A phase 1 study of the irreversible FLT3 inhibitor FF-10101 in relapsed or refractory acute myeloid leukemia.

ABSTRACT: FLT3 tyrosine kinase inhibitors (TKIs) have clinical efficacy for patients with FLT3-mutated AML (acute myeloid leukemia), but their impact is limited by resistance in the setting of monotherapy and by tolerability problems when used in combination therapies. FF-10101 is a novel compound that covalently binds to a cysteine residue near the active site of FLT3, irreversibly inhibiting receptor signaling. It is effective against most FLT3 activating mutations, and, unlike other inhibitors, is minimally vulnerable to resistance induced by FLT3 ligand. We conducted a phase 1 dose escalation study of oral FF-10101 in patients with relapsed and/or refractory AML, the majority of whom harbored FLT3-activating mutations and/or had prior exposure to FLT3 inhibitors. Fifty-four participants enrolled in cohorts receiving doses ranging from 10 to 225 mg per day and 50 to 100 mg twice daily (BID). The dose limiting toxicities were diarrhea and QT prolongation. Among 40 response-evaluable participants, the composite complete response rate was 10%, and the overall response rate (including partial responses) was 12.5%, including patients who had progressed on gilteritinib. Overall, 56% of participants had prior exposure to FLT3 inhibitors. The recommended phase 2 dose was 75 mg BID. FF-10101 potentially represents a next-generation advance in the management of FLT3-mutated AML. This trial was registered at www.ClinicalTrials.gov as #NCT03194685.

A phase 1/2a safety, pharmacokinetics, and efficacy study of the novel nucleoside analog FF-10502-01 for the treatment of advanced solid tumors.

BACKGROUND: The nucleoside FF-10502-01, structurally similar to but with different biologic effects than gemcitabine, shows promising activity both alone and combined with cisplatin in preclinical gemcitabine-resistant tumor models. We conducted an open-label, single-arm, 3 + 3 first-in-human trial to explore the safety, tolerability, and antitumor activity of FF-10502-01 in patients with solid tumors. METHODS: Patients with inoperable metastatic tumors refractory to standard therapies were enrolled. Escalating intravenous FF-10502-01 doses (8-135 mg/m2 ) were administered weekly for 3 weeks in 28-day cycles until progressive disease or unacceptable toxicity was observed. Three expansion cohorts were subsequently evaluated. RESULTS: A phase 2 dose of 90 mg/m2 was determined after evaluating 40 patients. Dose-limiting toxicities included hypotension and nausea. Phase 2a enrolled patients with cholangiocarcinoma (36), gallbladder cancer (10), and pancreatic/other tumors (20). Common adverse events were grade 1-2 rash, pruritus, fever, and fatigue. Grade 3 or 4 hematologic toxicities were observed at low incidences, including thrombocytopenia (5.1%) and neutropenia (2%). Confirmed partial responses (PRs) occurred in five patients with gemcitabine-refractory tumors, including three with cholangiocarcinoma and one each with gallbladder and urothelial cancer. Median progression-free and overall survival rates in patients with cholangiocarcinoma were 24.7 and 39.1 weeks, respectively. Prolonged progression-free survival in patients with cholangiocarcinoma was associated with BAP1 and PBRM1 mutations. CONCLUSION: FF-10502-01 was well tolerated with manageable side effects and limited hematologic toxicity. Durable PRs and disease stabilizations were observed in heavily pretreated biliary tract patients who had received prior gemcitabine. FF-10502-01 is distinct from gemcitabine and may represent an effective therapy.

Bayesian analysis of the association between effective strategies of multimodal nonpharmacological intervention and characteristics of cognitive function in nursing home residents with cognitive impairment: A cross-sectional study.

The cognitive function of nursing home (NH) residents with cognitive impairment (CI) tends to decline over time. An effective multimodal non-pharmacological intervention (MNPI) strategy is needed to improve the cognitive function of NH residents with CI.The aim of this study was to clarify the cognitive function characteristics of NH residents with CI in whom a non-pharmacological intervention (NPI) can be implemented, consisting of MNPI using a Bayesian analysis, and to incorporate suggestions to make the MNPI strategy as effective as possible.This study had a cross-sectional design. The 61 subjects were selected from the residents of 5 NHs, of whom 90.16% were female, and the mean (standard deviation) age was 87.20 ±â€Š6.90. Analyses were performed using a hierarchical Bayesian model, and the global and specific cognitive functions as assessed by the Japanese version of the Neurobehavioral Cognitive Status Examination were the response variables. Three types of NPI (cognitive enhancement NPI, physical NPI, psychological and psychosocial NPI), and activities of daily living (ADL), as assessed by the Barthel index, were the explanatory variables.Cognitive enhancement NPI was revealed to have no association with any cognitive function. Physical NPI was negatively associated with orientation [OR 0.31 (95% credible interval (95% CI) -2.33, -0.10)], comprehension [OR 0.16 (95% CI -2.78, -0.95)] and naming [OR 0.49 (95% CI -1.47, -0.02)]. Psychological and psychosocial NPI was positively associated with comprehension [OR 3.67 (95% CI 0.52, 2.13)]. Barthel index was positively associated with total Japanese version of the Neurobehavioral Cognitive Status Examination [OR 1.74 (95% CI 0.08, 2.12)], comprehension [OR 3.49 (95% CI 0.45, 4.67)], repetition [OR 10.07 (95% CI 0.53, 9.01)], naming [OR 2.24 (95% CI 0.07, 3.20)], and calculations [OR 18.82 (95% CI 2.71, 9.40)].The implementation of MNPI should be preceded by cognitive enhancement NPI and physical NPI. Providing ADL enhancing NPI in response to cognitive improvement may be an effective strategy. Providing cognitive enhancement NPI, physical NPI, psychological, and psychosocial NPI, as well as ADL-enhancing NPI at the same time, is also an effective strategy for subjects with mild dementia who are considered to have relatively high cognitive functions.

Phase I Study of P-cadherin-targeted Radioimmunotherapy with 90Y-FF-21101 Monoclonal Antibody in Solid Tumors.

PURPOSE: 90Y-FF-21101 is an Yttrium-90-conjugated, chimeric mAb that is highly specific for binding to human placental (P)-cadherin, a cell-to-cell adhesion molecule overexpressed and associated with cancer invasion and metastatic dissemination in many cancer types. We report the clinical activity of 90Y-FF-21101 in a first-in-human phase I study in patients with advanced solid tumors. PATIENTS AND METHODS: The safety and efficacy of 90Y-FF-21101 were evaluated in a phase I 3+3 dose-escalation study in patients with advanced solid tumors (n = 15) over a dose range of 5-25 mCi/m2. Dosimetry using 111In-FF-21101 was performed 1 week prior to assess radiation doses to critical organs. Patients who demonstrated clinical benefit received repeated 90Y-FF-21101 administration every 4 months. RESULTS: 111In-FF-21101 uptake was observed primarily in the spleen, kidneys, testes, lungs, and liver, with tumor uptake observed in the majority of patients. Organ dose estimates for all patients were below applicable limits. P-cadherin expression H-scores ranged from 0 to 242 with 40% of samples exhibiting scores ≥100. FF-21101 protein pharmacokinetics were linear with increasing antibody dose, and the mean half-life was 69.7 (±12.1) hours. Radioactivity clearance paralleled antibody clearance. A complete clinical response was observed in a patient with clear cell ovarian carcinoma, correlating with a high tumor P-cadherin expression. Stable disease was observed in a variety of other tumor types, without dose-limiting toxicity. CONCLUSIONS: The favorable safety profile and initial antitumor activity observed for 90Y-FF-21101 warrant further evaluation of this radioimmunotherapeutic (RIT) approach and provide initial clinical data supporting P-cadherin as a potential target for cancer treatment.

Skin stimulation by the fluid powered self-excited oscillation and its effect on the human body.

A novel fluid power actuator called Flat Ring Tube (FRT) is introduced in this paper. The mechanism of FRT is so simple that it only needs a urethane flat tube and water pressure power source. No valves or switches are required. Applying constant water pressure results in periodic oscillation of the tube. The frequency is proportional to the flow rate of water and inversely proportional to the tube length. By contacting the tube with a passively supported shaft, it rotates due to the periodic tube oscillation. This principle can also generate the linear driving force, when FRT is mounted so as to kick the ground. Such kind of performance can be also expected to stimulate the blood flow rate, when FRT touches on the skin of the human body appropriately. The experimental results showed us the developed wearable massage device could effectively improve both the circulation of the blood flow and the density of oxygen in blood, which resulted in let the people feel more comfortable than conventional massage devices.