Safety and RP2D
somnolence, DLTs, hypersomnia, diarrhea, neuropathy, anxiety, anxiety/depression/somnolence/hypersomnia, hyperglycemia, weight gain, agitation/anxiety/mania, memory impairment, hypertriglyceridemia, hallucinations/insomnia, depression, agitation/neuropathy
HYPERSOMNIA, ELEVATED CHOLESTEROL, NEUROPATHY, HYPERGLYCEMIA, HYPERTRIGLYCERIDEMIA, EDEMA LIMBS
A summary of DLTs used to determine dose escalation (all DLTs in course 1 plus CNS DLTs through course 2) and delayed DLTs are presented in Table DLTs by cohort and DLa. Five patients were not evaluable for dose-escalation decisions (Fig. b. Grade 3 diarrhea in course 1 in one patient; grade 2 hallucinations/insomnia in course 3 in another patient.c. Grade 3 hyperglycemia in course 3 in one patient; grade 2 memory impairment in course 7 in another patient.d. Grade 2–4 agitation/anxiety/mania in course 1.e. Grade 2–4 delusions/psychosis/suicide attempt in course 2 that recurred in course 3 despite dose reduction.f. Grade 3 agitation/neuropathy in course 2 that recurred in course 3 despite dose reduction.g. Grade 2 edema limbs and neuropathy in course 4.h. Grade 2 anxiety/depression/somnolence/hypersomnia in course 3.*DLTs used for dose escalation include all DLTs occurring in course 1 and any CNS DLT through course 2.In cohort A2, 100 mg dose, no DLTs occurred in courses 1 and 2. One adult had lorlatinib held for grade 2 memory impairment (course 7) that met criteria for late DLT that resolved with dose hold (Extended Data Table In cohort B2, no DLTs were observed at DL4 or DL5 of lorlatinib in combination with fixed doses of topotecan/cyclophosphamide. A delayed DLT of grade 2 anxiety, depression, somnolence and hypersomnia occurred in a 12-year-old on DL5 requiring dose interruption but tolerated rechallenge at DL4, receiving a total of five courses. These data supported DL5, 115 mg/mOverall, the most common grade 1–4 treatment-related AEs for single-agent lorlatinib across all ages were hypertriglyceridemia (90%), weight gain (87%) and elevated cholesterol (79%) (Extended Data Table Real-time neurobehavioral screening identified 12 of 48 (25%) patients across all cohorts (A1, A2 and B2) who had baseline pre-therapy concerns in cognitive processing speed and working memory, yet only three of six patients who experienced a CNS DLT were detected as having baseline neurobehavioral concerns (Extended Data Table 