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

Overview

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.

Full Title of Study: “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”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Parallel Assignment
    • Primary Purpose: Treatment
    • Masking: None (Open Label)
  • Study Primary Completion Date: August 1, 2026

Detailed 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.

Interventions

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

Arms, Groups and Cohorts

  • Experimental: A- Ruxolitinib
    • Treatment with Ruxolitinib
  • Active Comparator: B- Hydroxycarbamide OR Interferon A
    • Best Available Therapy (BAT), Treatment with hydroxycarbamide OR Interferon A

Clinical Trial Outcome Measures

Primary Measures

  • Event Free Survival (EFS)
    • Time Frame: 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
    • Event Free Survival

Secondary Measures

  • Major thrombosis
    • Time Frame: Occurring while on treatment (over 3 years)
    • As defined in the protocol, combined and split to venous and arterial
  • Major haemorrhage
    • Time Frame: Occurring while on treatment (over 3 years)
    • As defined in the protocol
  • Transformation to PPV-MF
    • Time Frame: Occurring while on treatment (over 3 years)
    • Transformation to PPV-MF
  • Transformation to MDS and/or AML
    • Time Frame: Occurring while on treatment (over 3 years)
    • Transformation to MDS and/or AML
  • Complete Haematological remission (CHR)
    • Time Frame: 1 year post-treatment
    • As defined by ELN response criteria at 1 year
  • Symptom burden/Quality of life (MPN-SAF)
    • Time Frame: Questionnaires collected at baseline, weeks 12, 26, 39, 55, months 15, 18, 24, 30 and 36
    • As measured via MPN-SAF
  • Symptom burden/Quality of life (MDASI)
    • Time Frame: Questionnaires collected at baseline, weeks 12, 26, 39, 55, months 15, 18, 24, 30 and 36
    • As measured via MDASI
  • Symptom burden/Quality of life (EQ-5D)
    • Time Frame: Questionnaires collected at baseline, weeks 12, 26, 39, 55, months 15, 18, 24, 30 and 36
    • As measured via EQ-5D
  • Health economics
    • Time Frame: At the end of the trial (trial duration of approximately 8 years)
    • Including cost utility and cost effectiveness analyses as defined by the protocol (e.g. QALYs)
  • Peripheral blood JAK2 V617F allele burden
    • Time Frame: At baseline and annually throughout the trial (from baseline until approximately 3 years post-randomisation)
    • According to ELN response criteria
  • Rates of discontinuation
    • Time Frame: From treatment prior to protocol defined 3 years
    • Trial discontinuation
  • Rate and severity of adverse events
    • Time Frame: Continuous throughout the trial (from randomisation until approximately 3 years post-randomisation))
    • collected according to CTCAE version 4.0 and the MITHRIDATE protocol
  • Spleen response
    • Time Frame: Response at 1 year post randomisation
    • in patients with splenomegaly
  • Time free from venesection
    • Time Frame: Defined as the mean time between venesections while on trial treatment (treatment duration of 3 years)
    • Time free from venesection
  • Secondary malignancy
    • Time Frame: Occurring throughout the trial (from randomisation until approximately 3 years post-randomisation)
    • Malignancy independent to the original diagnosis
  • Change in QRisk score
    • Time Frame: Collected at baseline and years 1, 2 and 3
    • Change in QRisk score

Participating in This Clinical Trial

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

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: N/A

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • University of Birmingham
  • Collaborator
    • Novartis
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • Claire Harrison, Principal Investigator, Acting on behalf of the Sponsor (UK), Guy’s Hospital, London, UK, SE1 9RT
    • Jean-Jacques Kiladjian, Principal Investigator, (France) Clinical Investigations Center, Saint-Louis Hospital, Paris, France
  • Overall Contact(s)
    • Alex Hainsworth, +44(0)121 414 2535, mithridate@trials.bham.ac.uk

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