Trial design: statistical methods
toxicity, toxicities, DLTs
DISEASE PROGRESSION
In this phase 1 trial, evaluation of lorlatinib DLs followed the 3 + 3 dose-escalation design in each of the three cohorts separately. Hence, at each DL during the escalation portion, the plan was to enroll either three or six patients who were evaluable for DLT, with six DLT-evaluable patients at the maximum tolerated dose (MTD) or highest DL planned. In this trial, two exceptions occurred. In cohort A1 at DL4, because two of the first five patients were inevaluable for DLT assessment (due to disease progression before starting the second course, although neither had experienced DLT in the first course), the Study Management Committee (SMC) decided to expand DL4 to two additional patients to further evaluate later course toxicities before escalating to DL5. Once none of the first five DLT-evaluable patients experienced DLT during the DLT observation period, the SMC decided to open DL5 (Table All DLTs in the first course of therapy and CNS DLTs through the second course of therapy had an impact on decisions regarding dose escalation due to delayed CNS toxicities observed in the adult lorlatinib trialsStandard statistical methods were used to summarize data; exact Clopper–Pearson CIs are reported for binomial probability or corresponding percentages. Analyses were performed with SAS software version 9.4. The cutoff for toxicity and response data for patients reported in this manuscript was 13 September 2022.