scholarly journals MEDI0382, a GLP-1/glucagon receptor dual agonist, meets safety and tolerability endpoints in a single-dose, healthy-subject, randomized, Phase 1 study

2018 ◽  
Vol 84 (10) ◽  
pp. 2325-2335 ◽  
Author(s):  
Philip D. Ambery ◽  
Sebastian Klammt ◽  
Maximillian G. Posch ◽  
Marcella Petrone ◽  
Wenji Pu ◽  
...  
Keyword(s):  
Single Dose ◽  
Healthy Subject ◽  
Phase 1 ◽  
Phase 1 Study ◽  
Glucagon Receptor ◽  
Dual Agonist

Pharmacokinetics, Safety, and Tolerability of Single‐Dose Intravenous Moxifloxacin in Pediatric Patients: Dose Optimization in a Phase 1 Study

2019 ◽  
Vol 59 (5) ◽  
pp. 654-667 ◽  
Author(s):  
Heino Stass ◽  
John Lettieri ◽  
Konstantina M. Vanevski ◽  
Stefan Willmann ◽  
Laura P. James ◽  
...  
Keyword(s):  
Single Dose ◽  
Pediatric Patients ◽  
Phase 1 ◽  
Dose Optimization ◽  
Phase 1 Study

scholarly journals Preliminary Results of a Phase 1 Study in Healthy Subjects Administered Inclacumab, a Fully Human IgG4 Anti-P-Selectin Monoclonal Antibody in Development for Treatment of Sickle Cell Disease

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 977-977
Author(s):  
Christina Mayer ◽  
Daniel Scott Cooper ◽  
Andrew Redfern ◽  
Xin Geng ◽  
Jianxia Shi ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Single Dose ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Healthy Subjects ◽  
Phase 1 ◽  
Advisory Board ◽  
Cell Disease ◽  
Phase 1 Study ◽  
Phase 3

Abstract Background: Inclacumab, a fully human IgG4 anti-P-selectin monoclonal antibody, is being developed for the reduction of vaso-occlusive crises (VOCs) in patients with sickle cell disease (SCD). P-selectin-mediated platelet-leukocyte aggregate (PLA) formation has been shown to contribute to vaso-occlusion. Safety and pharmacology of inclacumab have previously been well characterized in over 700 subjects (healthy volunteers and patients with cardiovascular disease), at doses up to 20 mg/kg every 4 weeks for up to 9 months. The current Phase 1 study was initiated to evaluate the safety and pharmacology of inclacumab at doses of 20 mg/kg and 40 mg/kg in healthy subjects in support of a target Phase 3 dose of 30 mg/kg administered every 12 weeks to patients with SCD. Methods: Healthy adult subjects over 18 years of age without significant current or prior health conditions received a single intravenous (IV) dose of 20 mg/kg inclacumab infused over approximately one hour (Cohort 1). Following a review of safety, a second cohort received a single IV dose of 40 mg/kg infused over approximately one hour (Cohort 2). The total study duration and sample collection period was 29 weeks. Final safety and preliminary pharmacokinetics (PK), anti-drug antibody (ADA), and ex vivo thrombin receptor-activating peptide (TRAP)-activated PLA formation data are reported. Results: Fifteen subjects received a single dose of inclacumab 20 mg/kg (n=6) or 40 mg/kg (n=9). Fourteen subjects completed the study. Median age was 42 years (range 22 - 52 years); median body weight was 73.6 kg (range 63.7 - 89.3 kg). Through the pre-specified 72-hour post-infusion safety assessment period in both cohorts, no treatment-emergent adverse events (AEs) > grade 1 (mild) nor dose-limiting toxicities were reported. During the duration of the study, there were no serious AEs, infusion-related reactions, or hypersensitivity reactions. Additionally, no clinically significant changes in vital signs, laboratory findings, or ECGs were observed. The most common AEs were headache, myalgia, and contact dermatitis. The only events assessed by the investigator as potentially related to inclacumab were headache and dizziness, which were experienced by one subject (20 mg/kg) and occurred 4 hours following the end of infusion. In healthy subjects, inclacumab demonstrated dose-proportional PK over the dose range tested; PK parameter estimates were consistent with those reported for monoclonal antibodies. Geometric mean C max following single doses of 20 and 40 mg/kg were 402 and 970 µg/mL, respectively. Mean TRAP-activated predose PLA formation was 33 - 39% across cohorts and decreased to 9-14% at 2 hours following end of infusion. PLA inhibition was sustained through at least 12 weeks for both the 20 and 40 mg/kg doses. Two subjects in the 40 mg/kg cohort were ADA-positive on Week 12 and thereafter; a preliminary analysis demonstrated no apparent impact on PK or safety in these subjects. Conclusions: Inclacumab displayed a well-tolerated safety profile for up to 29 weeks following a single dose of 20 or 40 mg/kg in healthy subjects. Durable inhibition of TRAP-activated PLA formation was observed through at least 12 weeks, consistent with prior observations. Overall, the results support a Phase 3 dose of 30 mg/kg every 12 weeks in patients with SCD-related VOCs. Funding: This study was supported by Global Blood Therapeutics. Disclosures Mayer: Global Blood Therapeutics: Consultancy. Redfern: Linear Clinical Research: Current Employment; Novartis: Other: Advisory Board; Pfizer: Other: Advisory Board; Roche: Other: Advisory Board; Eisai: Other: Advisory Board; Astra Zeneca: Other: Advisory Board. Geng: Global Blood Therapeutics: Current Employment. Shi: Global Blood Therapeutics: Current Employment. van Zutphen-van Geffen: Global Blood Therapeutics: Consultancy. Kuan: Global Blood Therapeutics: Consultancy. Koeck: Global Blood Therapeutics: Consultancy. Kastrissios: Global Blood Therapeutics: Consultancy. Patel: Global Blood Therapeutics: Consultancy. Davis: Global Blood Therapeutics: Current Employment. Yue: Global Blood Therapeutics: Current Employment.

A first-in-human phase 1 study of proxalutamide (GT0918), a dual MOA androgen receptor blocker in patients with advanced CRPC.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e16511-e16511
Author(s):  
Tie Zhou ◽  
Wei-Dong Xu ◽  
Chuang-Liang Xu ◽  
Xu Gao ◽  
Jian-Guo Hou ◽  
...  
Keyword(s):  
Single Dose ◽  
Androgen Receptor ◽  
Drug Exposure ◽  
Oral Absorption ◽  
Phase 1 ◽  
Dose Range ◽  
Repeated Dose ◽  
Phase 2 ◽  
Phase 1 Study ◽  
Drug Concentrations

e16511 Background: Proxaluatmide is a novel dual MOA androgen receptor (AR) blocker with potent AR antagonist activity and capability to down-regulate AR level. We conducted a first-in-human phase 1 study to investigate safety, tolerability, and pharmacokinetics of GT0918 in patients with advanced CRPC. Methods: All participating patients must be confirmed with advanced CRPC progressed on SoC, PS 0-1, went through 2 periods of time of both single-dose and repeated-dose PK. Patients received GT0918 once orally followed by PK in first 7 days, and then once daily continuously for 28 days for DLT evaluation and repeated-dose PK. PK of drug elimination was done at the end of first cycle (7 days off-treatment). By the end of first 28-day cycle, DLT was evaluated and dose escalation was determined by modified Fibonacci's rule of 3+3 design. If patient tolerated GT0918 well and had no sign of tumor progression, he continued on the study medication thereafter. Results: Ninteen patients were enrolled and 16 patients were treated with GT0918 at five dose levels: 50 mg (n = 2), 100 mg (n = 4), 200 mg (n = 3), 300 mg (n = 3) and 400 mg (n = 4). No DLT was observed. MTD was not reached. GT0918-related adverse events were relatively mild (CTCAE grade 1 or 2), including hypercholesterolemia, peripheral edma, fatigue, flush, constipation and anorexia. PK study showed plasma drug concentrations increased as dose increased from 50mg to 300mg and saturation observed between 300mg and 400mg. Compared single dose (D1) with repeated dose (D35), the elimination half-life (T1/2) were shown 14-35h and 28-51h, respectively. With consideration of overly drug exposure and saturation of oral absorption, 100-400mg were recommended to be the dose range for Phase 2 for further clinical evaluations and dose selection. Clinical activities have been observed in numbers of patients in 100/200/300/400mg dose cohorts. Conclusions: Proxalutamide (GT0918) dosed orally once a day continuously for 12 weeks was generally well tolerated. GT0918 showed promising preliminary anti-tumor activity. Dose range of 100-400mg was recommended for Phase 2 trial and for 24 weeks of treatment.

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