MITHRIDATE: Ruxolitinib Versus Hydroxycarbamide or Interferon as First Line Therapy in High Risk Polycythemia Vera

Polycythemia Vera Clinical Trial

— MITHRIDATE  

Official title:

A Phase III, Randomised, Open-label, Multicenter International Trial Comparing Ruxolitinib With Either HydRoxycarbamIDe or Interferon Alpha as First Line ThErapy for High Risk Polycythemia Vera

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04116502
• Other study ID #: RG_16-148
• Status: Recruiting
• Phase: Phase 3
• Start date: October 25, 2019
• Est. completion date: February 1, 2028

Study information

• Verified date: December 2022
• Source: University of Birmingham
• Contact: Alex Hainsworth
• Phone: +44(0)121 414 2535
• Email: mithridate[@]trials.bham.ac.uk
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The trial will be a phase III, randomised-controlled, multi-centre, international, open-label trial consisting of ruxolitinib versus best available therapy, where best available therapy is a choice of interferon alpha, any formulation permitted (IFN) or hydroxycarbamide (HC), and which will be elected by the Investigator prior to randomisation.

Description:

The trial will be a phase III, randomised-controlled, multi-centre, international, open-label trial consisting of ruxolitinib versus best available therapy, where best available therapy is a choice of interferon alpha, any formulation permitted (IFN) or hydroxycarbamide (HC), and which will be elected by the Investigator prior to randomisation. There will be no cross-over either between arm A and B or between therapies on Arm B HC and IFN will be provided as best available therapy, IFN can include standard of pegylated-interferon at Investigators discretion.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 586
• Est. completion date: February 1, 2028
• Est. primary completion date: August 1, 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Population:

High risk PV defined as WBC >11 x 10^9/l* AND at least ONE of the following

• Age >60 years
• Prior thrombosis or haemorrhage
• Platelet count >1000 x 10^9/l* (*At any time since diagnosis)

Inclusion Criteria:

1. Patient =18 years of age

2. Diagnosis of PV meeting the WHO criteria within the past 10 years

3. Meets criteria of high risk* PV (see above for specific population)

4. Patients may have received antiplatelet agents and venesection

5. Patients may have received ONE cytoreductive therapy for PV less than 5 years (BUT they should not be resistant or intolerant to that therapy)

6. Able to provide written informed consent

Exclusion Criteria:

1. Diagnosis of PV > 10 years previously

2. Absence of any JAK-2 mutation

3. Patients with any contraindications to any of the investigational medical products

4. Treatment with >1 cytoreductive therapy OR a cytoreductive treatment duration exceeding 5 years OR resistance/intolerance to that therapy

5. Active infection including hepatitis B, hepatitis C, Tuberculosis

6. Pregnant or lactating patients (Women of childbearing potential must have a negative urine or blood Human Chorionic Gonadotropin pregnancy test prior to trial entry)

7. Patients and partners of childbearing potential not prepared to adopt highly effective contraception measures (if sexually active) whilst on treatment and for at least 6 months after completion of study medication

8. ECOG Performance Status Score = 3

9. Uncontrolled rapid or paroxysmal atrial fibrillation, uncontrolled or unstable angina, recent (6 months) myocardial infarction or acute coronary syndrome or any clinically significant cardiac disease > NYHA (New York Heart Association) Class II

10. Patients who have transformed to myelofibrosis

11. Previous treatment with ruxolitinib

12. Previous (within the last 12 months) or current platelet count <100 x 109/L or neutrophil count < 1 x 109/L not due to therapy

13. Inadequate liver function as defined by ALT/AST > 2.0 x ULN

14. Inadequate renal function as defined by eGFR < 30 ml/min

15. Unable to give informed consent

Related Conditions & MeSH terms

• Polycythemia
• Polycythemia Vera

Intervention

Drug:
• Ruxolitinib
10mg of ruxolitinib twice daily (bd)
• Hydroxycarbamide
Via standard hospital mechanisms
• Interferon-Alpha
Any formulation, via standard hospital mechanisms

Locations

Country	Name	City	State
United Kingdom	Aberdeen Royal Infirmary	Aberdeen
United Kingdom	Birmingham Heartlands Hospital	Birmingham
United Kingdom	Blackpool Victoria Hospital	Blackpool
United Kingdom	Royal Bournemouth Hospital	Bournemouth
United Kingdom	Addenbrooke's Hospital	Cambridge
United Kingdom	Kent and Canterbury Hospital	Canterbury
United Kingdom	University Hospital of Wales	Cardiff
United Kingdom	St Richard's Hospital	Chichester
United Kingdom	Colchester Hospital	Colchester
United Kingdom	Castle Hill Hospital	Cottingham
United Kingdom	Western General Hospital	Edinburgh
United Kingdom	Royal Devon and Exeter Hospital	Exeter
United Kingdom	Gloucestershire Royal Hospital	Gloucester
United Kingdom	Calderdale Royal Hospital	Halifax
United Kingdom	Huddersfield Royal Infirmary	Huddersfield
United Kingdom	Raigmore Hospital	Inverness
United Kingdom	Leicester Royal Infirmary	Leicester
United Kingdom	St John's Hospital	Livingston
United Kingdom	Guy's Hospital	London
United Kingdom	St George's Hospital	London
United Kingdom	University College Hospital	London
United Kingdom	Freeman Hospital	Newcastle Upon Tyne
United Kingdom	Royal Gwent Hospital	Newport
United Kingdom	Northampton General Hospital	Northampton
United Kingdom	Nottingham City Hospital	Nottingham
United Kingdom	Churchill Hospital	Oxford
United Kingdom	Royal Berkshire Hospital	Reading
United Kingdom	Southampton General Hospital	Southampton
United Kingdom	Royal Stoke University Hospital	Stoke-on-Trent
United Kingdom	Sunderland Royal Hospital	Sunderland
United Kingdom	Good Hope Hospital	Sutton Coldfield
United Kingdom	Royal Cornwall Hospital	Truro
United Kingdom	Warwick Hospital	Warwick
United Kingdom	Arrowe Park Hospital	Wirral
United Kingdom	Worthing Hospital	Worthing

Sponsors (4)

Lead Sponsor	Collaborator
University of Birmingham	MPN Voice, National Cancer Institute, France, Novartis

Country where clinical trial is conducted

United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Progression of marrow fibrosis	Progression of marrow fibrosis (bone marrow collected and analysed at the Weatherall Institute of Molecular Medicine (WIMM) in Oxford	Occurring throughout the trial (from randomisation to approximately 3 years post-randomisation)
Other	Impact of treatment on molecular signatures of disease	Impact of treatment on molecular signatures of disease (as analysed by the WIMM in Oxford)	Occurring throughout the trial (from randomisation to approximately 3 years post-randomisation)
Other	Clonal involvement	within the stem/progenitor cell compartment (as analysed by the WIMM in Oxford)	Occurring throughout the trial (from randomisation to approximately 3 years post-randomisation)
Other	Clonal evolution	(acquisition of additional mutations, as analysed by the WIMM in Oxford)	Occurring throughout the trial (from randomisation to approximately 3 years post-randomisation)
Other	Reduction of peripheral blood allele burden	of other disease-association mutations (as analysed by the WIMM in Oxford)	Occurring throughout the trial (from randomisation to approximately 3 years post-randomisation)
Other	Assessment of the prevalence of clonality markers for haematological disease	and any change over time (as analysed by the WIMM in Oxford)	Occurring throughout the trial (from randomisation to approximately 3 years post-randomisation)
Other	Cardiac event	(angina, acute coronary syndrome, acute MI; arrhythmia)	Occurring throughout the trial (from randomisation to approximately 3 years post-randomisation)
Other	Pulmonary hypertension	Pulmonary hypertension as assessed clinically	Occurring throughout the trial (from randomisation to approximately 3 years post-randomisation)
Other	Coronary intervention	e.g. angiogram, angioplasty, CABG	Occurring throughout the trial (from randomisation to approximately 3 years post-randomisation)
Other	Deterioration in cardiac function	e.g. LVEF% on ECHO/MUGA and/or NYHA classification	Occurring throughout the trial (from randomisation to approximately 3 years post-randomisation)
Other	Cerebrovascular event	TIA, haemorrhagic CVA, non-haemorrhagic CVA	Occurring throughout the trial (from randomisation to approximately 3 years post-randomisation)
Other	Arterial vascular event	peripheral vascular disease: claudication, carotid stenosis	Occurring throughout the trial (from randomisation to approximately 3 years post-randomisation)
Other	Venous thrombosis	including DVT, PE, Cerebral, splanchnic, other	Occurring throughout the trial (from randomisation to approximately 3 years post-randomisation)
Other	Pregnancy loss	Pregnancy loss	Occurring throughout the trial (from randomisation to approximately 3 years post-randomisation)
Other	Thrombosis biomarkers	Correlation of thrombosis biomarkers with clinical thrombosis events	Occurring throughout the trial (from randomisation to approximately 3 years post-randomisation)
Primary	Event Free Survival (EFS)	Event Free Survival	the time from randomisation to the date of the first major thrombosis/haemorrhage, death,transformation to Myelodysplastic Syndromes, Acute Myeloid Leukaemia or Post-polycythemia Vera Myelofibrosis, if within the ~3 year trial period
Secondary	Major thrombosis	As defined in the protocol, combined and split to venous and arterial	Occurring while on treatment (over 3 years)
Secondary	Major haemorrhage	As defined in the protocol	Occurring while on treatment (over 3 years)
Secondary	Transformation to PPV-MF	Transformation to PPV-MF	Occurring while on treatment (over 3 years)
Secondary	Transformation to MDS and/or AML	Transformation to MDS and/or AML	Occurring while on treatment (over 3 years)
Secondary	Complete Haematological remission (CHR)	As defined by ELN response criteria at 1 year	1 year post-treatment
Secondary	Symptom burden/Quality of life (MPN-SAF)	As measured via MPN-SAF	Questionnaires collected at baseline, weeks 12, 26, 39, 55, months 15, 18, 24, 30 and 36
Secondary	Symptom burden/Quality of life (MDASI)	As measured via MDASI	Questionnaires collected at baseline, weeks 12, 26, 39, 55, months 15, 18, 24, 30 and 36
Secondary	Symptom burden/Quality of life (EQ-5D)	As measured via EQ-5D	Questionnaires collected at baseline, weeks 12, 26, 39, 55, months 15, 18, 24, 30 and 36
Secondary	Health economics	Including cost utility and cost effectiveness analyses as defined by the protocol (e.g. QALYs)	At the end of the trial (trial duration of approximately 8 years)
Secondary	Peripheral blood JAK2 V617F allele burden	According to ELN response criteria	At baseline and annually throughout the trial (from baseline until approximately 3 years post-randomisation)
Secondary	Rates of discontinuation	Trial discontinuation	From treatment prior to protocol defined 3 years
Secondary	Rate and severity of adverse events	collected according to CTCAE version 4.0 and the MITHRIDATE protocol	Continuous throughout the trial (from randomisation until approximately 3 years post-randomisation))
Secondary	Spleen response	in patients with splenomegaly	Response at 1 year post randomisation
Secondary	Time free from venesection	Time free from venesection	Defined as the mean time between venesections while on trial treatment (treatment duration of 3 years)
Secondary	Secondary malignancy	Malignancy independent to the original diagnosis	Occurring throughout the trial (from randomisation until approximately 3 years post-randomisation)
Secondary	Change in QRisk score	Change in QRisk score	Collected at baseline and years 1, 2 and 3