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

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

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

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.

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.

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

At baseline and annually throughout the trial (from baseline until approximately 3 years post-randomisation)

Defined as the mean time between venesections while on trial treatment (treatment duration of 3 years)

Progression of marrow fibrosis (bone marrow collected and analysed at the Weatherall Institute of Molecular Medicine (WIMM) in Oxford

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: Patient ≥18 years of age Diagnosis of PV meeting the WHO criteria within the past 10 years Meets criteria of high risk* PV (see above for specific population) Patients may have received antiplatelet agents and venesection Patients may have received ONE cytoreductive therapy for PV less than 5 years (BUT they should not be resistant or intolerant to that therapy) Able to provide written informed consent Exclusion Criteria: Diagnosis of PV > 10 years previously Absence of any JAK-2 mutation Patients with any contraindications to any of the investigational medical products Treatment with >1 cytoreductive therapy OR a cytoreductive treatment duration exceeding 5 years OR resistance/intolerance to that therapy Active infection including hepatitis B, hepatitis C, Tuberculosis Pregnant or lactating patients (Women of childbearing potential must have a negative urine or blood Human Chorionic Gonadotropin pregnancy test prior to trial entry) 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 ECOG Performance Status Score ≥ 3 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 Patients who have transformed to myelofibrosis Previous treatment with ruxolitinib 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 Inadequate liver function as defined by ALT/AST > 2.0 x ULN Inadequate renal function as defined by eGFR < 30 ml/min Unable to give informed consent