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

Sponsor

University of Birmingham (Other)

Overall Status

Recruiting

CT.gov ID

NCT04116502

Collaborator

Novartis (Industry), MPN Voice (Other), National Cancer Institute, France (Other)

586

Enrollment

Locations

Arms

99.3

Anticipated Duration (Months)

293

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

Brief 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.

Condition or Disease	Intervention/Treatment	Phase
Polycythemia Vera	Drug: Ruxolitinib Drug: Hydroxycarbamide Drug: Interferon-Alpha	Phase 3

Detailed Description

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 Design

Study Type:

Interventional

Anticipated Enrollment :

586 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

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

Actual Study Start Date :

Oct 25, 2019

Anticipated Primary Completion Date :

Aug 1, 2026

Anticipated Study Completion Date :

Feb 1, 2028

Arms and Interventions

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

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

Outcome Measures

Primary Outcome Measures

Event Free Survival (EFS) [the time from randomisation to the date of the first major thrombosis/haemorrhage, death,transformation to Myelodisplastic Syndromes, Acute Myeloid Leukaemia or Post-polycythemia Vera Myelofibrosis, if within the ~3 year trial period]
Event Free Survival

Secondary Outcome Measures

Major thrombosis [Occuring while on treatment (over 3 years)]
As defined in the protocol, combined and split to venous and arterial
Major haemorrhage [Occuring while on treatment (over 3 years)]
As defined in the protocol
Transformation to PPV-MF [Occuring while on treatment (over 3 years)]
Transformation to PPV-MF
Transformation to MDS and/or AML [Occuring while on treatment (over 3 years)]
Transformation to MDS and/or AML
Complete Haematological remission (CHR) [1 year post-treatment]
As defined by ELN response criteria at 1 year
Symptom burden/Quality of life (MPN-SAF) [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) [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) [Questionnaires collected at baseline, weeks 12, 26, 39, 55, months 15, 18, 24, 30 and 36]
As measured via EQ-5D
Health economics [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 [At baseline and annually throughout the trial (from baseline until approximately 3 years post-randomisation)]
According to ELN response criteria
Rates of discontinuation [From treatment prior to protocol defined 3 years]
Trial discontinuation
Rate and severity of adverse events [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 [Response at 1 year post randomisation]
in patients with splenomegaly
Time free from venesection [Defined as the mean time between venesections while on trial treatment (treatment duration of 3 years)]
Time free from venesection
Secondary malignancy [Occuring throughout the trial (from randomisation until approximately 3 years post-randomisation)]
Malignancy independent to the original diagnosis
Change in QRisk score [Collected at baseline and years 1, 2 and 3]
Change in QRisk score

Other Outcome Measures

Progression of marrow fibrosis [Occuring throughout the trial (from randomisation to approximately 3 years post-randomisation)]
Progression of marrow fibrosis (bone marrow collected and analysed at the Weatherall Institute of Molecular Medicine (WIMM) in Oxford
Impact of treatment on molecular signatures of disease [Occuring throughout the trial (from randomisation to approximately 3 years post-randomisation)]
Impact of treatment on molecular signatures of disease (as analysed by the WIMM in Oxford)
Clonal involvement [Occuring throughout the trial (from randomisation to approximately 3 years post-randomisation)]
within the stem/progenitor cell compartment (as analysed by the WIMM in Oxford)
Clonal evolution [Occuring throughout the trial (from randomisation to approximately 3 years post-randomisation)]
(acquisition of additional mutations, as analysed by the WIMM in Oxford)
Reduction of peripheral blood allele burden [Occuring throughout the trial (from randomisation to approximately 3 years post-randomisation)]
of other disease-association mutations (as analysed by the WIMM in Oxford)
Assessment of the prevalence of clonality markers for haematological disease [Occuring throughout the trial (from randomisation to approximately 3 years post-randomisation)]
and any change over time (as analysed by the WIMM in Oxford)
Cardiac event [Occuring throughout the trial (from randomisation to approximately 3 years post-randomisation)]
(angina, acute coronary syndrome, acute MI; arrhythmia)
Pulmonary hypertension [Occuring throughout the trial (from randomisation to approximately 3 years post-randomisation)]
Pulmonary hypertension as assessed clinically
Coronary intervention [Occuring throughout the trial (from randomisation to approximately 3 years post-randomisation)]
e.g. angiogram, angioplasty, CABG
Deterioration in cardiac function [Occuring throughout the trial (from randomisation to approximately 3 years post-randomisation)]
e.g. LVEF% on ECHO/MUGA and/or NYHA classification
Cerebrovascular event [Occuring throughout the trial (from randomisation to approximately 3 years post-randomisation)]
TIA, haemorrhagic CVA, non-haemorrhagic CVA
Arterial vascular event [Occuring throughout the trial (from randomisation to approximately 3 years post-randomisation)]
peripheral vascular disease: claudication, carotid stenosis
Venous thrombosis [Occuring throughout the trial (from randomisation to approximately 3 years post-randomisation)]
including DVT, PE, Cerebral, splanchnic, other
Pregnancy loss [Occuring throughout the trial (from randomisation to approximately 3 years post-randomisation)]
Pregnancy loss

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Population:

High risk PV defined as WBC >11 x 109/l* AND at least ONE of the following

Age >60 years
Prior thrombosis or haemorrhage
Platelet count >1000 x 109/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:

Major thrombosis (both combined and split into venous and arterial)
Major haemorrhage
Transformation to PPV-MF
Transformation to AML and/or MDS
Complete haematological response (CHR) as defined by ELN response criteria at 1 year
Symptom burden/(QALY)quality of life years gained
Health economics including cost utility and cost effectiveness analyses
Peripheral blood JAK2 V617F allele burden according to ELN response criteria
Rates of discontinuation
Adverse events
Spleen response in patients with splenomegaly at Baseline.
Time free from venesection
Rate of second malignancies
Change in QRisk score
Unable to give informed consent

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Guys' Hospital	London		United Kingdom	SE1 9RT
2	Churchill Hospital	Oxford		United Kingdom	OX3 7LE

Sponsors and Collaborators

University of Birmingham
Novartis
MPN Voice
National Cancer Institute, France

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