Study design
DLTs, neutropenia, fever, toxicity, PD, Cancer
ADVERSE EVENT, DISEASE PROGRESSION, NON-INFECTIOUS PNEUMONIA, NEUTROPENIA, ADVERSE EVENTS, THROMBOCYTOPENIA, DISEASE, SOLID TUMORS, ABNORMAL RENAL FUNCTION, ADVERSE EFFECT, CANCER
This was a single-center, open-label, phase I study to determine the safety, PK, the maximum tolerated dose (MTD), and preliminary efficacy of LXI-15029 monotherapy in Chinese patients with advanced malignant solid tumors. LXI-15029 capsules (provided by Shandong Luoxin Pharmaceutical Group Co., Ltd.) were administered orally twice daily (BID) under the fasting state. A conventional 3 + 3 dose escalation design was used to explore the MTD. At least three participants with evaluable dose-limiting toxicity (DLT) and tolerability were included in each dose group. According to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0.3 (NCI-CTCAE 4.0.3), DLTs were defined as adverse events (AEs) or abnormal laboratory values unrelated to disease progression and reasonably likely to be related to the investigational product within 30 days after the first dose (cycle 1), as grade 2 non-infectious pneumonia or abnormal renal function (increased creatinine), any grade 3 non-hematological AEs, grade 3 neutropenia with fever or thrombocytopenia, or any grade 4 hematological AEs.At least three participants were enrolled in each cohort. Participants were enrolled in the next dose cohort if no DLT was observed within 30 days after the first dose. If one case of DLT occurred, three additional participants would be enrolled in this cohort. Then, if no additional DLT occurred, participants were enrolled in the next higher-dose cohort. If additional DLTs occurred, the current dose was considered intolerable and enrollment in this cohort was discontinued. The decision to explore intermediate doses or define the previous dose level as the MTD was made by the Safety Review Committee (SRC). Participants with unevaluable DLT were replaced by another participant with evaluable DLT.The starting dose of LXI-15029 as a non-cytotoxic antitumor drug in this first-in-human phase I clinical trial was calculated as ≥ 1/5 of the no observed adverse effect level (NOAEL) in non-rodent animals, obtained in preclinical trials. The participants received LXI-15029 monotherapy in each dose cohort and multiple doses of LXI-15029 for 4 weeks (cycle 1) following a 1-day washout period after a single dose of LXI-15029. The participants continued therapy with LXI-15029 if good safety and tolerability were assessed by the investigators after one cycle of treatment. Five ascending dose groups of LXI-15029 BID (10, 20, 40, 60, and 80 mg) were planned to be evaluated, with 3 to 6 evaluable patients who received LXI-15029 monotherapy in each cohort. The following cohort was given dose escalation until the intolerable dose. The investigators could select higher doses (i.e., 110 and 150 mg, with reference to the modified Fibonacci method) if the 80 mg BID dose was well tolerated. The participants continued therapy with LXI-15029 until progressive disease (PD), the occurrence of intolerable toxicity, or withdrawal of consent.All interventions in this study were conducted in accordance with the Declaration of Helsinki guidelines of the International Conference for Harmonization/Good Clinical Practice guidelines and approved by the Independent Ethics Committee (IEC) of the National Cancer Center/Cancer Hospitals. Written informed consent was obtained from all study participants before enrollment. The first registration at ClinicalTrial.gov is 24/04/2017 with full registration number NCT03125746.