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Background and Objective Gilteritinib is a novel, highly selective tyrosine kinase inhibitor approved in the USA, Canada, Europe, Brazil, Korea, and Japan for the treatment of FLT3 mutation-positive acute myeloid leukemia. This article describes the clinical pharmacokinetic profile of gilteritinib. Methods The pharmacokinetic profile of gilteritinib was assessed from five clinical studies. Results Dose-proportional pharmacokinetics was observed following once-daily gilteritinib administration (dose range 20–450 mg). Median maximum concentration was reached 2–6 h following single and repeat dosing of gilteritinib; mean elimination half-life was 113 h. Elimination was primarily via feces. Exposure to gilteritinib was comparable under fasted and fed conditions. Gilteritinib is primarily metabolized via cytochrome P450 (CYP) 3A4; coadministration of gilteritinib with itraconazole (a strong P-glycoprotein inhibitor and CYP3A4 inhibitor) or rifampicin (a strong P-glycoprotein inducer and CYP3A inducer) significantly affected the gilteritinib pharmacokinetic profile. No clinically relevant interactions were observed when gilteritinib was coadministered with midazolam (a CYP3A4 substrate) or cephalexin (a multidrug and toxin extrusion 1 substrate). Unbound gilteritinib exposure was similar between subjects with hepatic impairment and normal hepatic function. Conclusions Gilteritinib exhibits a dose-proportional pharmacokinetic profile in healthy subjects and in patients with relapsed/refractory acute myeloid leukemia. Gilteritinib exposure is not significantly affected by food. Moderate-to-strong CYP3A inhibitors demonstrated a significant effect on gilteritinib exposure. Coadministration of gilteritinib with CYP3A4 or multidrug and toxin extrusion 1 substrates did not impact substrate concentrations. Unbound gilteritinib was comparable between subjects with hepatic impairment and normal hepatic function; dose adjustment is not warranted for patients with hepatic impairment. Clinical Trial Registration NCT02014558, NCT02456883, NCT02571816.

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. Gilteritinib, a novel, highly specific, potent fms‐like tyrosine kinase 3/AXL inhibitor, has demonstrated antileukemic activity in patients with relapsed/refractory (R/R) acute myeloid leukemia (AML). This phase 1 study evaluated the safety/tolerability of once‐daily gilteritinib in a Japanese R/R AML patient population. Gilteritinib was well tolerated and induced antileukemic responses in Japanese R/R AML patients.

Metastatic renal-cell carcinoma has an extremely poor prognosis, with a median survival of less than one year. 1 , 2 Systemic treatment with cytotoxic chemotherapy is usually ineffective. 3 The introduction of interleukin-2 and interferon alfa for the treatment of metastatic disease provided, for the first time, therapy that induced complete and durable responses. 4 , 5 Although some patients who have a complete response to such cytokine-based therapy survive for long periods, the overall rate of response to these agents, either alone or in combination, is usually less than 20 percent. 6 Renal-cell carcinoma is unusual among solid tumors because of its immunogenic properties. 7 , . . .

The FLT3 inhibitor gilteritinib has clinical activity in patients with FLT3‐mutated (FLT3mut+) relapsed/refractory (R/R) acute myeloid leukemia (AML). The impact of FLT3 mutation clearance and the achievement of composite complete remission (CRc) and complete remission/complete remission with partial hematologic recovery (CR/CRh) on overall survival (OS) in patients with FLT3mut+ R/R AML treated with single‐agent gilteritinib in a phase 1/2 trial were evaluated. Using next‐generation sequencing, a FLT3‐ITD variant allele frequency of ≤10−4 was used to define FLT3‐ITD clearance in patients with no morphologic leukemia (ie, CRc). A total of 108 patients with FLT3‐ITD‐positive (FLT3‐ITD+) R/R AML were analyzed; 95 of these patients had received ≥80‐mg/day gilteritinib. Ten of the 95 patients had FLT3‐ITD clearance; eight of these 10 patients achieved CRc and were considered negative for measurable residual disease. There was a trend toward longer OS in patients who attained CRc with FLT3‐ITD clearance (131.4 weeks) versus those who achieved CRc and did not have FLT3‐ITD clearance (n = 41; 43.3 weeks; HR = 0.416; p = 0.066). Among patients treated with ≥80‐mg/day gilteritinib who achieved CR/CRh (n = 24), seven had FLT3‐ITD clearance. Among patients who received 120‐mg/day gilteritinib, those who achieved CR/CRh had a longer median OS (70.6 weeks) and higher 52‐week survival probability (66.7%) than patients who did not achieve CR/CRh (n = 71; median OS, 41.7 weeks; 52‐week survival probability, 20.2%). Overall, these data suggest that gilteritinib can induce deep molecular responses in patients with FLT3‐ITD+ R/R AML, and in the setting of CRc or CR/CRh, these responses may be associated with prolonged survival. In patients with FLT3‐mutated relapsed/refractory acute myeloid leukemia, the FLT3 inhibitor gilteritinib induced deep molecular responses characterized by FLT3–internal tandem duplication (FLT3‐ITD) mutation clearance. Among patients who achieved morphologic remission with gilteritinib therapy, FLT3‐ITD mutation clearance was associated with a trend toward longer survival.

Background ASP3026 is a second-generation anaplastic lymphoma kinase (ALK) inhibitor that has potent in vitro activity against crizotinib-resistant ALK -positive tumors. This open-label, multicenter, first-in-human phase I study ( NCT01284192 ) assessed the safety, pharmacokinetic profile, and antitumor activity of ASP3026. Methods Advanced solid tumor patients received oral ASP3026 in 3 + 3 dose-escalation cohorts at doses of 25–800 mg once daily in 28-day cycles. The endpoints were to identify the maximum tolerated dose (MTD), the recommended phase II dose (RP2D), and the pharmacokinetic profile of ASP3026. A phase Ib expansion cohort enrolled patients with metastatic, crizotinib-resistant ALK -positive solid tumors at the RP2D, and response was evaluated by RECIST 1.1. Results The dose-escalation cohort enrolled 33 patients, including three crizotinib-resistant, ALK -positive patients, and the dose-expansion cohort enrolled another 13 crizotinib-resistant, ALK -positive non-small cell lung cancer (NSCLC) patients. ASP3026 demonstrated both linear pharmacokinetics and dose-proportional exposure for area under the plasma concentration–time curve and maximum concentration observed with a median terminal half-life of 35 h, supporting the daily dosing. Grade 3 rash and elevated transaminase concentrations were dose-limiting toxicities observed at 800 mg; hence, 525 mg daily was the MTD and RP2D. The most common treatment-related adverse events were nausea (38 %), fatigue (35 %), and vomiting (35 %). Among the 16 patients with crizotinib-resistant ALK -positive tumors (15 NSCLC, 1 neuroblastoma), eight patients achieved partial response (overall response rate 50 %; 95 % confidence interval 25–75 %) and seven patients (44 %) achieved stable disease. Conclusions ASP3026 was well tolerated and had therapeutic activity in patients with crizotinib-resistant ALK -positive advanced tumors. Trial registration ClinTrials.gov: NCT01284192

Oral use of the selective FLT3 kinase inhibitor gilteritinib in patients who had relapsed or refractory acute myeloid leukemia with FLT3 mutations led to a median overall survival of 9.3 months (vs. 5.6 months with standard chemotherapy) and complete remission with full or partial hematologic recovery in 34.0% of patients (vs. 15.3%).

Internal tandem duplication mutations in FLT3 are common in acute myeloid leukaemia and are associated with rapid relapse and short overall survival. The clinical benefit of FLT3 inhibitors in patients with acute myeloid leukaemia has been limited by rapid generation of resistance mutations, particularly in codon Asp835 (D835). We aimed to assess the highly selective oral FLT3 inhibitor gilteritinib in patients with relapsed or refractory acute myeloid leukaemia. In this phase 1–2 trial, we enrolled patients aged 18 years or older with acute myeloid leukaemia who either were refractory to induction therapy or had relapsed after achieving remission with previous treatment. Patients were enrolled into one of seven dose-escalation or dose-expansion cohorts assigned to receive once-daily doses of oral gilteritinib (20 mg, 40 mg, 80 mg, 120 mg, 200 mg, 300 mg, or 450 mg). Cohort expansion was based on safety and tolerability, FLT3 inhibition in correlative assays, and antileukaemic activity. Although the presence of an FLT3 mutation was not an inclusion criterion, we required ten or more patients with locally confirmed FLT3 mutations (FLT3mut+) to be enrolled in expansion cohorts at each dose level. On the basis of emerging findings, we further expanded the 120 mg and 200 mg dose cohorts to include FLT3mut+ patients only. The primary endpoints were the safety, tolerability, and pharmacokinetics of gilteritinib. Safety and tolerability were assessed in the safety analysis set (all patients who received at least one dose of gilteritinib). Responses were assessed in the full analysis set (all patients who received at least one dose of study drug and who had at least one datapoint post-treatment). Pharmacokinetics were assessed in a subset of the safety analysis set for which sufficient data for concentrations of gilteritinib in plasma were available to enable derivation of one or more pharmacokinetic variables. This study is registered with ClinicalTrials.gov, number NCT02014558, and is ongoing. Between Oct 15, 2013, and Aug 27, 2015, 252 adults with relapsed or refractory acute myeloid leukaemia received oral gilteritinib once daily in one of seven dose-escalation (n=23) or dose-expansion (n=229) cohorts. Gilteritinib was well tolerated; the maximum tolerated dose was established as 300 mg/day when two of three patients enrolled in the 450 mg dose-escalation cohort had two dose-limiting toxicities (grade 3 diarrhoea and grade 3 elevated aspartate aminotransferase). The most common grade 3–4 adverse events irrespective of relation to treatment were febrile neutropenia (97 [39%] of 252), anaemia (61 [24%]), thrombocytopenia (33 [13%]), sepsis (28 [11%]), and pneumonia (27 [11%]). Commonly reported treatment-related adverse events were diarrhoea (41 [16%] of 252]), fatigue (37 [15%]), elevated aspartate aminotransferase (33 [13%]), and elevated alanine aminotransferase (24 [10%]). Serious adverse events occurring in 5% or more of patients were febrile neutropenia (78 [31%] of 252; five related to treatment), progressive disease (43 [17%]), sepsis (36 [14%]; two related to treatment), pneumonia (27 [11%]), acute renal failure (25 [10%]; five related to treatment), pyrexia (21 [8%]; three related to treatment), bacteraemia (14 [6%]; one related to treatment), and respiratory failure (14 [6%]). 95 people died in the safety analysis set, of which seven deaths were judged possibly or probably related to treatment (pulmonary embolism [200 mg/day], respiratory failure [120 mg/day], haemoptysis [80 mg/day], intracranial haemorrhage [20 mg/day], ventricular fibrillation [120 mg/day], septic shock [80 mg/day], and neutropenia [120 mg/day]). An exposure-related increase in inhibition of FLT3 phosphorylation was noted with increasing concentrations in plasma of gilteritinib. In-vivo inhibition of FLT3 phosphorylation occurred at all dose levels. At least 90% of FLT3 phosphorylation inhibition was seen by day 8 in most patients receiving a daily dose of 80 mg or higher. 100 (40%) of 249 patients in the full analysis set achieved a response, with 19 (8%) achieving complete remission, ten (4%) complete remission with incomplete platelet recovery, 46 (18%) complete remission with incomplete haematological recovery, and 25 (10%) partial remission. Gilteritinib had a favourable safety profile and showed consistent FLT3 inhibition in patients with relapsed or refractory acute myeloid leukaemia. These findings confirm that FLT3 is a high-value target for treatment of relapsed or refractory acute myeloid leukaemia; based on activity data, gilteritinib at 120 mg/day is being tested in phase 3 trials. Astellas Pharma, National Cancer Institute (Leukemia Specialized Program of Research Excellence grant), Associazione Italiana Ricerca sul Cancro.

Background and Objective Anaplastic lymphoma kinase gene rearrangements ( ALKr ) resulting in EML4–ALK proteins occur in a subset of solid tumors and are targeted by ALK inhibitors. Given the development of drug resistance to ALK inhibitors, ALK inhibitors with different kinase selectivity are required. Methods This phase I, non-randomized, open-label study evaluated the dose-limiting toxicity (DLT), safety, pharmacokinetics, and antitumor activity of ASP3026, a second-generation ALK inhibitor, in Japanese patients with solid tumors. Between 1 June 2011 and 20 January 2014, 29 patients received different daily doses of ASP3026 in the escalation (25 mg, n  = 3; 50 mg, n  = 3; 75 mg, n  = 3; 125 mg, n  = 4; 200 mg, n  = 3; or 325 mg, n  = 7) and expansion (200 mg, n  = 6) cohorts. Results Three patients had DLTs at the 325-mg dose: cataract exacerbation, increased aspartate transaminase and alanine transaminase, and impaired hepatic function (all Grade 3 severity). Thus, the maximum tolerated dose was 200 mg. The treatment-emergent adverse event incidence was 100%; the most common events were nausea ( n  = 8, 27.6%), decreased appetite ( n  = 10, 34.5%), and fatigue ( n  = 9, 31.0%) of mild or moderate severity. Six patients were positive for ALK protein and three had ALKr . Two patients achieved partial responses: one with Ewing sarcoma (75-mg dose group) and one with an ALKr -positive inflammatory myofibroblastic tumor (125-mg dose group). Conclusion ASP3026 at a 200-mg dose may provide therapeutic benefit for patients with solid tumors, with a tolerable safety profile. Clinical Trial registration This study is registered at ClinicalTrials.gov under the identifier NCT01401504 on July 25, 2011

Almost half of the deaths that result from myelodysplastic syndromes are due to cytopenia associated with bone marrow failure. Treatment is mostly supportive care. To determine whether treatment with antithymocyte globulin improves cytopenia and reverses dependence on red blood cell transfusions in patients with myelodysplastic syndromes. Single-treatment, prospective study. Tertiary referral center. 61 patients with myelodysplastic syndromes. Antithymocyte globulin, 40 mg/kg of body weight, given daily for 4 days. Evaluation of bone marrow, blood counts, transfusions, progression, and survival for a median of 30 months (range, 1 to 88 months). Within 8 months of treatment, 21 of 61 patients (34%) no longer required red blood cell transfusions. This independence from transfusions was maintained in 17 responders (81%) for a median of 36 months (range, 3 to 72 months). Ten of 21 patients (47.5%) with severe thrombocytopenia had sustained platelet count increases, and 6 of 11 patients (55%) with severe neutropenia had sustained neutrophil counts of greater than 1 x 10(9) cells/L. Characteristics favorable for response were younger patient age (P = 0.005) and lower platelet counts (P = 0.038). One of the 21 responders (5%) and 22 of the 40 nonresponders (55%) died before the end of the study (P = 0.008). One of the 21 responders (5%) and 13 of the 40 nonresponders (33%) had disease progression (P = 0.086). Although this study was a nonrandomized, single-treatment study, 34% of patients treated with antithymocyte globulin became transfusion independent. Response was associated with a statistically significant longer survival and an almost significant decreased time to disease progression. Treatment with antithymocyte globulin did not seem to be detrimental because historical overall median survival times were similar to those of nonresponders.