Phase I study of bosutinib, a src/Abl tyrosine kinase inhibitor, administered to patients with advanced solid tumors

Purpose: Bosutinib, a potent ATP-competitive, quinolinecarbonitrile Src/Abl kinase inhibitor, was tested in this first-in-human phase I trial in patients with advanced solid tumor malignancies. Patients and Methods: This trial was conducted in 2 parts. In part 1 (dose escalation), increasing oral bosutinib doses were administered using a 3 + 3 design. In part 2 (dose expansion), approximately 30 patients each with refractory colorectal, pancreas, or non–small cell lung cancer were treated at the recommended phase II dose (RP2D). Primary efficacy endpoints for part 2 were median progression-free survival (colorectal and non–small cell lung) and median overall survival (pancreas). Results: In part 1, dose-limiting toxicities of grade 3 diarrhea (two patients) and grade 3 rash occurred with bosutinib 600 mg/day and the maximum tolerated dose identified was 500 mg/day. However, the majority of patients treated with 500 mg/day had grade 2 or greater gastrointestinal toxicity, and 400 mg/day was identified as the RP2D. The most common bosutinib-related adverse events were nausea (60% patients), diarrhea (47%), vomiting (40%), fatigue (38%), and anorexia (36%). Bosutinib had a mean half-life of 19 to 20 hours at the RP2D. A partial response (breast) and unconfirmed complete response (pancreas) were observed; 8 of 112 evaluable patients had stable disease for 22 to 101 weeks. However, the primary efficacy endpoints for part 2 were not met. Conclusions: Bosutinib was generally well tolerated in patients with solid tumors, with the main toxicity being gastrointestinal. The RP2D was 400 mg/day orally. Further study of bosutinib is planned in combination regimens

Pharmacokinetics of Novel Plant Cell-Expressed Taliglucerase Alfa in Adult and Pediatric Patients with Gaucher Disease

<div><p>Taliglucerase alfa is a beta-glucocerebrosidase enzyme replacement therapy approved in the United States, Israel, and other countries for treatment of Type 1 Gaucher disease in adults, and is the first approved plant cell—expressed recombinant protein. In this report, taliglucerase alfa pharmacokinetics were assessed in adult and pediatric patients with Gaucher disease from separate multicenter trials of 30 Units/kg and 60 Units/kg doses infused every 2 weeks. Serial blood samples were obtained from adult patients following single-dose administration on day 1 (n = 26) and multiple doses at week 38 (n = 29), and from pediatric patients following administration of multiple doses of taliglucerase alfa for 10–27 months (n = 10). In both adult and pediatric patients, maximum plasma concentration (C_max), area under the plasma concentration-time curve from time zero to last measureable concentration (AUC_0-t), and from time zero to infinity (AUC_0-∞) were higher after 60 Units/kg dose than 30 Units/kg dose. No tendency for accumulation or change in taliglucerase alfa pharmacokinetic parameters over time from day 1 to week 38 was observed with repeated doses of 30 or 60 Units/kg in adults. After multiple doses, mean (range) dose-normalized pharmacokinetic parameters were similar for adult versus pediatric patients receiving 60 Units/kg: C_max expressed in ng/mL/mg was 42.4 (14.5–95.4) in adults and 46.6 (34.4–68.4) in pediatric patients, AUC_{0 t} expressed in ng•h/mL/mg was 63.4 (26.3–156) in adults and 63.9 (39.8–85.1) in pediatric patients, t_1/2 expressed in minutes was 34.8 (11.3–104) in adults and 31.5 (18.0–42.9) in pediatric patients and total body clearance expressed in L/h was 19.9 (6.25–37.9) in adults and 17.0 (11.7–24.9) in pediatric patients. These pharmacokinetic data extend the findings of taliglucerase alfa in adult and pediatric patients.</p><p>Trial Registration</p><p>ClinicalTrials.gov. <a href="http://clinicaltrials.gov/show/NCT00376168" target="_blank">NCT00376168</a> (in adults); <a href="http://clinicaltrials.gov/show/NCT01411228" target="_blank">NCT01411228</a> (in children)</p></div

Taliglucerase alfa plasma concentration in adult patients.

<p>Mean plasma concentration-versus-time curve of taliglucerase alfa in adult patients for 120-minute infusions showing dose-dependent increase (linear plot): a) on day 1; b) at week 38. Abbreviation: U/kg, Units/kg. Error bars represent standard deviations.</p

Desvenlafaxine Versus Placebo in a Fluoxetine-Referenced Study of Children and Adolescents with Major Depressive Disorder

Objectives: To evaluate the short-term efficacy and safety of desvenlafaxine (25-50mg/d) compared with placebo in children and adolescents with major depressive disorder (MDD). Methods: Outpatient children (7-11 years) and adolescents (12-17 years) who met DSM-IV-TR criteria for MDD and had screening and baseline Children's Depression Rating Scale-Revised (CDRS-R) total scores >40 were randomly assigned to 8-week treatment with placebo, desvenlafaxine (25, 35, or 50mg/d based on baseline weight), or fluoxetine (20mg/d). The primary efficacy endpoint was change from baseline in CDRS-R total score at week 8, analyzed using a mixed-effects model for repeated measures. Secondary efficacy endpoints included week 8 Clinical Global Impressions-Severity, Clinical Global Impressions-Improvement (CGI-I), and response (CGI-I 2). Safety assessments included adverse events, physical and vital sign measurements, laboratory evaluations, electrocardiogram, and the Columbia-Suicide Severity Rating Scale. Results: The safety population included 339 patients (children, n=130; adolescents, n=209). The primary endpoint, change from baseline in CDRS-R total score at week 8, did not statistically separate from placebo, for either desvenlafaxine (adjusted mean [standard error] change, -22.6 [1.17]) or fluoxetine (-24.8 [1.17]; placebo, -23.1 [1.18]). Week 8 CGI-I response rates were significantly greater for fluoxetine (78.2%; p=0.017) than for placebo (62.6%); desvenlafaxine (68.7%) did not differ from placebo. Other secondary outcomes were consistent with those obtained with CDRS-R. Rates of treatment-emergent adverse events were comparable among treatment groups (desvenlafaxine, 60.0%; placebo, 70.5%; and fluoxetine, 64.3%). Conclusion: Desvenlafaxine did not demonstrate efficacy for treating MDD in children and adolescents in this trial. Because neither desvenlafaxine nor the reference medication, fluoxetine, demonstrated a statistically significant difference from placebo on the primary endpoint, this was considered a failed trial and no efficacy conclusions can be drawn. Desvenlafaxine 25-50mg/d was generally safe and well tolerated in children and adolescents in this study.Pfizer Inc.12 month embargo; Published online: 30 November 2017This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Summary of PK parameters of taliglucerase alfa in pediatric patients.

<p>AUC_0–t, area under the plasma concentration-time curve from time zero to the last sampling time; AUC_0–∞, area under the plasma concentration-time curve extrapolated from time zero to infinity; CL, total body clearance; C_max, maximum plasma concentration; PK, pharmacokinetics; SD, standard deviation; T_max, time of maximum plasma concentration; t_1/2, elimination half-life; U/kg, Units/kg; V_ss, volume of distribution during steady-state.</p><p>Summary of PK parameters of taliglucerase alfa in pediatric patients.</p

Taliglucerase alfa plasma concentration in pediatric patients.

<p>Mean plasma concentration-versus-time curve of taliglucerase alfa in pediatric patients for approximately 100-minute infusions showing dose-dependent increase (linear plot). Abbreviation: U/kg, Units/kg. Error bars represent standard deviations.</p