Clinical trial NCT04116502: MITHRIDATE: Ruxolitinib Versus Hydroxycarbamide or Interferon as First Line Therapy in High Risk Polycythemia Vera
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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Polycythemia Vera
Lead sponsor: University of Birmingham
Sponsor class: OTHER
Collaborators: name: Novartis
name: MPN Voice
name: French National Cancer Institute (Institut National Du Cancer - France)
First posted: 2019-10-04
Enrollment: 586
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Eligibility criteria: 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\*
* Hypertension or diabetes requiring pharmacological therapy (\*At any time since diagnosis)

Inclusion Criteria:

1. Patient ≥18 years of age
2. Diagnosis of PV meeting the WHO criteria within the past 15 years
3. Meets criteria of high risk\* PV (see above for specific population)
4. Patients must have a screening haemoglobin of \>8g/dl
5. Patients may have received antiplatelet agents and venesection
6. Patients may have received ONE cytoreductive therapy for PV less than 10 years (BUT they should not be resistant or intolerant to that therapy)
7. Able to provide written informed consent

Exclusion Criteria:

1. Diagnosis of PV \> 15 years previously
2. Absence of 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 10 years OR resistance/intolerance to that therapy
5. Active infection including Human Immunodeficiency Virus (HIV), hepatitis B, hepatitis C, autoimmune hepatitis, 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 with lactose allergies, hypersensitivities, or rare hereditary problems, of galactose intolerance, total lactase deficiency or glucose- galactose malabsorption
8. Patients with uncontrolled neuropsychiatric disorders
9. Patients with uncontrolled cutaneous cancers
10. Patients and partners 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
11. ECOG Performance Status Score ≥ 3
12. Uncontrolled rapid or paroxysmal atrial fibrillation, uncontrolled or unstable angina, recent (within the last 6 months) myocardial infarction or acute coronary syndrome or any clinically significant cardiac disease \> NYHA ( New York Heart Association) Class II
13. Patients who have transformed to myelofibrosis
14. Previous treatment with ruxolitinib
15. 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
16. Inadequate liver function as defined by ALT/AST \>2.0 x ULN
17. Inadequate renal function as defined by eGFR \< 30 mls/min
18. Unable to give informed consent

    Additional Exclusion Criteria for France Only
19. All women of childbearing potential (as per Appendix 8 definition)
20. No affiliation with the French healthcare system
21. Persons under psychiatric care that would impede understanding of informed consent and optimal treatment and follow-up
22. Adults subject to a legal protection measure (guardianship, curatorship and safeguard of justice)
23. Patients deprived of their liberty by a judicial or administrative decision

Primary outcomes:
measure: Event Free Survival (EFS)
timeFrame: 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 outcomes:
measure: Major thrombosis
timeFrame: Occurring while on treatment (over 3 years)
measure: Major haemorrhage
timeFrame: Occurring while on treatment (over 3 years)
measure: Transformation to PPV-MF
timeFrame: Occurring while on treatment (over 3 years)
measure: Transformation to MDS and/or AML
timeFrame: Occurring while on treatment (over 3 years)
measure: Complete Haematological remission (CHR)
timeFrame: 1 year post-treatment
measure: Symptom burden/Quality of life (MPN-SAF)
timeFrame: Questionnaires collected at baseline, weeks 12, 26, 39, 55, months 15, 18, 24, 30 and 36
measure: Symptom burden/Quality of life (MDASI)
timeFrame: Questionnaires collected at baseline, weeks 12, 26, 39, 55, months 15, 18, 24, 30 and 36
measure: Symptom burden/Quality of life (EQ-5D)
timeFrame: Questionnaires collected at baseline, weeks 12, 26, 39, 55, months 15, 18, 24, 30 and 36
measure: Health economics
timeFrame: At the end of the trial (trial duration of approximately 8 years)
measure: Peripheral blood JAK2 V617F allele burden
timeFrame: At baseline and annually throughout the trial (from baseline until approximately 3 years post-randomisation)
measure: Rates of discontinuation
timeFrame: From treatment prior to protocol defined 3 years
measure: Rate and severity of adverse events
timeFrame: Continuous throughout the trial (from randomisation until approximately 3 years post-randomisation))
measure: Spleen response
timeFrame: Response at 1 year post randomisation
measure: Time free from venesection
timeFrame: Defined as the mean time between venesections while on trial treatment (treatment duration of 3 years)
measure: Secondary malignancy
timeFrame: Occurring throughout the trial (from randomisation until approximately 3 years post-randomisation)
measure: Change in QRisk score
timeFrame: Collected at baseline and years 1, 2 and 3
Other outcomes:
measure: Progression of marrow fibrosis
timeFrame: Occurring throughout the trial (from randomisation to approximately 3 years post-randomisation)
measure: Impact of treatment on molecular signatures of disease
timeFrame: Occurring throughout the trial (from randomisation to approximately 3 years post-randomisation)
measure: Clonal involvement
timeFrame: Occurring throughout the trial (from randomisation to approximately 3 years post-randomisation)
measure: Clonal evolution
timeFrame: Occurring throughout the trial (from randomisation to approximately 3 years post-randomisation)
measure: Reduction of peripheral blood allele burden
timeFrame: Occurring throughout the trial (from randomisation to approximately 3 years post-randomisation)
measure: Assessment of the prevalence of clonality markers for haematological disease
timeFrame: Occurring throughout the trial (from randomisation to approximately 3 years post-randomisation)
measure: Cardiac event
timeFrame: Occurring throughout the trial (from randomisation to approximately 3 years post-randomisation)
measure: Pulmonary hypertension
timeFrame: Occurring throughout the trial (from randomisation to approximately 3 years post-randomisation)
measure: Coronary intervention
timeFrame: Occurring throughout the trial (from randomisation to approximately 3 years post-randomisation)
measure: Deterioration in cardiac function
timeFrame: Occurring throughout the trial (from randomisation to approximately 3 years post-randomisation)
measure: Cerebrovascular event
timeFrame: Occurring throughout the trial (from randomisation to approximately 3 years post-randomisation)
measure: Arterial vascular event
timeFrame: Occurring throughout the trial (from randomisation to approximately 3 years post-randomisation)
measure: Venous thrombosis
timeFrame: Occurring throughout the trial (from randomisation to approximately 3 years post-randomisation)
measure: Pregnancy loss
timeFrame: Occurring throughout the trial (from randomisation to approximately 3 years post-randomisation)
measure: Thrombosis biomarkers
timeFrame: Occurring throughout the trial (from randomisation to approximately 3 years post-randomisation)
Locations:
city: Aberdeen
country: United Kingdom
facility: Aberdeen Royal Infirmary
city: Bath
country: United Kingdom
facility: Royal United Hospital
city: Belfast
country: United Kingdom
facility: Belfast City Hospital
city: Birmingham
country: United Kingdom
facility: Birmingham Heartlands Hospital
city: Blackpool
country: United Kingdom
facility: Blackpool Victoria Hospital
city: Bournemouth
country: United Kingdom
facility: Royal Bournemouth Hospital
city: Bristol
country: United Kingdom
facility: Southmead Hospital
city: Cambridge
country: United Kingdom
facility: Addenbrooke's Hospital
city: Canterbury
country: United Kingdom
facility: Kent and Canterbury Hospital
city: Cardiff
country: United Kingdom
facility: University Hospital of Wales
city: Chichester
country: United Kingdom
facility: St Richard's Hospital
city: Colchester
country: United Kingdom
facility: Colchester Hospital
city: Cottingham
country: United Kingdom
facility: Castle Hill Hospital
city: Dudley
country: United Kingdom
facility: Russells Hall Hospital
city: Edinburgh
country: United Kingdom
facility: Western General Hospital
city: Exeter
country: United Kingdom
facility: Royal Devon and Exeter Hospital
city: Gloucester
country: United Kingdom
facility: Gloucestershire Royal Hospital
city: Halifax
country: United Kingdom
facility: Calderdale Royal Hospital
city: Huddersfield
country: United Kingdom
facility: Huddersfield Royal Infirmary
city: Inverness
country: United Kingdom
facility: Raigmore Hospital
city: Kettering
country: United Kingdom
facility: Kettering General Hospital
city: Leicester
country: United Kingdom
facility: Leicester Royal Infirmary
city: Livingston
country: United Kingdom
facility: St John's Hospital
city: London
country: United Kingdom
facility: University College Hospital
city: London
country: United Kingdom
facility: Guy's Hospital
city: London
country: United Kingdom
facility: St George's Hospital
city: Manchester
country: United Kingdom
facility: Wythenshawe Hospital
city: Middlesbrough
country: United Kingdom
facility: The James Cook University Hospital
city: Newcastle Upon Tyne
country: United Kingdom
facility: Freeman Hospital
city: Newport
country: United Kingdom
facility: Royal Gwent Hospital
city: North Shields
country: United Kingdom
facility: North Tyneside General Hospital
city: Northampton
country: United Kingdom
facility: Northampton General Hospital
city: Norwich
country: United Kingdom
facility: Norfolk and Norwich University Hospital
city: Nottingham
country: United Kingdom
facility: Nottingham City Hospital
city: Oxford
country: United Kingdom
facility: Churchill Hospital
city: Reading
country: United Kingdom
facility: Royal Berkshire Hospital
city: Runcorn
country: United Kingdom
facility: Halton Hospital
city: Slough
country: United Kingdom
facility: Wexham Park Hospital
city: Southampton
country: United Kingdom
facility: Southampton General Hospital
city: Stoke-on-Trent
country: United Kingdom
facility: Royal Stoke University Hospital
city: Sunderland
country: United Kingdom
facility: Sunderland Royal Hospital
city: Sutton Coldfield
country: United Kingdom
facility: Good Hope Hospital
city: Truro
country: United Kingdom
facility: Royal Cornwall Hospital
city: Warwick
country: United Kingdom
facility: Warwick Hospital
city: Wirral
country: United Kingdom
facility: Arrowe Park Hospital
city: Wolverhampton
country: United Kingdom
facility: New Cross Hospital
city: Worthing
country: United Kingdom
facility: Worthing Hospital
Study officials:
affiliation: Acting on behalf of the Sponsor (UK), Guy's Hospital, London, UK, SE1 9RT
name: Claire Harrison
role: PRINCIPAL_INVESTIGATOR
affiliation: (France) Clinical Investigations Center, Saint-Louis Hospital, Paris, France
name: Jean-Jacques Kiladjian
role: PRINCIPAL_INVESTIGATOR
References: