Condition category
Cancer
Date applied
18/03/2015
Date assigned
19/03/2015
Last edited
22/04/2016
Prospective/Retrospective
Prospectively registered
Overall trial status
Ongoing
Recruitment status
Recruiting

Contact information

Type

Scientific

Primary contact

Mrs Sonia Fox

ORCID ID

Contact details

University of Birmingham
Edgbaston
Birmingham
B15 2TT
United Kingdom

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

Topic: Cancer; Subtopic: All Cancers/Misc Sites; Disease: Leukaemia (acute myeloid), Myelodysplastic syndromes

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

Phase

Drug names

Primary outcome measures

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

01/06/2015

Overall trial end date

04/06/2018

Reason abandoned

Eligibility

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

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

15/08/2015

Recruitment end date

04/06/2018

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

Trial participating centre

Queen Elizabeth Hospital Birmingham
Birmingham
B15 2TH
United Kingdom

Trial participating centre

Royal Liverpool University Hospital
Liverpool
L7 8XP
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

Sponsor information

Organisation

The University of Birmingham (UK)

Sponsor details

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

Sponsor type

University/education

Website

Funders

Funder type

Government

Funder name

Leukaemia and Lymphoma Research

Alternative name(s)

Funding Body Type

private sector organisation

Funding Body Subtype

other non-profit

Location

United Kingdom

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.

Intention to publish date

Participant level data

Not provided at time of registration

Results - basic reporting

Publication summary

Publication citations

Additional files

Editorial Notes

22/04/2016: Plain English summary link added.