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Author(s):  
Mary Beth Wire ◽  
Soo Youn Jun ◽  
In-Jin Jang ◽  
Seung-Hwan Lee ◽  
Jun Gi Hwang ◽  
...  

Thirty-two healthy male subjects (8 per cohort) were randomized 6:2 to active:placebo. LSVT-1701, an anti-staphylococcal lysin, was administered intravenously as a 6 mg/kg single dose and as 1.5, 3, and 4.5 mg/kg twice daily for 4 days. LSVT-1701 exposure increased in a greater than dose proportional manner and did not accumulate. Treatment-emergent adverse events (TEAEs) were predominantly of mild intensity. The most common TEAEs were chills, pyrexia, headache, infusion site events, cough, rhinorrhea, and increases in C-reactive protein.


Author(s):  
Wenhui Zhang ◽  
Astrid Scalori ◽  
Franklin Fuh ◽  
Jacqueline McBride ◽  
Gaohong She ◽  
...  

Abstract Background Etrolizumab, a humanized anti-β7 antibody, has not been studied in children. Here, we evaluate the pharmacokinetics, pharmacodynamics, and safety of etrolizumab in children with inflammatory bowel disease. Methods Patients age 4 to 17 years with moderately to severely active ulcerative colitis or Crohn’s disease were randomized 1:1 to receive 1.5mg/kg of etrolizumab subcutaneously every 4 weeks (q4w) or 3.0mg/kg every 8 weeks (q8w) for 16 weeks in this open-label phase 1 trial. Pharmacokinetics, pharmacodynamics, safety, and efficacy were assessed. Results Of the 24 patients treated, 21 completed the study. In the groups of 1.5mg/kg q4w and 3.0mg/kg q8w, respectively, mean (SD) maximum concentration (Cmax) was 9.8 (4.86) µg/mL and 18.1 (6.25) µg/mL; and mean (SD) area under the curve within a dosing interval (AUCtau) was 167 (86.9) and 521 (306) μg·day/mL after the last dose. The Cmax increased dose proportionally. The AUC over an 8-week period was slightly higher in the 3.0mg/kg q8w dose group. Median half-life was similar for both dosing regimens. Median numbers of free β7high gut-homing T and B cell subsets declined below 10% of baseline, confirming β7 target engagement and complete/near-complete receptor occupancy. Adverse events were consistent with the safety profile in adults. Approximately 60% of patients achieved a clinical response. Conclusions Etrolizumab showed a dose-proportional increase in Cmax and a slightly greater than dose-proportional increase in AUCtau. Both regimens achieved complete/near-complete β7 receptor occupancy, with a similar relationship to concentration as adults. Etrolizumab was well tolerated and demonstrated clinical activity in children.


2021 ◽  
pp. 135965352110565
Author(s):  
Edward Gane ◽  
Mina Pastagia ◽  
Ullrich Schwertschlag ◽  
An De Creus ◽  
Christian Schwabe ◽  
...  

Background This Phase I, two-part, first-in-human study assessed safety/tolerability and pharmacokinetics/pharmacodynamics of single-ascending doses (SAD) and multiple doses (MD) of the oral toll-like receptor-7 agonist, JNJ-64794964 (JNJ-4964) in healthy adults. Methods In the SAD phase, participants received JNJ-4964 0.2 ( N = 6), 0.6 ( N = 6), 1.25 ( N = 8) or 1.8 mg ( N = 6) or placebo ( N = 2/dose cohort) in a fasted state. Food effect was evaluated for the 1.25 mg cohort following ≥6 weeks washout. In the MD phase, participants received JNJ-4964 1.25 mg ( N = 6) or placebo ( N = 2) weekly (fasted) for 4 weeks. Participants were followed-up for 4 weeks. Results No serious adverse events (AEs) occurred. 10/34 (SAD) and 5/8 (MD) participants reported mild-to-moderate (≤Grade 2), transient, reversible AEs possibly related to JNJ-4964. Five (SAD) participants had fever/flu-like AEs, coinciding with interferon-α serum levels ≥100 pg/mL and lymphopenia (<1 × 109/L), between 24–48 h after dosing and resolving approximately 96 h after dosing. One participant (MD) had an asymptomatic Grade 1 AE of retinal exudates (cotton wool spots) during follow-up, resolving 6 weeks after observation. JNJ-4964 exhibited dose-proportional pharmacokinetics, with rapid absorption (tmax 0.5–0.75 h) and distribution, and a long terminal half-life (150–591 h). Overall, no significant differences in JNJ-4964 pharmacokinetic parameters were observed in the fed versus fasted state. JNJ-4964 dose-dependently and transiently induced cytokines with potential anti-HBV activity, including interferon-α, IP-10, IL-1 RA, and/or MCP-1, and interferon-stimulated genes (ISG15, MX1, and OAS1) in serum. Conclusions In healthy adults, JNJ-4964 was generally well-tolerated, exhibited dose-proportional pharmacokinetics and induced cytokines/ISGs, with possible anti-HBV activity.


Author(s):  
Adam J. DiPippo ◽  
Patrick M. McDaneld ◽  
Frank P. Tverdek ◽  
Dimitrios P. Kontoyiannis

Posaconazole (POS) appears to have dose-proportional pharmacokinetics, however there is paucity of real-life data. We retrospectively evaluated 67 patients with hematological cancer who had POS dose increase from 300 mg/d to either 400 mg/d (n=52) or 300 mg twice daily (BID; n=15) and POS serum levels measured. Median POS levels were 840 ng/mL, 1625 ng/mL, and 2710 ng/mL on the 300mg/d, 400mg/d and 300mg BID doses respectively. Significant inter-patient variability in serum levels was noted.


Author(s):  
Yinjuan Li ◽  
Lu Qi ◽  
Haihong Bai ◽  
Chunyun Sun ◽  
Shuping Xu ◽  
...  

SCTA01 is a novel monoclonal antibody with promising prophylactic and therapeutic potential for COVID-19. This study aimed to evaluate the safety, tolerability, pharmacokinetics (PK) and immunogenicity of SCTA01 in healthy adults. This was a randomized, double-blind, placebo-controlled, dose-escalation phase I clinical trial. Healthy adults were randomly assigned into the following four cohorts, Cohort 1 (n=5, 3:2), Cohort 2 (n=8, 6:2), Cohort 3 and Cohort 4 (both n=10, 8:2), to receive SCTA01 (5, 15, 30 and 50 mg/kg, respectively) versus placebo. All participants were followed up for clinical, laboratory, PK and immunogenicity assessments for 84 days. The primary outcomes were the dose-limiting toxicity (DLT) and maximal tolerable dose (MTD), and the secondary outcomes included PK parameters, immunogenicity and adverse events (AE). Of the 33 participants, 18 experienced treatment-related AEs; the frequency was 52.0% (13/25) in participants receiving SCTA01 and 62.5% (5/8) in those receiving placebo. All AEs were mild. There was no serious AE or death. No DLT was reported, and MTD of SCTA01 was not reached. SCTA01 with a dose range 5-50mg/kg had nearly linear dose-proportional increases in C max and AUC parameters. An anti-drug antibody response was detected in four (16.0%) participants receiving SCTA01, with low titers, between the baseline and day 28, but all became negative later. In conclusion, SCTA01 up to 50mg/kg was safe and well-tolerated in healthy participants. Its PK parameters were nearly linear dose-proportional.


Author(s):  
Antoine Italiano ◽  
Wilson H. Miller ◽  
Jean-Yves Blay ◽  
Jourik A. Gietema ◽  
Yung-Jue Bang ◽  
...  

Summary Aim The oral MDM2 antagonist idasanutlin inhibits the p53-MDM2 interaction, enabling p53 activation, tumor growth inhibition, and increased survival in xenograft models. Methods We conducted a Phase I study of idasanutlin (microprecipitate bulk powder formulation) to determine the maximum tolerated dose (MTD), safety, pharmacokinetics, pharmacodynamics, food effect, and clinical activity in patients with advanced malignancies. Schedules investigated were once weekly for 3 weeks (QW × 3), once daily for 3 days (QD × 3), or QD × 5 every 28 days. We also analyzed p53 activation and the anti-proliferative effects of idasanutlin. Results The dose-escalation phase included 85 patients (QW × 3, n = 36; QD × 3, n = 15; QD × 5, n = 34). Daily MTD was 3200 mg (QW × 3), 1000 mg (QD × 3), and 500 mg (QD × 5). Most common adverse events were diarrhea, nausea/vomiting, decreased appetite, and thrombocytopenia. Dose-limiting toxicities were nausea/vomiting and myelosuppression; myelosuppression was more frequent with QD dosing and associated with pharmacokinetic exposure. Idasanutlin exposure was approximately dose proportional at low doses, but less than dose proportional at > 600 mg. Although inter-patient variability in exposure was high with all regimens, cumulative idasanutlin exposure over the whole 28-day cycle was greatest with a QD × 5 regimen. No major food effect on pharmacokinetic exposure occurred. MIC-1 levels were higher with QD dosing, increasing in an exposure-dependent manner. Best response was stable disease in 30.6% of patients, prolonged (> 600 days) in 2 patients with sarcoma. Conclusions Idasanutlin demonstrated dose- and schedule-dependent p53 activation with durable disease stabilization in some patients. Based on these findings, the QD × 5 schedule was selected for further development. Trial registration NCT01462175 (ClinicalTrials.gov), October 31, 2011.


2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 3021-3021
Author(s):  
Jacob Stephen Thomas ◽  
Diane Habib ◽  
Diana L. Hanna ◽  
Irene Kang ◽  
Syma Iqbal ◽  
...  

3021 Background: FID-007 (FID) consists of paclitaxel encapsulated in a polyethyloxazoline (PEOX) polymer excipient designed to enhance PK, biodistribution, and tolerability. In addition to allowing the drug to remain in solution until it can enter a cancer cell, the PEOX nanoparticle preferentially delivers paclitaxel to the tumor through the leaky hyperpermeable vasculature. In xenograft studies, FID reduced or limited tumor growth in multiple tumor types including lung, gastric, breast, pancreatic, and ovarian cancer. FID was more effective at lower or comparable taxane doses with fewer side effects. We present the first-in-human trial of FID. Methods: The study is evaluating the safety, PK, and efficacy of FID in pts with advanced solid tumors. The primary objective is to determine the MTD and RP2D. Pts received FID in doses between 15mg/m2 and 125mg/m2 using a standard 3+3 dose escalation design. FID was given IV on Days 1, 8, and 15 of a 28-day cycle. Eligibility included ECOG 0-2, adequate organ function, and no more than 3 prior lines of cytotoxic therapy for advanced disease. Results: Twenty-five pts were treated across 6 dose levels. Median age was 62 (44-76). ECOG PS was 2 in 1 pt and 1 in 64%. Median number of cycles was 2 (1-16). There were 2 DLTs of grade 3 rash at 100 mg/m2. Given the transient nature of the rash and response to topical therapy, DLT definition was modified to exclude grade 3 rash that lasts ≤ 7 days and additional patients were treated at 100 mg/m2 which was deemed tolerable. There was 1 DLT of grade 3 neutropenia at 125 mg/m2. All grade treatment related adverse events (TRAEs) in ≥ 25% of pts were rash (64%), alopecia (52%), pruritus (44%), anemia (44%) leukopenia, fatigue (40% each), dysgeusia, anorexia, nausea (32% each), and neutropenia (28%). Grade 3/4 TRAEs occurring in > 1 pt were anemia (20%), neutropenia, leukopenia, and maculopapular rash (16%). There were no treatment discontinuations due to toxicity. Twenty-two pts were evaluable for response by RECIST 1.1 with a PR rate of 14% (PR in pancreatic, biliary tract and NSCLC) and disease control rate of 59%. PK is linear and dose proportional. There is no paclitaxel accumulation after weekly dosing, and the t1/2 is between 18-26 hours. Conclusions: FID has a manageable safety profile with MTD not reached. Accrual is continuing at 125 mg/m2. PK is linear, dose proportional and comparable to that of nab-paclitaxel. There is preliminary evidence of anti-tumor activity in heavily pre-treated pts across different tumor types. Enrollment in dose escalation continues. Combination studies with immunotherapeutic agents are planned. Clinical trial information: NCT03537690.


2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A524-A524
Author(s):  
Rosa Luo ◽  
Gerald Burke ◽  
Cosina Mui ◽  
Sepehr Shakib ◽  
Christine Ferrara-Cook ◽  
...  

Abstract Depot injection formulations of peptide somatostatin receptor ligands (SRLs) are routinely used to treat acromegaly and neuroendocrine tumors (NETs). Paltusotine (CRN00808), an orally administered small molecule nonpeptide selective somatostatin receptor 2 (SST2) agonist has been shown to maintain GH and IGF-1 levels in acromegaly patients previously on depot SRLs (ACROBAT Edge NCT03789656). In this study, a capsule formulation was used, which did not exhibit dose proportional pharmacokinetics (PK) at doses &gt;40 mg, required a 2-hour post-dose fast in overnight fasted patients, and had the potential for reduced bioavailability when taken with proton-pump inhibitors (PPI). A spray-dried dispersion (SDD) tablet formulation was developed with improved solubility in the physiological pH range and its performance was evaluated in healthy volunteers. Male and female healthy volunteers who met inclusion/exclusion criteria were enrolled in a single-center Phase 1 study (ANZCTR registration ACTRN12619001562167). A Cohort of 12 subjects was administered a single dose of paltusotine in a four-period cross-over design. Periods 1 and 2 assessed the effect of lansoprazole (a PPI) on PK of 20 mg dose of paltusotine SDD tablets. In Period 3, 20 mg dose of paltusotine SDD tablets was co-administered with a high fat, high-calorie meal. In Period 4, a 60 mg dose of paltusotine SDD tablets was administered to assess dose proportionality. In a separate cohort of subjects (n=12; also, a 4-period cross-over design), the relative bioavailability of capsules and SDD tablets was assessed, and the effect of food administration 0.5, 1, and 2 hour post-dose was evaluated. Subsequently, in another cohort of 12 subjects (a 3-period cross-over design), dose proportionality of the SDD tablets was evaluated at 40 mg and 80 mg dose with a 1-hour post-dose fast. A 4 hours post-dose fast was also assessed for the 80 mg dose. Pharmacokinetics and safety of paltusotine were evaluated. Paltusotine was generally well tolerated in this study. SDD tablets exhibited dose proportional increase in total systemic exposure (AUC) up to a dose of 80 mg. Healthy volunteers pretreated with the PPI, lansoprazole (15 mg bid for 3 days), and co-administered with paltusotine SDD tablets exhibited a small decrease (approximately 25%) in systemic exposure to paltusotine compared with the same subjects that had washed out from the PPI-pretreatment. SDD tablets exhibited significant reduction in systemic exposure when co-administered with a high-fat, high-calorie meal. However, the SDD formulation was less sensitive to timing of post-dose food administration compared to the capsule formulation. These data suggest that the SDD tablet formulation of paltusotine improves flexibility in dose administration, can be co-administered with PPIs and other agents that increase stomach pH, and reduces the post-dose fasting requirement.


Author(s):  
David C. Griffith ◽  
Elizabeth E. Morgan ◽  
Michael N. Dudley ◽  
Jeffery S. Loutit

The pharmacokinetics and safety of biapenem were studied in 36 healthy adult subjects in a randomized, placebo-controlled, double blind, sequential single and multiple-ascending dose study using doses from 250 to 1250 mg administered three times a day using 3-hour infusions. Maximum concentrations for biapenem were achieved at the end of the 3-hour infusion. Biapenem exposure (AUC) increased in a slightly greater than dose-proportional manner following single and multiple doses with no evidence of accumulation with multiple doses. Plasma AUCs increased from 18 mg*h/L at 250 mg to 150 mg*h/L at 1250 mg. Urinary recovery ranged from 14.2% at 250 mg to 42.3% at 1250 mg. Biapenem was well tolerated up to 1000 mg administered every 8 hours by 3-hour infusion for 7 days; however, a higher incidence of nausea, vomiting, and rash was reported at 1250 mg. There were no serious adverse events (SAEs) reported following either single or multiple doses of biapenem and all AEs were mild or moderate in severity.


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