A randomized, controlled trial evaluating the efficacy and safety of BTH1677 in combination with bevacizumab, carboplatin, and paclitaxel in first-line treatment of advanced non-small cell lung cancer.

BACKGROUND: BTH1677, a beta-glucan pathogen-associated molecular pattern molecule, drives an anti-cancer immune response in combination with oncology antibody therapies. This phase II study explored the efficacy, pharmacokinetics (PK), and safety of BTH1677 combined with bevacizumab/carboplatin/paclitaxel in patients with untreated advanced non-small cell lung cancer (NSCLC). METHODS: Patients were randomized to the BTH1677 arm (N = 61; intravenous [IV] BTH1677, 4 mg/kg, weekly; IV bevacizumab, 15 mg/kg, once each 3-week cycle [Q3W]; IV carboplatin, 6 mg/mL/min Calvert formula area-under-the-curve, Q3W; and IV paclitaxel, 200 mg/m2, Q3W) or Control arm (N = 31; bevacizumab/carboplatin/paclitaxel as above). Carboplatin/paclitaxel was discontinued after 4-6 cycles and patients who responded or remained stable received maintenance therapy with BTH1677/bevacizumab (BTH1677 arm) or bevacizumab (Control arm). Efficacy assessments, based on blinded central radiology review, included objective response rate (ORR; primary endpoint), disease control rate, duration of objective response, and progression-free survival. Overall survival and adverse events (AEs) were also assessed. RESULTS: ORR was higher in the BTH1677 vs Control arm but the difference between groups was not statistically significant (60.4% vs 43.5%; P = .2096). All other clinical endpoints also favored the BTH1677 arm but none statistically differed between arms. PK was consistent with previous studies. Although a higher incidence of Grade 3/4 AEs occurred in the BTH1677 vs Control arm (93.2% vs 66.7%), no unexpected AEs were observed. Serious AEs and discontinuations due to AEs were lower in the BTH1677 vs Control arm. CONCLUSIONS: Improvements in tumor assessments and survival were observed with BTH1677/bevacizumab/carboplatin/paclitaxel compared with control treatment in patients with advanced NSCLC. TRIAL REGISTRATION: ClinicalTrials.gov registration ID: NCT00874107 . Registered 2 April 2009. First participant was enrolled on 29 September 2009.

Comparison of the Pharmacokinetics of Ketorolac Tromethamine After Continuous Subcutaneous Infusion and Repeat Intramuscular Bolus Injections in Healthy Adult Subjects.

Ketorolac tromethamine is a nonsteroidal anti-inflammatory drug that exhibits analgesic activity with no sedative or anxiolytic properties. Twelve healthy male subjects were enrolled in a study to receive either of 2 treatments over 2 periods in an open-label, randomized, 2-way crossover design: (A) 120 mg of ketorolac tromethamine administered as a continuous subcutaneous infusion over a 24-hour period; or (B) an identical total daily dose administered as 4 intramuscular bolus injections of 30 mg each given every 6 hours (current labeled treatment regimen). The pharmacokinetic and safety profiles were evaluated for both treatments. Both modes of administration have similar values for area under the curve (AUC) and half-life (t1/2 ), suggesting that continuous subcutaneous infusion and repeated intramuscular bolus injections have similar bioavailability. The peak plasma concentration (Cmax ) was 40% lower when ketorolac was administered as a continuous subcutaneous infusion compared with repeat intramuscular bolus injections. The concentration at steady-state (Css ) for continuous subcutaneous infusion was between the Cmax and Ctrough values obtained following the 4 intramuscular injections. Both treatment arms were well tolerated.

A strategy to reduce biliary clearance in early drug discovery.

INTRODUCTION: Biliary excretion can modulate the pharmacokinetic profile of drug candidates, and may represent a liability for drug-drug interactions. This study proposes a strategy to reduce biliary clearance using the efflux ratio in Caco-2 cells in parallel to an abbreviated pharmacokinetic study in bile duct-cannulated rats (BDC). METHODS: Apical to basolateral (A to B) and basolateral to apical (B to A) permeability of 20 new chemical entities (NCEs) were determined in a 24-well permeability assay. In parallel, biliary excretion was determined in an abbreviated format in BDC rats. Test compounds were administered via an intravenous dose of 1 mg/kg and the percentage (%) of parent compound excreted in the bile in the first 3 hours after dosing was determined by LC-MS/MS analysis. RESULTS: A reasonably good correlation (r(2)=0.635) between the in vitro efflux ratio from the Caco-2 assay and in vivo biliary excretion of parent compound in BDC rats was observed. All seven compounds with an efflux ratio of <5 had less than 25% of the parent excreted in rat bile. In contrast, 3 out of the 13 compounds with an efflux ratio >5 had less than 25% of the dose excreted in rat bile. DISCUSSION: This suggests that a compound with an efflux ratio of <5 is at lower risk of having significant biliary clearance and that Caco-2 efflux ratio obtained from a high throughput screening assay may be used as an early indicator of biliary excretion. Although, we propose to reduce the occurrence of false positive prediction for biliary clearance (23%) by performing abbreviated PK in BDC rats for compounds with high efflux ratio.