The Design of a Phase 2 Study to Evaluate the Safety and Efficacy of Ropeginterferon Alfa-2b (P1101) in Chinese Patients with Polycythemia Vera Resistant or Intolerant to Hydroxyurea (HU)

Background: Polycythemia vera (PV) is the most common type of Philadelphia-negative myeloproliferative neoplasms (MPNs). PV is a long-term debilitating and life-threatening cancer that is associated with the risk of thrombosis, hemorrhage, and a long-term risk of developing myelofibrosis and acute myeloid leukemia. Early intervention with a disease-modifying treatment that can eradicate the mutated clones is needed to prevent disease progression and transformation. To date, therapeutic options for PV are limited and they only address the signs and symptoms. Most low-risk patients with PV are treated with phlebotomy and low-dose aspirin to manage increased blood viscosity and reduce the risk of vascular events, whereas high-risk and certain low-risk patients are treated with cytoreductive agents. Several cytoreductive agents are available such as hydroxyurea (HU) which is commonly used as a first-line therapy. Ruxolitinib, a JAK2 inhibitor, is also used. While interferon alfa agents have been used off label in clinical practice for more than three decades, their use has been limited due to the tolerability concerns.

Ropeginterferon alfa-2b (P1101), a long-acting, mono-pegylated proline interferon, was developed for the treatment of MPNs, including PV. The novel formulation of P1101 improves its pharmacokinetic properties allowing treatment every 2 weeks with improved tolerability and convenience. P1101 was evaluated for the treatment of PV in the phase 3 PROUD-PV trial and its extension study CONTINUATION-PV. In the PROUD-PV study, due to the slow P1101 titration schedule, the maximum P1101 dose was not reached until week 28 and the primary analysis was done at 52 weeks. In CONTINUATION-PV, when patients were on their effective doses, a significantly higher proportion of patients treated with P1101 achieved a complete hematologic response (CHR) with improved disease burden compared to HU-treated patients. At 48 months there was a significant reduction in allelic burden from a baseline of 37.3% to 9.8% with 13.8% of patients achieving a complete molecular response (CMR). The molecular response rates (complete + partial) at 60 months was 69.1%. P1101 was approved by the European Medicines Agency in 2019 and the Taiwan Food and Drug Administration in 2020 as monotherapy in adults for the treatment of PV without symptomatic splenomegaly. Here, we describe a phase 2 study of P1101 in Chinese patients with PV utilizing an accelerated P1101 dose titration schedule.

Study Design and Methods: This phase 2, multicenter, single-arm study is designed to evaluate safety and efficacy of P1101 in Chinese patients with PV utilizing a 250-350-500 ug P1101 dose titration schedule. The primary analysis will be conducted at 24 weeks. The study will recruit approximately 49 subjects in 15-20 sites in China. Key eligibility criteria include diagnosis of PV according to the 2016 WHO criteria, and resistance or intolerance to prior HU according to 2020 guidelines of CSCO. Patients who previously received interferon therapy have to be anti-P1101 binding antibody negative during the screening visit to be eligible. The study excludes patients with symptomatic splenomegaly.

Eligible patients receive subcutaneous administration of P1101. Patients will receive an initial dose of 250 µg at Week 0, 350 µg at Week 2, and then 500 µg at Week 4. The dose is maintained at the highest dose that can be tolerated and delivers the best disease response. The maximum recommended dose is 500 μg every 2 weeks. Low-dose aspirin is administered during the 52 weeks of study treatment, unless contraindicated. The primary efficacy endpoint is the phlebotomy-free CHR rate at Week 24. Secondary endpoints include changes in hematocrit, white blood cell count, platelet count; time requiring no phlebotomy; time to first response; and duration of response. All patients will continue receiving treatment until week 52 to provide long-term follow-up information (blood parameters, molecular and cytogenetic data, safety parameters, and optional bone marrow data).

This study has been granted IND approval by China CDE on Apr2021. Recruitment is expected to begin in early September 2021 with trial results expected in Q3 2022.

Figure： Study Design

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