The Benefit/Risk Profile of AOP2014 in Low-risk Patients With PV

The Low-PV study is a multicenter, phase II, randomized trial aimed to assess whether the addition of Pegylated Proline-interferon-alpha-2b to the best therapeutic current strategy available based on phlebotomies and low dose acetylsalicylic acid (ASA) could improve the efficacy of treatment of patients with PV at low risk of thrombosis (younger than 60 years and without prior vascular events), in term of control of recommended level of hematocrit \< 45%, over a period of 12 months.

Sex

All

Minimum age

18 Years

Maximum age

60 Years

Inclusion Criteria:

* Age 18-60 years
* Diagnosis of Polycythemia Vera according to World Health Organization 2016 criteria
* Diagnosis of Polycythemia Vera including a recent bone marrow (BM) biopsy (performed within 3 years prior randomization in the study) and never treated with cytoreductive drugs
* HCT\<45%
* Ability and willingness to comply with all study requirements
* Signed written informed consent.

Exclusion Criteria:

* Any previous well documented cardiovascular PV-related events (see Appendix 1 for description)
* Previous cytoreductive drugs
* Known hypersensitivity or contraindications to the Investigational Medicinal Product (Pegylated Proline-Interferon alpha-2b) including:

evidence of severe retinopathy (e.g. cytomegalovirus retinitis, macular degeneration) or clinically relevant ophthalmological disorder (due to diabetes mellitus or hypertension); thyroid dysfunction not adequately controlled; patients tested positively with Thyroglobulin antibody and / or TPOAb at screening; documented autoimmune disease at screening or in the medical history; history or presence of depression requiring treatment with antidepressant; any risk of suicide at screening or previous suicide attempts;

* Previous exposure to a non-pegylated or pegylated interferon α
* Clinically relevant pulmonary infiltrates, pneumonia, and pneumonitis
* Systemic infections, e.g. hepatitis B, hepatitis C, or HIV at screening
* Significant liver (AST or alanine aminotransferase \> 2.5 times ULN) or renal disease (creatinine \> 2 mg/ml)
* Presence of any life-threatening condition or of any disease (e.g. cancer) that is likely to significantly shorten life expectancy
* History of active substance or alcohol abuse within the last year
* Any condition that in the opinion of the investigator would jeopardize the evaluation of efficacy or safety or be associated with poor adherence to the protocol
* Pregnant or lactating women and women\*/men of childbearing potential who are not using or are not willing to use any effective means of contraception (i.e. sexual abstinence, hormonal contraceptive, intra-uterine device, barrier method such as diaphragms or condoms, surgical methods).

  * Pregnancy test will be performed in order to ascertain negativity of human chorionic gonadotropin (β-hCG) test and confirm that childbearing women are not pregnant.

• BACKGROUNDKralovics R, Passamonti F, Buser AS, Teo SS, Tiedt R, Passweg JR, Tichelli A, Cazzola M, Skoda RC. A gain-of-function mutation of JAK2 in myeloproliferative disorders. N Engl J Med. 2005 Apr 28;352(17):1779-90. doi: 10.1056/NEJMoa051113. PMID 15858187
• BACKGROUNDScott LM, Tong W, Levine RL, Scott MA, Beer PA, Stratton MR, Futreal PA, Erber WN, McMullin MF, Harrison CN, Warren AJ, Gilliland DG, Lodish HF, Green AR. JAK2 exon 12 mutations in polycythemia vera and idiopathic erythrocytosis. N Engl J Med. 2007 Feb 1;356(5):459-68. doi: 10.1056/NEJMoa065202. PMID 17267906
• BACKGROUNDPassamonti F, Elena C, Schnittger S, Skoda RC, Green AR, Girodon F, Kiladjian JJ, McMullin MF, Ruggeri M, Besses C, Vannucchi AM, Lippert E, Gisslinger H, Rumi E, Lehmann T, Ortmann CA, Pietra D, Pascutto C, Haferlach T, Cazzola M. Molecular and clinical features of the myeloproliferative neoplasm associated with JAK2 exon 12 mutations. Blood. 2011 Mar 10;117(10):2813-6. doi: 10.1182/blood-2010-11-316810. Epub 2011 Jan 11. PMID 21224469
• BACKGROUNDVannucchi AM, Rotunno G, Bartalucci N, Raugei G, Carrai V, Balliu M, Mannarelli C, Pacilli A, Calabresi L, Fjerza R, Pieri L, Bosi A, Manfredini R, Guglielmelli P. Calreticulin mutation-specific immunostaining in myeloproliferative neoplasms: pathogenetic insight and diagnostic value. Leukemia. 2014 Sep;28(9):1811-8. doi: 10.1038/leu.2014.100. Epub 2014 Mar 12. PMID 24618731
• BACKGROUNDBarbui T, Barosi G, Birgegard G, Cervantes F, Finazzi G, Griesshammer M, Harrison C, Hasselbalch HC, Hehlmann R, Hoffman R, Kiladjian JJ, Kroger N, Mesa R, McMullin MF, Pardanani A, Passamonti F, Vannucchi AM, Reiter A, Silver RT, Verstovsek S, Tefferi A; European LeukemiaNet. Philadelphia-negative classical myeloproliferative neoplasms: critical concepts and management recommendations from European LeukemiaNet. J Clin Oncol. 2011 Feb 20;29(6):761-70. doi: 10.1200/JCO.2010.31.8436. Epub 2011 Jan 4. PMID 21205761
• BACKGROUNDNajean Y, Rain JD. The very long-term evolution of polycythemia vera: an analysis of 318 patients initially treated by phlebotomy or 32P between 1969 and 1981. Semin Hematol. 1997 Jan;34(1):6-16. No abstract available.