/12/2022.
05/11/2021: The following changes have been made:
1. The overall trial end date has been changed from 31/10/2020 to 31/12/2021.
2. The intention to publish date has been changed from 31/10/2021 to 31/03/2022.
12/04/2019: IPD sharing statement added.
04/04/2019: The recruitment end date was changed from 31/03/2019 to 30/04/2019.
03/04/2019: The condition has been changed from "Topic: Cancer; Subtopic: All Cancers/Misc Sites; Disease: Leukaemia (acute myeloid), Myelodysplastic syndromes" to "Myeloproliferative neoplasms (MPN), including myelodysplastic syndromes (MDS) or acute myeloid leukaemia (AML) arising from MPN" following a request from the NIHR.
15/01/2019: The following changes have been made to the trial record:
1. The recruitment end date has been changed from 31/12/2018 to 31/03/2019.
2. The overall trial end date has been changed from 31/07/2020 to 31/10/2020.
3. The intention to publish date has been changed from 31/07/2021 to 31/10/2021.
03/08/2018: The recruitment start date was changed from 15/08/2015 to 05/01/2016
01/08/2018: The following changes have been made to the trial record:
1. The recruitment end date has been changed from 04/06/2018 to 31/12/2018
2. The trial start date has been changed from 01/06/2015 to 05/01/2016
3. The trial end date has been changed from 04/06/2018 to 31/07/2020
4. The intention to publish date was added.
5. The participant inclusion criteria were updated
6. The participant exclusion criteria were updated
7. Royal Liverpool University Hospital was removed as a trial participating centre.
8. The Clatterbridge Cancer Centre, Addenbrooke's Hospital and University College London Hospital were added as trial participating centres
9. The funder name was changed from Leukaemia and Lymphoma Research to Bloodwise TAP
22/04/2016: Plain English summary link added.