6 research outputs found
Brown ring formation and streak mottle, two distinct syndromes in lilies associated with complex infections of lily symptomless virus and tulip breaking virus
Randomized, Open-Label, Crossover Studies Evaluating the Effect of Food and Liquid Formulation on the Pharmacokinetics of the Novel Focal Adhesion Kinase (FAK) Inhibitor BIÂ 853520
Background: BI 853520 is a potent inhibitor of focal adhesion kinase and is currently under clinical development for the treatment of non-hematological malignancies. Objective: The objective of this study was to evaluate the effect of food and liquid dispersion on the pharmacokinetics of BIÂ 853520 in two open-label, crossover substudies. Patients and Methods: Sixteen patients with advanced solid tumors were enrolled in each substudy. The order of administration was randomized, and pharmacokinetic samples were collected for 48Â h after administration of a 200Â mg dose of BIÂ 853520. Lack of effect would be demonstrated if the 90% confidence interval (CI) of the ratio of the adjusted geometric mean (GMR) of the area under the plasma curve (area under the plasma concentrationâtime curve from time zero to the last quantifiable concentration at t z [AUC0-tz] and observed area under the plasma concentrationâtime curve extrapolated from time zero to infinity [AUC 0ââ,obs ]) and maximum plasma concentration (C max ) did not cross the 80â125% (bioequivalence) boundaries. Results: Adjusted GMRs (90% CIs) for the fed versus fasted state were 92.46% (74.24â115.16), 98.17% (78.53â122.74), and 87.34% (71.04â107.38) for AUC0-tz, AUC 0ââ,obs , and C max , respectively. Although the 90% CIs were not within bioequivalence limits for the food-effect study, the limited reductions in these pharmacokinetic parameters after administration with a high-fat meal are unlikely to be clinically relevant. Compared with a tablet, administration of BIÂ 853520 as a liquid dispersion did not strongly affect AUC0-tz, AUC 0ââ,obs , or C max , resulting in adjusted GMRs (90% CIs) of 1.00 (0.92â1.09), 0.98 (0.90â1.07), and 0.93 (0.86â1.01), respectively. Conclusions: These studies demonstrate that BIÂ 853520 can be given with no food restrictions, and as a liquid dispersion, without strongly impacting pharmacokinetics. These pharmacokinetic properties may help make BIÂ 853520 dosing more convenient and flexible, improving treatment compliance. Clinical trials registration: ClinicalTrials.gov identifier: NCT01335269
Phase I Study of BI 853520, an Inhibitor of Focal Adhesion Kinase, in Patients with Advanced or Metastatic Nonhematologic Malignancies
BACKGROUND: Overexpression/activation of focal adhesion kinase (FAK) in human malignancies has led to its evaluation as a therapeutic target. We report the first-in-human phase I study of BI 853520, a novel, potent, highly selective FAK inhibitor. OBJECTIVE: Our objectives were to identify the maximum tolerated dose (MTD), and to evaluate safety, pharmacokinetics (PK), pharmacodynamics (PD), biomarker expression, and preliminary activity. PATIENTS AND METHODS: The study comprised a standard 3â+â3 dose-escalation phase followed by an expansion phase in patients with selected advanced, nonhematologic malignancies. RESULTS: Thirty-three patients received BI 853520 in the dose-escalation phase; the MTD was 200 mg once daily (QD). Dose-limiting toxicities included proteinuria and fatigue, both of which were grade 3. Preliminary PK data supported QD dosing. In the expansion cohort, 63 patients received BI 853520 200 mg QD. Drug-related adverse events (AEs) inâ>â10% of patients included proteinuria (57%), nausea (57%), fatigue (51%), diarrhea (48%), vomiting (40%), decreased appetite (19%), and peripheral edema (16%). Most AEs were grade 1-2; grade 3 proteinuria, reported in 13 patients (21%), was generally reversible upon treatment interruption. Nineteen patients underwent dose reduction due to AEs, and three drug-related serious AEs were reported, none of which were fatal. Preliminary PD analysis indicated target engagement. Of 63 patients, 49 were evaluable; 17 (27%) achieved a best response of stable disease (4 with 150â+âdays), and 32 (51%) patients had progressive disease. CONCLUSIONS: BI 853520 has a manageable and acceptable safety profile, favorable PK, and modest antitumor activity at an MTD of 200 mg QD in patients with selected advanced nonhematologic malignancies. CLINICALTRIALS. GOV IDENTIFIER: NCT01335269
Phase 1 study of the pan-HER inhibitor dacomitinib plus the MEK1/2 inhibitor PD-0325901 in patients with KRAS-mutation-positive colorectal, non-small-cell lung and pancreatic cancer
BACKGROUND: Mutations in KRAS result in a constitutively activated MAPK pathway. In KRAS-mutant tumours existing treatment options, e.g. MEK inhibition, have limited efficacy due to resistance through feedback activation of epidermal growth factor receptors (HER). METHODS: In this Phase 1 study, the pan-HER inhibitor dacomitinib was combined with the MEK1/2 inhibitor PD-0325901 in patients with KRAS-mutant colorectal, pancreatic and non-small-cell lung cancer (NSCLC). Patients received escalating oral doses of once daily dacomitinib and twice daily PD-0325901 to determine the recommended Phase 2 dose (RP2D). (Clinicaltrials.gov: NCT02039336). RESULTS: Eight out of 41 evaluable patients (27 colorectal cancer, 11 NSCLC and 3 pancreatic cancer) among 8 dose levels experienced dose-limiting toxicities. The RP2D with continuous dacomitinib dosing was 15âmg of dacomitinib plus 6âmg of PD-0325901 (21 days on/7 days off), but major toxicity, including rash (85%), diarrhoea (88%) and nausea (63%), precluded long-term treatment. Therefore, other intermittent schedules were explored, which only slightly improved toxicity. Tumour regression was seen in eight patients with the longest treatment duration (median 102 days) in NSCLC. CONCLUSIONS: Although preliminary signs of antitumour activity in NSCLC were seen, we do not recommend further exploration of this combination in KRAS-mutant patients due to its negative safety profile
Evaluation of the Khorana, PROTECHT, and 5-SNP scores for prediction of venous thromboembolism in patients with cancer
Background: The Khorana score is a validated tool to identify cancer patients at higher risk of venous thromboembolism (VTE). Objective: We compared its predictive performance to that of the clinical PROTECHT and the polygenic 5-SNP scores in patients who participated in the Dutch CPCT-02Â study. Patients/methods: Data on VTE and its risk factors were retrospectively collected for 2729 patients with advanced stage solid tumors planned for systemic cancer treatment. Patients were followed for 6Â months. Overall discriminatory performance of the scores was evaluated by time-dependent c-indices. The scores were additionally evaluated dichotomously in competing risk models. Results: A total of 160 (5.9%) patients developed VTE during follow-up. Time-dependent c-indices at 6Â months for the Khorana, PROTECHT, and 5-SNP scores were 0.57 (95% confidence interval [CI]: 0.55â0.60), 0.60 (95% CI: 0.57â0.62), and 0.54 (95% CI: 0.51â0.57), respectively. The dichotomous scores classified 9.6%, 16.8%, and 9.5% as high-risk, respectively. VTE risk was about 2-fold higher among high-risk patients than low-risk patients for the Khorana (subdistribution hazard ratio [SHR] 1.9, 95% CI: 1.3â3.0), PROTECHT (SHR 2.1, 95% CI: 1.5â3.0), and 5-SNP scores (SHR 1.7, 95% CI: 1.03â2.8). The sensitivity at 6Â months was 16.6% (95% CI: 10.5â22.7), 28.9% (95% CI: 21.5â36.3), and 14.9% (95% CI: 8.5-21.2), respectively. Conclusions: Performance of the PROTECHT or 5-SNP score was not superior to that of the Khorana score. The majority of cancer patients who developed VTE during 6-month follow-up were not identified by these scores. Future directions for studies on cancer-associated VTE prediction may include combined clinical-genetic scores