A Phase 3b, Randomized, Open-Label, Parallel Group, Multicenter Study to Assess Efficacy, Safety, and Tolerability of Two Dosing Regimens of Ropeginterferon Alfa-2b-Njft (P1101) in Adult Patients with Polycythemia Vera

Background and Significance: Polycythemia vera (PV), the most common chronic myeloproliferative neoplasm in the United States, is a long-term, debilitating, life-threatening cancer with limited treatment options. Most patients with PV receive phlebotomy and low-dose aspirin to prevent thrombosis. Cytoreductive therapy is recommended for high-risk and in some low-risk patients. Ropeginterferon alfa-2b-njft (P1101) is the first and only FDA-approved interferon for treating PV regardless of patients' risk category or past treatment history. The FDA-approved dosing for ropeginterferon alfa-2b-njft in patients with PV is a starting dose of 50 or 100 mcg every 2 weeks, with dose increases of 50 mcg every 2 weeks up to a maximum of 500 mcg. Clinical trial results confirmed high complete hematologic response (CHR) rates and molecular responses to ropeginterferon alfa-2b-njft, however, time to achieve CHR can take 6 months or longer because dose escalation to the highest maintenance dose ranged from 16 to 28 weeks. It is expected that the faster and simpler dosing scheme of 250-350-500 mcg, escalated every 2 weeks may allow patients to achieve complete hematologic responses significantly earlier with acceptable tolerability and safety. This notion was supported in a recently reported clinical study (Jin et al. Exp Hematol Onc 2023). To further assess the 250-350-500 mcg dosing regimen, this Phase 3b, randomized, open-label, parallel group, multicenter study (NCT05481151) of U.S. and Canadian patients will evaluate the efficacy and safety of ropeginterferon alfa-2b-njft when using the above described dose-escalation scheme directly compared with the approved dosing scheme. Study Design and Methods: The planned enrollment for this study is approximately 100 patients with PV aged ≥18 years from the U.S. and Canada. Patients will be randomized (1:1) into either the approved dosing regimen arm or the amended dose-escalation scheme arm (Figure 1). Inclusion criteria include diagnosis of PV according to the WHO 2008 or 2016 criteria, hemoglobin ≥10 g/dL for females, and hemoglobin ≥11 g/dL for males at screening, neutrophil count ≥1.5 × 10 9/L at screening. Exclusion criteria include: any contraindications to interferon alfa or hypersensitivity to interferon alfa, having stopped prior interferon alfa therapy due to low efficacy or poor tolerability, severe or serious diseases or any other diseases that the investigator determines may affect the subject's participation in this study, or the use of any investigational drug <4 weeks prior to the first dose of ropeginterferon alfa-2b-njft. Treatment-naïve patients and those pretreated with hydroxyurea (HU) will be included. Patients in the approved dosing arm will undergo HU tapering by 25% for the first 2 weeks, followed by 50% for weeks 3-4, 75% for weeks 5-6, and discontinuing completely during week 7 and onwards. Patients in the amended dose-escalation scheme arm are required to discontinue HU immediately upon initiation of ropeginterferon alfa-2b-njft. The primary efficacy endpoint is CHR (defined as hematocrit <45% in the absence of phlebotomy in the previous 12 weeks, white blood cell count ≤10 × 10 9/L, and platelets ≤400 × 10 9/L) at Week 24. Secondary endpoints include time to CHR, proportion of patients in CHR at Weeks 8, 12, 16, 20, 24, 36, and 48; time to maintenance dose (stable dose for 3 consecutive doses); and time to freedom from phlebotomies. The core treatment period will be 24 weeks followed by a 24-week extension period and a 4-week safety follow-up. Ropeginterferon alfa-2b-njft (P1101) will be provided in single-use 500-mcg prefilled syringes for subcutaneous administration every 2 weeks. The approved dosing arm will initiate with a starting dose of 100 mcg (Day 0) and increase by 50-mcg every 2 weeks up to a maximum dose of 500 mcg. The amended dosing arm will initiate with a starting dose of 250 mcg (Day 0), increase to 350 mcg at Week 2, and increase to a maximum of 500 mcg at Week 4. Dose adjustments will be allowed if safety or tolerability concerns arise. Cochran-Mantal-Haenszel test stratified by investigator sites will be used for analyzing the primary efficacy endpoint at Week 24. General statistical summaries will be applied to primary and secondary endpoints. For categorical variables, frequency and percentage will be presented with a 95% confidence interval.