Polycythemia Vera
Conditions
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.
Interventions
DRUGRuxolitinib
10mg of ruxolitinib twice daily (bd)
DRUGHydroxycarbamide
Via standard hospital mechanisms
DRUGInterferon-Alpha
Any formulation, via standard hospital mechanisms
Sponsors
Novartis
MPN Voice
French National Cancer Institute (Institut National Du Cancer - France)
University of Birmingham
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Event Free Survival (EFS) | 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
| Measure | Time frame | Description |
|---|---|---|
| Major haemorrhage | Occurring while on treatment (over 3 years) | As defined in the protocol |
| Major thrombosis | Occurring while on treatment (over 3 years) | As defined in the protocol, combined and split to venous and arterial |
| Transformation to PPV-MF | Occurring while on treatment (over 3 years) | Transformation to PPV-MF |
| Transformation to MDS and/or AML | Occurring 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 | Occurring 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
| Measure | Time frame | Description |
|---|---|---|
| Impact of treatment on molecular signatures of disease | Occurring 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 | Occurring throughout the trial (from randomisation to approximately 3 years post-randomisation) | within the stem/progenitor cell compartment (as analysed by the WIMM in Oxford) |
| Reduction of peripheral blood allele burden | Occurring 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 | Occurring 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 | Occurring throughout the trial (from randomisation to approximately 3 years post-randomisation) | (angina, acute coronary syndrome, acute MI; arrhythmia) |
| Pulmonary hypertension | Occurring throughout the trial (from randomisation to approximately 3 years post-randomisation) | Pulmonary hypertension as assessed clinically |
| Coronary intervention | Occurring throughout the trial (from randomisation to approximately 3 years post-randomisation) | e.g. angiogram, angioplasty, CABG |
| Deterioration in cardiac function | Occurring throughout the trial (from randomisation to approximately 3 years post-randomisation) | e.g. LVEF% on ECHO/MUGA and/or NYHA classification |
| Cerebrovascular event | Occurring throughout the trial (from randomisation to approximately 3 years post-randomisation) | TIA, haemorrhagic CVA, non-haemorrhagic CVA |
| Arterial vascular event | Occurring throughout the trial (from randomisation to approximately 3 years post-randomisation) | peripheral vascular disease: claudication, carotid stenosis |
| Venous thrombosis | Occurring throughout the trial (from randomisation to approximately 3 years post-randomisation) | including DVT, PE, Cerebral, splanchnic, other |
| Pregnancy loss | Occurring throughout the trial (from randomisation to approximately 3 years post-randomisation) | Pregnancy loss |
| Thrombosis biomarkers | Occurring throughout the trial (from randomisation to approximately 3 years post-randomisation) | Correlation of thrombosis biomarkers with clinical thrombosis events |
| Progression of marrow fibrosis | Occurring 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 |
| Clonal evolution | Occurring throughout the trial (from randomisation to approximately 3 years post-randomisation) | (acquisition of additional mutations, as analysed by the WIMM in Oxford) |
Countries
United Kingdom
Contacts
Primary ContactAlex Hainsworth
Outcome results
None listed