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

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.

Study Overview

• Status: Recruiting
• Conditions: Polycythemia Vera
• Intervention / Treatment: Drug: Ruxolitinib; Drug: Hydroxycarbamide; Drug: Interferon-Alpha

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.

• Study Type: Interventional
• Enrollment (Anticipated): 586
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Alex Hainsworth; Phone Number: +44(0)121 414 2535; Email: mithridate@trials.bham.ac.uk

Study Locations

• United Kingdom
  • Aberdeen, United Kingdom, AB25 2ZN
    • Recruiting
    • Aberdeen Royal Infirmary
  • Birmingham, United Kingdom, B9 5SS
    • Recruiting
    • Birmingham Heartlands Hospital
  • Blackpool, United Kingdom, FY3 8NR
    • Recruiting
    • Blackpool Victoria Hospital
  • Bournemouth, United Kingdom, BH7 7DW
    • Recruiting
    • Royal Bournemouth Hospital
  • Cambridge, United Kingdom, CB2 0QQ
    • Recruiting
    • Addenbrooke's Hospital
  • Canterbury, United Kingdom, CT1 3NG
    • Active, not recruiting
    • Kent and Canterbury Hospital
  • Cardiff, United Kingdom, CF14 4XW
    • Recruiting
    • University Hospital of Wales
  • Chichester, United Kingdom, PO19 6SE
    • Recruiting
    • St Richard's Hospital
  • Colchester, United Kingdom, CO4 5JL
    • Recruiting
    • Colchester Hospital
  • Cottingham, United Kingdom, HU16 5JQ
    • Recruiting
    • Castle Hill Hospital
  • Edinburgh, United Kingdom, EH4 2XU
    • Recruiting
    • Western General Hospital
  • Exeter, United Kingdom, EX2 5DW
    • Recruiting
    • Royal Devon and Exeter Hospital
  • Gloucester, United Kingdom, GL1 3NN
    • Recruiting
    • Gloucestershire Royal Hospital
  • Halifax, United Kingdom, HX3 0PW
    • Active, not recruiting
    • Calderdale Royal Hospital
  • Huddersfield, United Kingdom, HD3 3EA
    • Active, not recruiting
    • Huddersfield Royal Infirmary
  • Inverness, United Kingdom, IV2 3UJ
    • Recruiting
    • Raigmore Hospital
  • Leicester, United Kingdom, LE1 5WW
    • Recruiting
    • Leicester Royal Infirmary
  • Livingston, United Kingdom, EH54 6PP
    • Recruiting
    • St John's Hospital
  • London, United Kingdom, NW1 2BU
    • Active, not recruiting
    • University College Hospital
  • London, United Kingdom, SE1 9RT
    • Recruiting
    • Guy's Hospital
  • London, United Kingdom, SW17 0QT
    • Recruiting
    • St George's Hospital
  • Newcastle Upon Tyne, United Kingdom, NE7 7DN
    • Recruiting
    • Freeman Hospital
  • Newport, United Kingdom, NP20 2UB
    • Recruiting
    • Royal Gwent Hospital
  • Northampton, United Kingdom, NN1 5BD
    • Recruiting
    • Northampton General Hospital
  • Nottingham, United Kingdom, NG5 1PB
    • Recruiting
    • Nottingham City Hospital
  • Oxford, United Kingdom, OX3 7LE
    • Recruiting
    • Churchill Hospital
  • Reading, United Kingdom, RG1 5AN
    • Recruiting
    • Royal Berkshire Hospital
  • Southampton, United Kingdom, SO16 6YD
    • Recruiting
    • Southampton General Hospital
  • Stoke-on-Trent, United Kingdom, ST4 6QG
    • Recruiting
    • Royal Stoke University Hospital
  • Sunderland, United Kingdom, SR4 7TP
    • Recruiting
    • Sunderland Royal Hospital
  • Sutton Coldfield, United Kingdom, B75 7RR
    • Recruiting
    • Good Hope Hospital
  • Truro, United Kingdom, TR1 3LJ
    • Recruiting
    • Royal Cornwall Hospital
  • Warwick, United Kingdom, CV34 5BW
    • Recruiting
    • Warwick Hospital
  • Wirral, United Kingdom, CH49 5PE
    • Recruiting
    • Arrowe Park Hospital
  • Worthing, United Kingdom, BN11 2DH
    • Recruiting
    • Worthing Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: A- Ruxolitinib; Treatment with Ruxolitinib	Drug: Ruxolitinib; 10mg of ruxolitinib twice daily (bd); Other Names: Jakavi®
Active Comparator: B- Hydroxycarbamide OR Interferon A; Best Available Therapy (BAT), Treatment with hydroxycarbamide OR Interferon A	Drug: Hydroxycarbamide; Via standard hospital mechanisms; Other Names: Hydroxyurea; Drug: Interferon-Alpha; Any formulation, via standard hospital mechanisms; Other Names: Interferon, alpha interferon, Intron® A, Roferon® A

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Major thrombosis	As defined in the protocol, combined and split to venous and arterial	Occurring while on treatment (over 3 years)
Major haemorrhage	As defined in the protocol	Occurring while on treatment (over 3 years)
Transformation to PPV-MF	Transformation to PPV-MF	Occurring while on treatment (over 3 years)
Transformation to MDS and/or AML	Transformation to MDS and/or AML	Occurring while on treatment (over 3 years)
Complete Haematological remission (CHR)	As defined by ELN response criteria at 1 year	1 year post-treatment
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
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
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
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)
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)
Rates of discontinuation	Trial discontinuation	From treatment prior to protocol defined 3 years
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))
Spleen response	in patients with splenomegaly	Response at 1 year post randomisation
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 malignancy	Malignancy independent to the original diagnosis	Occurring throughout the trial (from randomisation until approximately 3 years post-randomisation)
Change in QRisk score	Change in QRisk score	Collected at baseline and years 1, 2 and 3

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
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)
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)
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)
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)
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)
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)
Cardiac event	(angina, acute coronary syndrome, acute MI; arrhythmia)	Occurring throughout the trial (from randomisation to approximately 3 years post-randomisation)
Pulmonary hypertension	Pulmonary hypertension as assessed clinically	Occurring throughout the trial (from randomisation to approximately 3 years post-randomisation)
Coronary intervention	e.g. angiogram, angioplasty, CABG	Occurring throughout the trial (from randomisation to approximately 3 years post-randomisation)
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)
Cerebrovascular event	TIA, haemorrhagic CVA, non-haemorrhagic CVA	Occurring throughout the trial (from randomisation to approximately 3 years post-randomisation)
Arterial vascular event	peripheral vascular disease: claudication, carotid stenosis	Occurring throughout the trial (from randomisation to approximately 3 years post-randomisation)
Venous thrombosis	including DVT, PE, Cerebral, splanchnic, other	Occurring throughout the trial (from randomisation to approximately 3 years post-randomisation)
Pregnancy loss	Pregnancy loss	Occurring throughout the trial (from randomisation to approximately 3 years post-randomisation)
Thrombosis biomarkers	Correlation of thrombosis biomarkers with clinical thrombosis events	Occurring throughout the trial (from randomisation to approximately 3 years post-randomisation)

Collaborators and Investigators

• Sponsor: University of Birmingham
• Collaborators: Novartis; National Cancer Institute, France; MPN Voice
• Investigators: Principal Investigator: Claire Harrison, Acting on behalf of the Sponsor (UK), Guy's Hospital, London, UK, SE1 9RT; Principal Investigator: Jean-Jacques Kiladjian, (France) Clinical Investigations Center, Saint-Louis Hospital, Paris, France

Study record dates

Study Major Dates

• Study Start (Actual): October 25, 2019
• Primary Completion (Anticipated): August 1, 2026
• Study Completion (Anticipated): February 1, 2028

Study Registration Dates

• First Submitted: September 9, 2019
• First Submitted That Met QC Criteria: October 3, 2019
• First Posted (Actual): October 4, 2019

Study Record Updates

• Last Update Posted (Estimate): December 9, 2022
• Last Update Submitted That Met QC Criteria: December 7, 2022
• Last Verified: December 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms; Neoplasms by Site; Bone Marrow Diseases; Hematologic Diseases; Myeloproliferative Disorders; Bone Marrow Neoplasms; Hematologic Neoplasms; Polycythemia Vera; Polycythemia; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Antineoplastic Agents; Immunologic Factors; Antisickling Agents; Interferons; Interferon-alpha; Interferon alpha-2; Hydroxyurea
• Other Study ID Numbers: RG_16-148

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No