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475 Final Results from PROUD-PV a Randomized Controlled Phase 3 Trial Comparing Ropeginterferon Alfa-2b to Hydroxyurea in Polycythemia Vera Patients

Myeloproliferative Syndromes: Clinical
Program: Oral and Poster Abstracts
Type: Oral
Session: 634. Myeloproliferative Syndromes: Clinical: Clinical Trials with Agents Other Than JAK Inhibitors
Sunday, December 4, 2016: 4:30 PM
Marriott Grand 8-9 (Marriott Marquis San Diego Marina)

Heinz Gisslinger, MD1, Christoph Klade2*, Pencho Georgiev3*, AleksanderSkotnicki, MD, PhD4, Liana Gercheva-Kyuchukova, MD5*, Miklos Egyed6, Viktor Rossiev, MD7*, Petr Dulicek8*, Arpad Illes, MD, PhD9*, HalynaPylypenko, MD10*, Liliya Sivcheva11*, Jiri Mayer, MD12, Barbara Grohmann-Izay, MD2*, Hans Hasselbalch, MD13, Robert Kralovics, Ph.D.14 and Jean-Jacques Kiladjian, MD, PhD15

1Department of Hematology and Blood Coagulation, Medical University of Vienna, Vienna, Austria
2AOP Orphan Pharmaceuticals AG, Vienna, Austria
3University Multiprofile Hospital for Active Treatment “SvetiGeorgi’, Plovdiv, Bulgaria
4Dept. of Hematology, Jagiellonian University, Krakow, Poland
5Teaching Unit of the Hematology Department, Multiprofile Hospital in Krakow, Krakow, Poland
6Department of Internal Medicine, Kaposi Mor Teaching Hospital, Kaposvar, Hungary
7Department of Internal Medicine II, Samara Kalinin Regional Clinical Hospital, Kaposvar, Hungary
8Department of Clinical Hematology, University Hospital Hradec Kralove, Hradec Kralove, Czech Republic
9Department of Hematology, University of Debrecen Medical and Health Science Center, Debrecen, Hungary
10Department of Hematology, Cherkassy Regional Oncological Center, Cherkassy, Ukraine
11First Department of Internal Medicine, Multiprofile Hospital for Active Treatment – HristoBotev, Vratsa, Bulgaria
12Department of Internal Medicine – Hematology and Oncology, Center of Molecular Biology and Gene Therapy, University Hospital and Masaryk University, Brno, Czech Republic
13Department of Hematology, Roskilde University Hospital, Roskilde, Denmark
14CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
15Centre d’InvestigationsCliniques (INSERM CIC 1427), Hopital Saint-Louis and Paris Diderot University, Paris, France

Background:Interferon alfa (IFNa) based therapies have been successfully applied in myeloproliferative neoplasms (MPN) for over thirty years. Several uncontrolled phase II trials have independently shown high rates of hematologic, splenic and sustained mutant JAK2 molecular responses in Polycythemia vera (PV) patients. However, a head-to-head assessment versus other treatment options in confirmatory trials has been lacking so far. Here we report 12 month data from a randomized controlled phase III trial comparing the novel, long-acting Ropeginterferon alfa-2b (AOP2014) with hydroxyurea (HU) in PV patients.

Study design:Randomized, controlled, parallel group multicenter phase III trial assessing efficacy, safety and tolerability in patients diagnosed with PV according to WHO2008 criteria, either naive to cytoreduction or HU experienced (but neither intolerant nor complete responders, cumulative HU exposure max. 3 years). The primary endpoint was non-inferiority of AOP2014 vs. HU at 12 months of therapy in terms of complete hematological response (CHR) rate. CHR was defined as normal hematocrit, leukocyte and platelet counts, spleen size and absence of phlebotomy in the preceding 3 months. As important secondary endpoint the effect of treatment on mutant JAK2 allele burden was assessed as rate of complete and partial molecular response (C/PMR) rate according to modified ELN criteria. Both cohorts are followed up further maintaining the original randomization for assessing effects of prolonged therapy.

Results:257 patients were randomized in 48 sites in 13 European countries and treated with response-driven escalating doses of either AOP2014, or HU. 62% of patients were naive to cytoreduction, 38% HU experienced; 19% had a previous thrombotic event. Response-driven dose escalation was done in both treatment arms applying up to 10 dose levels (50-500μg AOP2014 every other week, or 250-3000 mg HU daily). Both treatments were well tolerated. The drop-out rate after 12 months was low with ~15% in both arms, the majority of drop-outs were due to administrative reasons (bi-weekly hospital visits).

This presentation will provide the detailed analysis of primary and secondary endpoints of the trial, which is still blinded as of 4th Aug 2016. Preliminary pooled analysis revealed that at 12 months 45% of patients had a hematologic response: mean Hct values dropped from 48% to 42%, leukocyte counts from 12 to 6 *109/L and platelets from 530 to 260 *109/L. Need for phlebotomy within 3 months dropped from 86% to 6%. 37% of patients achieved a JAK2 molecular response (PMR or CMR), mean mutant JAK2 allele burden went from 42,5% to 28,7%.

Conclusions:This is the first phase III trial formally assessing efficacy, safety and tolerability of Ropeginterferon alfa-2b versus HU. Both cohorts are followed-up for prolonged treatment duration, and it is expected that the currently available and emerging data will establish the role of Ropeginterferon alfa-2b as first-line treatment for PV.

Disclosures: Gisslinger: AOP Orphan Pharmaceuticals AG, Novartis, Celgene, Baxalta: Consultancy, Honoraria, Research Funding. Klade: AOP Orphan: Employment. Georgiev: Alnylam Pharmaceuticals: Consultancy. Illes:University of Debrecen faculty of medicine department of hematology: Employment. Mayer: AOP Orphan Pharmaceuticals:Research Funding; Novartis: Research Funding. Grohmann-Izay: AOP Orphan Pharmaceuticals AG: Employment. Kralovics: Qiagen: Membership on an entity’s Board of Directors or advisory committees; AOP Orphan: Research Funding. Kiladjian: Novartis: Research Funding; AOP Orphan: Research Funding.

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