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

Overview

Sponsor-declared trial summary

Key facts

Sponsor

The University Of Birmingham

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04], Diseases [C] - Hemic and Lymphatic Diseases [C15]

Trial duration

9 Dec 2024 → ongoing

Decision date (initial)

2024-11-08

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Guy's and St Thomas' Charity (MPN Voice) · Institut National Du Cancer · Novartis Pharma AG

External identifiers

EU CT number

2024-516109-21-00

EudraCT number

2018-001908-11

ClinicalTrials.gov

NCT04116502

ISRCTN

ISRCTN12885480

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Efficacy, Safety

To compare the time to combined incidence of; major thrombosis, major haemorrhage, death, transformation to Myelodysplastic syndrome, Acute Myeloid Leukaemia, or post-PV (PPV) Myelofibrosis in high risk PV patients randomised to ruxolitinib versus best available therapy.

Secondary objectives 11

1. To compare the incidence of major thrombosis, major haemorrhage and transformation to PPV MF in high-risk PV patients receiving ruxolitinib or best available therapy (two listed comparators).
2. To compare the incidence of transformation to MDS and/or AML and complete haematological response (CHR) between best available therapy and ruxolitinib.
3. To determine the symptom burden, quality of life and health economics including cost utility and cost effectiveness analyses of high-risk PV patients in each of the treatment groups and to establish the change in peripheral blood JAK2 V617F allele burden.
4. To determine the rates of discontinuation from treatment and the rate and severity of adverse events in both treatment groups.
5. To compare spleen response and time free from venesection in both of the treatment groups.
6. To compare the incidence of secondary malignancy and the change in Qrisk in both treatment groups.
7. EXPLORATORY 1: To compare in an exploratory way the impact of the treatment on the progression of marrow fibrosis and the molecular signature of the disease
8. EXPLORATORY 2: To establish the clonal evolution and involvement within stem/progenitor cell compartment in each treatment arm.
9. EXPLORATORY 3: To establish the change in peripheral blood allele burden and assess the prevalence of clonality markers for disease, including their change over time by treatment arm.
10. EXPLORATORY 4: Determine the correlation of thrombosis markers with clinical thrombosis events in each treatment arm.
11. EXPLORATORY METABOLIC 1: To establish the incidence rate in each treatment arm of cardiac events, pulmonary hypertension, coronary intervention, deterioration in cardiac function, cerebrovascular events, arterial vascular events, venous thrombosis and pregnancy loss.

Conditions and MedDRA coding

Polycythaemia Vera (PV)

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 7

1. 1. Patient ≥ 18 years of age
2. 2. Diagnosis of PV meeting WHO criteria within past 15 years
3. 3. Meets criteria of high risk PV (High risk PV defined as WBC >11 x 109/l* AND at least ONE of the following • Age >60 years • Prior thrombosis or major haemorrhage related to disease • Platelet count >1000 x 109/l* • Hypertension or diabetes requiring pharmacological therapy. *At any time since diagnosis)
4. 4. Patients must have a screening haemoglobin of >8g/dl
5. 5. Patients may have received antiplatelet agents and venesection
6. 6. Patients may have received ONE or less cytoreductive therapy for less than 10 years (BUT they should not be resistant or intolerant to that therapy)
7. 7. Able to provide written informed consent

Exclusion criteria 23

1. 1. Diagnosis of PV > 15 years previously
2. 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
3. 11. ECOG Performance Status Score ≥ 3
4. 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
5. 13. Patients who have transformed to myelofibrosis
6. 14. Previous treatment with ruxolitinib
7. 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
8. 16. Inadequate liver function as defined by ALT/AST >2.0 x ULN
9. 17. Inadequate renal function as defined by eGFR < 30 mls/min
10. 18. Unable to give informed consent
11. 2. Absence of any JAK-2 mutation
12. 3. Patients with any contraindications to any of the investigational medical products
13. 4. Treatment with >1 cytoreductive therapy OR a cytoreductive treatment duration exceeding 10 years OR resistance/intolerance to that therapy
14. 5. Active infection including Human Immunodeficiency Virus (HIV), hepatitis B, hepatitis C, autoimmune hepatitis, Tuberculosis
15. 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)
16. 7. Patients with lactose allergies, hypersensitivities, or rare hereditary galactose intolerance, total lactase deficiency or glucose- galactose malabsorption
17. 8. Patients with uncontrolled neuropsychiatric disorders
18. 9. Patients with uncontrolled cutaneous cancers
19. 19. All women of childbearing potential (as per Appendix 8 definition) FRANCE ONLY
20. 20. No affiliation with the French healthcare system FRANCE ONLY
21. 21. Persons under psychiatric care that would impede understanding of informed consent and optimal treatment and follow-up FRANCE ONLY
22. 23. Patients deprived of their liberty by a judicial or administrative decision FRANCE ONLY
23. 22. Adults subject to a legal protection measure (guardianship, curatorship and safeguard of justice) FRANCE ONLY

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Event Free Survival (EFS): defined as the time from randomisation to the date of the first event including: Major thrombosis, Major haemorrhage, Death, Transformation to MDS, AML or PPV-MF. Patients who do not experience an event during the trial will be censored at their date last seen.

Secondary endpoints 29

1. 1. Major thrombosis (both combined and split into venous and arterial)
2. 2. Major haemorrhage
3. 3. Transformation to PPV-MF
4. 4. Transformation to AML and/or MDS
5. 5. Complete haematological response (CHR) as defined by ELN response criteria at 1 year
6. 6. Symptom burden/(QALY)quality of life years gained
7. 7. Health economics including cost utility and cost effectiveness analyses
8. 8. Peripheral blood JAK2 V617F allele burden according to ELN response criteria
9. 9. Rates of discontinuation
10. 10. Adverse events
11. 11. Spleen response in patients with splenomegaly at Baseline
12. 12. Time free from venesection
13. 13. Rate of second malignancies
14. 14. Change in Qrisk score
15. Exploratory 1: Progression of marrow fibrosis
16. Exploratory 2: Impact of the treatment on molecular signatures of disease
17. Exploratory 3. Clonal involvement within the stem/progenitor cell compartment
18. Exploratory 4. Clonal evolution (acquisition of additional mutations)
19. Exploratory 5. Reduction of peripheral blood allele burden of other disease-associated mutations
20. Exploratory 6. Assessment of the prevalence of clonality markers for haematological disease and any change over time
21. Exploratory 7. Correlation of thrombosis biomarkers with clinical thrombosis events
22. Exploratory Metabolic: 1. Cardiac event (angina, acute coronary syndrome, acute MI; arrhythmia)
23. Exploratory Metabolic 2. Pulmonary hypertension
24. Exploratory Metabolic 3. Coronary intervention: e.g. angiogram, angioplasty, CABG
25. Exploratory Metabolic 4. Deterioration in cardiac function e.g. LVEF% on ECHO/ MUGA and/or NYHA classification
26. Exploratory Metabolic 5. Cerebrovascular event (TIA, haemorrhagic CVA, non-haemorrhagic CVA)
27. Exploratory Metabolic 6. Arterial vascular event (peripheral vascular disease: claudication, carotid stenosis)
28. Exploratory Metabolic 7. Venous thrombosis including DVT, PE, Cerebral, splanchnic, other
29. Exploratory Metabolic 8. Pregnancy loss

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Comparator 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

The University Of Birmingham

Sponsor organisation

The University Of Birmingham

Address

Vincent Drive

City

Birmingham

Postcode

B15 2TT

Country

United Kingdom

Scientific contact point

Organisation

The University Of Birmingham

Contact name

Clinical Trial Coordinator

Public contact point

Organisation

The University Of Birmingham

Contact name

Clinical Trial Coordinator

Third parties 1

Locations

1 EU/EEA country · 35 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Oversight and notifications

Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77

Urgent safety measures 1 · Art. 54 CTR

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 9 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

3 submissions — initial application plus substantial / non-substantial modifications