Gilteritinib, a novel, highly specific, potent fms‐like tyrosine kinase 3/AXL inhibitor, demonstrated antileukemic activity in patients with relapsed/refractory (R/R) acute myeloid leukemia (AML). In this open‐label phase 1 study (NCT02181660), Japanese patients (aged ≥18 years) with R/R AML received once‐daily gilteritinib, escalating from 20 to 300 mg/d. Primary endpoints were safety/tolerability, including the maximum tolerated dose (MTD) and the recommended dose (RD); secondary endpoints were antileukemic activity and pharmacokinetics (PK). Twenty‐four Japanese patients with R/R AML received once‐daily oral gilteritinib in 1 of 6 dose‐escalation cohorts (20, 40, 80, 120, 200, and 300 mg/d). Gilteritinib was well tolerated. The MTD was 200 mg/d; dose‐limiting toxicities were grade 3 tumor lysis syndrome (120 mg/d; n = 1); and grade 3 elevated blood lactate dehydrogenase, amylase, blood creatine phosphokinase levels, and syncope (all n = 2; 300 mg/d). The RD was 120 mg/d. The most common drug‐related grade ≥3 adverse events were thrombocytopenia (n = 4 [16.7%]) and increased blood creatine phosphokinase (n = 3 [12.5%]). Gilteritinib had a dose‐proportional PK profile. Among patients with mutated fms‐like tyrosine kinase 3, the overall response rate (ORR) was 80% (n = 4 of 5; complete remission [CR] with incomplete platelet recovery, 1 [20%]; CR with incomplete hematologic recovery, 2 [40%]; partial remission (PR), 1 [20%]). Among patients with wild‐type fms‐like tyrosine kinase 3, ORR was 36.4%; (n = 4 of 11; CR, 1 [9.1%]; CR with incomplete platelet recovery, 2 [18.2%]; PR, 1 [9.1%]). In conclusion, gilteritinib was well tolerated and demonstrated antileukemic activity in a Japanese R/R AML population.

Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?  In Japan, this is the first comprehensive study on expanded access clinical trials (EACTs). WHAT QUESTION DID THIS STUDY ADDRESS?  This study clarified the current status and issues with EACTs conducted to date. WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?  Differences and similarities between the compassionate use systems in Japan and the United States and the European Union. HOW MIGHT THIS CHANGE CLINICAL PHARMA-COLOGY OR TRANSLATIONAL SCIENCE? It is important to get patients to access really good medicines as early as possible by solving problems. The authors proposed a single-patient EACT system.

Background Until recently, no effective targeted therapies for FLT3-mutated (FLT3mut+) relapsed/refractory (R/R) acute myeloid leukemia (AML) were available in Japan. The FLT3 inhibitor, gilteritinib, was approved in Japan for patients with FLT3mut+ R/R AML based on the phase 3 ADMIRAL trial, which demonstrated the superiority of gilteritinib over salvage chemotherapy (SC) with respect to overall survival (OS; median OS, 9.3 vs 5.6 months, respectively; hazard ratio, 0.64 [95% confidence interval 0.49, 0.83]; P < 0.001). Methods We evaluated the Japanese subgroup (n = 48) of the ADMIRAL trial, which included 33 patients randomized to 120-mg/day gilteritinib and 15 randomized to SC. Results Median OS was 14.3 months in the gilteritinib arm and 9.6 months in the SC arm. The complete remission/complete remission with partial hematologic recovery rate was higher in the gilteritinib arm (48.5%) than in the SC arm (13.3%). After adjustment for drug exposure, fewer adverse events (AEs) occurred in the gilteritinib arm than in the SC arm. Common grade ≥ 3 AEs related to gilteritinib were febrile neutropenia (36%), decreased platelet count (27%), and anemia (24%). Conclusion Findings in Japanese patients are consistent with those of the overall ADMIRAL study population.

samples was sequenced on NextSeq platform at 500X and 1500X. Data analysis was performed with an optimized in-house bioinformatics pipeline to reduce background noise in variant calling. Variant allele frequency (VAF) was limited to 5%. Variants were ranked attending to VAF. Known pathogenic variants were determined based on our knowledge somatic variant database. Statistical analysis included log-rank test, Fischer's exact test and Kaplan-Meier curves.Results: All patients presented at least one cancer somatic mutation (CSM) trackable by ctDNA analysis. Known pathogenic mutations were found in only 134 (89.3%). The mean number of CSM versus pathogenic mutations were 14 and 2, respectively. We identified 12 recurrently mutated genes which did not concur when we considered both known and unknown CSM. In patients harboring only one pathogenic variant (29.3%), 34% of times did not coincide with the somatic variant with the highest VAF. In those with 2 pathogenic variants (60%), just 12.2% coincided with the highest CSM. After a median follow-up of 35.8 months, 19 patients recurred.Conclusions: In localized CC, when only known pathogenic mutations were studied, almost 11% of cases could not be tracked. In contrast, targeted sequencing of matched tumor and WBCs samples revealed novel cancer CMS and increased the sensitivity to universally track MRD in plasma.Legal entity responsible for the study: Andrés Cervantes.