Efficacy and Safety of Pegylated Peptide Agonist of Thrombopoietin Receptor (PN20) in Secondary Prevention of Chemotherapy-Induced Thrombocytopenias: A Multicenter, Single Arm, Phase Ib Trial

Introduction: Chemotherapy-induced thrombocytopenia (CIT) is one of the most common hematological toxicities caused by chemotherapy, refers to the suppression of bone marrow megakaryocytes, leading to a peripheral blood platelet count (PLT) below 100×10^9/L. PN20 is a pegylated thrombopoietin receptor peptide agonist that mimics the domain of TPO. Phase Ia study (NCT06523088) of PN20 in healthy Chinese subjects has been completed. After a single subcutaneous administration at doses ranging from 0.05 to 0.2 μg/kg, plasma PLT levels significantly increased in a dose-dependent manner. PLT began to rise on Day 3 - 5 post-administration, peaked on Day 11 - 13, and returned to normal on Day 21. All dose groups showed good safety and tolerability, with no unexpected adverse events observed. The PLT increased more than twice from baseline in the 0.2 μg/kg group. In this phase Ib study of PN20 (NCT06521931), we are applying PN20 to prevent severe CIT in patients at high risk of bleeding, and ensure that the next chemotherapy could be administered at proper dosage and time. Methods: This study is a single-arm, dose-escalation phase Ib trial, evaluating the safety, tolerability, pharmacokinetics, pharmacodynamics and preliminary efficacy of PN20 in adult Chinese patients with CIT. The study is designed with three escalating dose groups (0.2, 0.5 and 0.75 μg/kg, administered once per cycle before chemotherapy), planning to enroll 24 CIT patients with lymphoma or solid tumors who are 18 years or older, with 8 patients per dose group. Participants have a previous decrease in PLT to 25-75×10^9/L (Grade 2-3 thrombocytopenia) in the last chemotherapy cycle before enrollment, and the PLT was between 75-150 × 10^9/L on the day before chemotherapy or enrollment in the first treatment cycle of this study. Patients received a single subcutaneous injection of PN20 within 1 hour before chemotherapy on Day 1 of the chemotherapy cycle (21 days per cycle). After the 21-day observation period following the first dose of PN20, if the subject meets the criteria for multiple-dose (PLT on Day 21 ≥ 100×10^9/L and meets the criteria for the next chemotherapy cycle), a second treatment cycle could be conducted. The primary endpoint of this study is the incidence of drug-related adverse events within 21 days after administration, and secondary endpoints include the proportion of subjects with PLT ≥ 100×10^9/L at the end of each cycle, pharmacokinetics and immunogenicity of PN20. Results: The enrollment of patients in 0.2 and 0.5 μg/kg dose groups has been completed, and recruitment for 0.75 μg/kg group is ongoing. The 18 enrolled patients include those with colorectal cancer (n=6), gastric and cardia cancer (n=5), lung cancer (n=3), and bile duct cancer (n=2). The mean minimum PLT of these patients in the last chemotherapy cycle was 51×10^9/L, and the mean baseline PLT was 117×10^9/L. After administration of PN20 before chemotherapy in the first cycle, at the end of first cycle (Day 21), 63% (5/8) and 100% (8/8) of patients in 0.2 and 0.5 μg/kg groups have PLT above 75×10^9/L, and 63% (5/8) and 88% (7/8) have PLT above 100×10^9/L. Following the administration of 0.5 μg/kg PN20, the mean PLT on Day 4, 8, 11, 13 and 21 of the first cycle are 125, 162, 183, 178 and 137×10^9/L, respectively. The median time to reach the peak PLT is 11 days in this group. There were 4 and 6 patients in 0.2 and 0.5 μg/kg groups respectively, entered the second cycle of PN20 treatment. The mean minimum PLT during the second cycle in each group was 78×10^9/L and 94×10^9/L respectively, and at the end of the second cycle, 100% (4/4) and 83% (5/6) of patients in the two groups have PLT above 75×10^9/L, and 75% (3/4) and 50% (3/6) have PLT above 100×10^9/L. No PN20-related adverse events were observed in the 0.2 and 0.5 μg/kg groups. During the study period, no patients require rescue treatment due to thrombocytopenia, nor did it lead to a delay of the next chemotherapy cycle or a reduction in the intensity of chemotherapy dosage. Conclusions: The study indicates that a single dose of PN20 on the first day of the chemotherapy cycle, prior to chemotherapy, is safe for the prevention of CIT, and both dosage groups have shown preliminary efficacy. This ongoing study is expected to provide a basis for the dosage selection of PN20 for CIT patients. In addition, a phase Ib clinical trial of PN20 for the treatment of primary immune thrombocytopenia (ITP) is also currently underway.