Phase Ⅰ Study Of The Safety, Tolerability And Pharmacokinetics Of Topotecan And Simotinib In Patients With Advanced Cancer

In this study, we aim to assess the phase I clinical pharmacokinetic profile, safety and tolerability of oral topotecan and simotinib in patients with advanced cancer, respectively. Results of present study were utilized to optimally guide the choice of the recommended phase II dose. A method for determination of topotecan and simotnib in human plasma using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was developed and fully validated.Section 1. Oral topotecan:absolute bioavailability, safety, tolerability and impact of ABCG2 genotyping in Chinese patients with advanced cancerTopotecan is a semi-synthetic water-soluble analog of camptothecin; it exists in a lactone form and a carboxylate form at physiological pH. Topotecan has been shown to be a specific inhibitor of topoisomerase I, and was effective against a variety of human tumor types which were resistant to chemotherapy. Compared to the infusion formulation, oral topotecan showed the consistent therapeutic efficacy but less adverse effect and more convenience for patients. The current study aimed to investigate the absolute bioavailability, safety and tolerability of oral topotecan in Chinese patients with advanced cancers.Chapter 1:Development and validation of a UPLC-MS/MS method for determination of total topotecan in human plasma. Protein precipitation was used as sample preparation, and the supernatants were acidified with 5% formic acid to convert fully the carboxylate form to the lactone form. The assay was validated over the concentration range of 0.5-100 ng/mL. The intra-and inter-day precision and accuracy of the quality control samples showed≤11.2% relative standard deviation (RSD) and-0.3 to 5.7% relative errors (RE). The mean recovery was greater than 85%. The method was successfully applied to perform plasma pharmacokinetic studies of total topotecan in human plasma.Chapter 2:Development and validation of a UPLC-MS/MS method for determination of lactone topotecan in human plasma.300 μL of cold methanol at-20℃ was added to 100 μL of plasma. The assay was validated over the concentration range of 0.1-50 ng/mL. The intra- and inter-day precision and accuracy of the quality control samples showed < 10.7% relative standard deviation (RSD) and -1.6 to 5.4% relative errors (RE). The mean recovery was greater than 90%. The method was successfully applied to perform plasma pharmacokinetic studies of lactone topotecan in human plasma.Chapter 3:Clinical pharmacokinetic and absolute bioavailability studies of oral topotecan in advanced cancer patients. The pharmacokinetic studies were simultaneously conducted in this nonrandomized, open label and single center phase I trial. All of the patients were treated with an approved intravenous dose of 1.5 mg/m2 over 30 min (Hycamtin) on day 1, and took the oral topotecan at one of two dose levels:1.5 mg/m2 (6 patients) or 1.9 mg/m2 (5 patients) on day 2. The absolute bioavailability of total topotecan in the 1.5 mg/m2 and 1.9 mg/m2 groups averaged (41.23 ± 11.8)% and (36.00 ± 14.8)%, respectively. The absolute bioavailability of lactone topotecan in the two doseage groups averaged (46.0 ± 15.4)% and (38.3 ± 14.3)%, respectively. The bioavailability of topotecan after oral administration illustrates good systemic exposure at dosages of 1.5 mg/m2 and 1.9 mg/m2 over a five day schedule in Chinese patients, and was not dependent on ABCG2 421C> A and 34G> A genotypes. The dose limited toxibility of oral topotecan was myelosuppression.The patients show good tolerance to the 1.5 mg/m2 dose level, and the maximum tolerability dose (MTD) was 1.9 mg/m2. For the young patients with good physique and slight previous chemoradiotherapy, the 1.9 mg/m2 dose level deserves further study.Section 2. Phase I clinical pharmacokinetics, safety and tolerability of simotinib in advanced lung cancer patientsSimotinib is a novel oral small molecule epithelial growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) that has demonstrated equal or superior antineoplastic activities to erlotinib in preclinical studies. In this study, we aim to investigate the pharmacokinetics of simotinib in advanced lung cancer patients after single and multiple oral administration.Chapter 1:Development and validation of a rapid and sensitive UPLC-MS/MS method for determination of simotinib in human plasma. The sample preparation procedure involved a simple protein precipitation with methanol. The total LC analysis time per injection was 4 min with a flow rate of 0.2 mL/min. The recovery was greater than 90%, and no significant matrix effect was observed. The assay was validated over the concentration range of 1-1000 ng/mL. The intra- and inter-day precision and accuracy of the quality control samples at low, medium, and high concentration levels showed≤ 9.3% relative standard deviation (RSD) and -2.5% to 2.9% relative errors (RE). The method was successfully applied to perform plasma pharmacokinetic studies of simotinib in a cancer patient after oral administration.Chapter 2:Clinical pharmacokinetics, safety and tolerability studies of simotinib in advanced lung cancer patients. The single and multiple pharmacokinetic studies were simultaneously conducted in this open label and single center phase I trial. A total of 21 patients were enrolled and given oral simotinib. The concentration-time curve declined biphasicly from maximum concentration after single administration, and the drug exposure increased with the dose proportionately from 200 mg to 650 mg. Aaccumulation was not significant after multiple oral administration on day 15 between 200-650 mg, and a certain degree of absorption saturation was observed between 300～ 650 mg. Oral simotinib was generally well tolerated. The most frequent treatment-related adverse events were rash, diarrhea and a decrease in white blood cells. The MTD was not reached. Simotinib showed positive clinical anti-tumor activities in advanced NSCLC patients with EGFR mutation.