Background Fms-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) mutations are common in acute myeloid leukemia (AML) and are associated with rapid relapse and short survival. In relapsed/refractory (R/R) AML, the clinical benefit of FLT3 inhibitors has been limited by rapid generation of resistance mutations, especially FLT3-D835. Gilteritinib is a potent, highly selective oral FLT3/AXL inhibitor with preclinical activity against FLT3-ITD and FLT3-D835 mutations. The aim of this Phase 1/2 study was to assess the safety, tolerability, and pharmacokinetic (PK) effects of gilteritinib in FLT3 mutation-positive (FLT3mut+) R/R AML. Methods This ongoing pharmacodynamic-driven Phase 1/2 trial (NCT02014558) enrolled subjects from October 2013 to August 2015 who were aged ≥18 years and were either refractory to induction therapy or had relapsed after achieving remission with prior therapy. Subjects were enrolled in one of seven dose-escalation or dose-expansion cohorts that were assigned to receive once-daily doses of oral gilteritinib (20, 40, 80, 120, 200, 300, or 450 mg). Cohort expansion was based on safety/tolerability, FLT3 inhibition in correlative assays, and antileukemic activity; the 120 and 200 mg dose cohorts were further expanded to include FLT3mut+ patients only. Safety and tolerability, and PK effects were the primary endpoints; antileukemic response was the main secondary endpoint. Safety and tolerability were assessed by monitoring dose-limiting toxicities and treatment-emergent adverse events, and safety assessments (eg, clinical laboratory evaluations, electrocardiograms) in the Safety Analysis Set. Findings A total of 252 adults with R/R AML, including 58 with wild-type FLT3 and 194 with FLT3 mutations (FLT3-ITD, n=162; FLT3-D835, n=16; FLT3-ITD and -D835, n=13; other, n=3), received oral gilteritinib (20–450 mg) once daily in one of seven dose-escalation (n=23) or dose-expansion (n=229) cohorts. Gilteritinib was well tolerated in this heavily pretreated population; Grade 3 diarrhea and hepatic transaminase elevation limited dosing above 300 mg/d. The most common Grade 3/4 adverse events were febrile neutropenia (39%; n=97/252), anemia (24%; n=61/252), thromobocytopenia (13%; n=33/252), sepsis (11%; n=28/252), and pneumonia (11%; n=27/252). Serious adverse events in ≥5% of patients were febrile neutropenia (31%; n=78/252), progressive disease (17%; n=43/252), sepsis (14%; n=36/252), pneumonia (11%; n=27/252), and acute renal failure (10%; n=25/252), pyrexia (8%; n=21/252), bacteremia (6%; n=14/252), and respiratory failure (6%; n=14/252). Gilteritinib demonstrated consistent, potent inhibition of FLT3 phosphorylation at doses ≥80 mg/d in correlative assays. While responses were observed across all dose levels regardless of FLT3 mutation status (overall response rate [ORR]=40%), response rate was improved in FLT3mut+ patients at doses ≥80 mg/d (ORR=52%). Among patients with FLT3-ITD, the additional presence of FLT3-D835 did not alter response rate; patients with only FLT3-D835 respond...

Purpose: OSI-7904L is a liposomal formulation of a potent noncompetitive thymidylate synthase inhibitor (TSI) that does not require polyglutamation for activity. This phase I study was done to establish the safety, tolerability, maximum tolerated dose, recommended dose, and pharmacokinetics of OSI-7904L in patients with advanced solid tumors refractory to standard therapy. Design: OSI-7904L was given as a 30-minute i.v. infusion every 21 days to 31patients at eight dose levels from 0.4 to 15.0 mg/m 2 , using three patients per dose level, up to 10 patients at the recommended dose. Baseline plasma homocysteine and 2V -deoxyuridine and genotype polymorphism were measured as potential predictors of biological activity. Results: Minimal toxicity was reported up to 9.6 mg/m 2 , but dose-limiting toxicity was seen in both patients at 15 mg/m 2 including stomatitis, fatigue, tachyarrhythmia, rash and hand-foot syndrome, diarrhea, and fatal neutropenic sepsis. Other toxicity such as nausea and vomiting was mild or moderate.This resulted in the investigation of an intermediate dose level of 12 mg/m 2 , identified as the recommended dose for phase II studies. Prolonged disease stabilization was reported in 11of 31heavily pretreated patients. Pharmacokinetic data indicate that this liposomal formulation alters the disposition properties of the parent drug resulting in a prolonged plasma residence time. Conclusions: OSI-7904L given as a 30-minute i.v. infusion every 21 days is feasible and well tolerated at the recommended phase II dose of 12 mg/m 2 . The main toxicities are rash, pruritis, lethargy, stomatitis, and myelosuppression. Observed toxicities were predictable and characteristic forTSIs.Thymidylate synthase is the rate-limiting enzyme in the biosynthesis of DNA catalyzing the methylation of dUMP to TMP, an essential precursor for DNA synthesis (1). Because thymidine nucleotides are used exclusively for synthesis of DNA, thymidylate synthase is an important target for anticancer therapy. Thymidylate synthase inhibitors (TSI) such as members of the fluoropyrimidine family [5-fluorouracil (5-FU), capecitabine, UFT, and S-1 or newer antifolates such as raltitrexed and pemetrexed] have shown efficacy in colon, breast, mesothelioma, and non -small cell lung carcinomas (2 -10). Resistance to available TSIs occurs via several mechanisms, including (i) increased gene expression resulting in elevated enzyme levels, (ii) reduced polyglutamation due to decreased activity or lower levels of folypolyglutamate synthase, or (iii) reduction of fluoropyrimidine drug levels by increased metabolism by dihydropyrimidine dehydrogenase. There is therefore a strong rationale to develop new potent TSIs that circumvent those mechanisms of resistance.OSIis a potent TSI with an inhibition constant (K i ) of 90 pmol/L. Although structurally related to the folate cofactor, OSI-7904 is a noncompetitive inhibitor and its binding to thymidylate synthase in the ternary complex with dUMP is unaffected by 5,10-methylenetetrahydrofolate (11,...

Overexpression of human epidermal growth factor receptor (HER/EGFR) is associated with various tumors, including ependymomas. To investigate whether EGFR inhibition was of benefit in pediatric patients with recurrent ependymoma, a multi-center, randomized, open-label, phase 2 study of oral erlotinib versus oral etoposide was undertaken. Twenty-five patients were randomized to receive erlotinib 85 mg/m(2) daily or etoposide 50 mg/m(2)/day for 21 consecutive days followed by a 7-day rest period. Courses were repeated every 28 days. In the erlotinib arm, no patient achieved a complete, partial, or minor response, and only 2 (15.4 %) patients showed stable disease as their best response. In the etoposide arm, 2 patients (16.7 %) demonstrated partial responses, 1 (8.3 %) patient demonstrated a minor response, and 2 (16.7 %) showed prolonged stable disease, for a prolonged disease control rate of 41.7 %. Three patients received at least nine cycles of etoposide (range 9-24 cycles) before discontinuing at the request of the physician and/or family. Four patients who failed etoposide in this study received erlotinib in a companion single arm study; none had a response. The futility criteria were met at the second interim analysis, and both studies were discontinued. Pharmacokinetics of erlotinib were similar to previous observations in pediatric patients. Overall, erlotinib was well tolerated and safety was consistent with its established profile in adults. The overall risk-benefit profile does not support the use of erlotinib in pediatric patients with recurrent ependymoma, whereas single-agent etoposide appears to have efficacy in a subset of patients.

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