Trough Serum Research Articles

Post-market safety and efficacy profile of subcutaneous testosterone enanthate-autoinjector: a cohort analysis.

A subcutaneous testosterone enanthate-autoinjector (SCTE-AI) was recently approved by the Food and Drug Administration for patient-administered weekly testosterone replacement therapy (TRT). From January 2019 to October 2019, 110 hypogonadal men were treated with SCTE-AI at two institutions. Patients were assessed in a pretherapy visit prior to receiving SCTE-AI and re-assessed 6 weeks after treatment initiation. Patients with a history of prostate cancer were excluded. Trough serum total testosterone (TT), estradiol (E2), prostate-specific antigen (PSA), and hematocrit (HCT) levels were collected at clinic visits. Therapeutic phlebotomy was recommended for HCT > 54%, and treatment was discontinued for significant increases in PSA as well as for significant treatment-related adverse events. Values from each visit were compared with univariate analysis. 110 patients completed the 6 weeks of observation with a mean age of 40.3 (SD: 10.5). TT significantly rose from 246.6 ng/dL (SD:113.3) pretherapy to 538.4 ng/dL (SD: 209.3) at 6 weeks (p < 0.001). Post-therapy, 101/110 (91.8%) of patients had TT > 300 ng/dL. No patients had HCT > 54%. 74 patients (70.5%) had PSA increase with only 3 (2.9%) experiencing an increase >1.0 ng/dL. There was a significant increase in mean PSA from 1.07 ng/dL (SD: 0.8) pretherapy to 1.18 ng/dL (SD: 0.9) at 6 weeks (p = 0.01). One patient had immediate treatment cessation following diagnosis of prostate cancer. This is the largest non-industry sponsored safety and efficacy profile of SCTE-AI application in urology clinics. After 6 weeks of observation, TT levels increased significantly without any reports of adverse events. SCTE-AI is a safe and effective alternative delivery system of TRT.

Safety and Efficacy of Long-Term Administration of Dipeptidyl peptidase IV Inhibitors in Patients With New Onset Diabetes After Kidney Transplant.

The appearance of new onset diabetes is common after kidney transplant. Treatment options are limited because of renal function-related contraindications, interactions with immunosuppressive drugs, and side effects. We investigated the long-term safety and efficacy of dipeptidyl peptidase IV inhibitors in renal transplant recipients with new onset diabetes. We treated 12 patients with dipeptidyl peptidase IV inhibitors, and 5 patients received insulin monotherapy as initial treatment of new onset diabetes after kidney transplant. All patients were followed for 12 months after diagnosis. Glycosylated hemoglobin A1c, estimated glomerular filtration rate (Chronic Kidney Disease Epidemiology Collaboration equation), plasma immunosuppressive trough levels, serum lipids, blood pressure, and body weight were measured during outpatient visits. Effects of dipeptidyl peptidase IV inhibitors and insulin on the aforementioned parameters were measured to compare values at time of diagnosis versus mean values of the last 6 months of follow-up. Patients were treated with linagliptin (4 patients), sitagliptin (4 patients), vildagliptin (2 patients), and alogliptin (2 patients). Patients had a mean age of 59.4 ± 12 years and a mean glycosylated hemoglobin A1c of 6.6% at diagnosis, which was decreased to 6.1% (P = .03) at 1 year of follow-up. Renal function remained stable, and plasma tacrolimus levels did not appear to be affected. No significant differences were shown in serum total, low-density lipoprotein, and high-density lipoprotein cholesterol levels aftertreatment. Nevertheless,triglyceride levels were significantly reduced (from 214.4 to 174.9 mg/dL; P = .0039). A decrease in body weight was also observed. Finally, patients treated with dipeptidyl peptidase V inhibitors achieved better glycosylated hemoglobin A1c levels than those treated with insulin. Dipeptidyl peptidase IV inhibitors appear to be a safe, effective, and hypoglycemia-free option fortreatment of new onset diabetes in renaltransplant recipients and possibly provide better diabetes control than insulin therapy.

Quality Improvement Methodology Optimizes Infliximab Levels in Pediatric Patients with Inflammatory Bowel Disease.

We participated in Intermediate Improvement Science Series, a course at Cincinnati Children's Hospital Medical Center designed to catalyze change using quality improvement methodology. We implemented interventions through plan-do-study-act cycles. Our outcome measure was balanced by 2 process measures to determine what actions impacted improvement. These measures included the percentage of infusion plans revised in response to a drug level <5 μg/mL and the proportion of plans for which a follow-up drug level was ordered. We increased the percentage of infusion plans revised before the next infusion from 63% to 87% and the percentage of plans that had an appropriate drug level recheck from 61% to 83% from July 2017 to January 2018. We increased the percentage of patients with an infliximab level >5 μg/mL, and results checked in the last 12 months, from 73% to 80%. Quality improvement methodology was effective in improving provider adherence to infliximab therapeutic drug monitoring guidelines. Improvement in adherence to guidelines directly improved the percentage of patients achieving target infliximab levels at any time during infliximab therapy.

46P Fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection (PH FDC SC) plus chemotherapy in HER2-positive early breast cancer (EBC): Safety results from the adjuvant phase of the randomised, open-label, multicentre phase III (neo)adjuvant FeDeriCa study

In the primary analysis of the neoadjuvant phase of the FeDeriCa study (NCT03493854; Tan AR, et al. Lancet Oncol 2021), PH FDC SC cycle 7 P + H serum trough concentrations were non-inferior to intravenous (IV) P + H, with comparable total pathological complete response rates and safety profiles. We present updated descriptive safety data that span the adjuvant phase of the study, with an additional 12 months beyond the primary analysis.

Association of Calculated Area under the Curve or Cyclosporine C0 and C2 Level Monitoring in Pediatric Renal Transplant Patients

Cyclosporine A (CsA) is highly variable pharmacokinetically and has a narrow therapeutic window; the serum level of patients treated with CsA must be monitored carefully. We investigated the trough and second-hour serum levels of CsA, the calculated area under the curve (AUC), and their association of those factors with chronic allograft dysfunction in pediatric patients.

Impact of the Implementation of a Vancomycin Protocol on Trough Serum Vancomycin Concentrations in a Pediatric Intensive Care Unit.

Vancomycin is an antibiotic that is widely used in pediatric intensive care, but the safe and effective use of this drug is challenging. This study aimed to assess the impact of a vancomycin protocol on trough serum concentrations. We conducted a retrospective quasiexperimental study in patients aged ≤18 years in intensive care who received vancomycin for at least 5 days. Patients were divided into two groups: before and after a protocol implemented in 2017 that suggested an initial vancomycin dose of 60 mg/kg/day, target serum levels of 15-20 μg/mL, and dose adjustments. We compared patient characteristics, target serum level achievement, and vancomycin levels over time. Each group contained 65 patients; most were male infants with heart disease as the main reason for hospitalization. Only 29.2% of the patients had pretreatment cultures for bacteria identification recorded, with 1.5% identified as methicillin-resistant Staphylococcus aureus. For the first serum levels, 10.8% of patients in the pre-protocol group and 21.5% in the post-protocol group achieved the 15-20 μg/mL target (p = 0.153); during the first 5 days of treatment, this proportion significantly increased from 52.3 to 73.8% (p = 0.018). We observed a difference between the first and fifth levels: 8.9 μg/mL (95% confidence interval [CI] -3.1 to 21) pre-protocol and 0.4 μg/mL (95% CI -6.1 to 6.9) post-protocol (p = 0.175). Reaching adequate trough vancomycin concentrations in critically ill pediatric patients remains a challenge, and clinical practice protocols allow better dose adjustment and control even when monitoring technologies are unavailable.

Evaluating risk factors for acute graft versus host disease in pediatric hematopoietic stem cell transplant patients receiving tacrolimus.

To identify the clinical and pharmacological risk factors associated with tacrolimus pharmacodynamics for acute graft‐versus‐host disease (aGVHD) in pediatric patients receiving allogeneic hematopoietic stem cell transplantation (HSCT) from a matched related donor. A retrospective cohort single center chart review study was conducted with pediatric patients who received tacrolimus prophylaxis after allogeneic HSCT between January 1, 2017, and December 31, 2019. Potential risk factors were tested separately between aGVHD and non‐aGVHD cohorts and were further analyzed in a logistic regression model with backward elimination and a partial least squares discriminant analysis. Thirty‐three patient cases were included in our study and 52% (17/33) developed aGVHD while on tacrolimus prophylaxis. When tested independently, donor age and sibling versus parent donor/recipient relation were shown to be statistically significant between aGVHD and non‐aGVHD patients (p < 0.005). Pharmacological factors associated with tacrolimus treatment failed to demonstrate a significant impact on patient’s risk of aGVHD. Using a best fit logistic regression model that tested all the variables together, donor age was the only significant variable predicting patient’s risk of aGVHD (p < 0.01). Donor relationship and donor age were unable to be evaluated separately and are therefore confounding variables. Among pediatric patients receiving allogeneic HSCT, aGVHD risk is significantly decreased by either sibling donor and/or younger donors. Although no conclusions were drawn on the effect of tacrolimus therapy (p = 0.08), results warrant additional research with a larger sample size to evaluate the accuracy of monitoring tacrolimus serum trough levels.

Enhancing clinical and immunological effects of anti-PD-1 with belapectin, a galectin-3 inhibitor

BackgroundPD-1/PD-L1 engagement and overexpression of galectin-3 (Gal-3) are critical mechanisms of tumor-induced immune suppression that contribute to immunotherapy resistance. We hypothesized that Gal-3 blockade with belapectin (GR-MD-02) plus anti-PD-1 (pembrolizumab)...

Results of a Dose‐Finding Phase 1b Study of Subcutaneous Atezolizumab in Patients With Locally Advanced or Metastatic Non–Small Cell Lung Cancer

Intravenous (IV) atezolizumab is approved for non–small cell lung and other cancers. Subcutaneous (SC) atezolizumab coformulated with recombinant human hyaluronidase, a permeation enhancer for SC dispersion and absorption, is being developed to improve treatment options, reduce burden, and increase efficiency for patients and practitioners. IMscin001 (NCT03735121), a 2‐part, open‐label, global, multicenter, phase 1b/3 study, is evaluating the pharmacokinetics (PK), safety, and efficacy of SC atezolizumab. The part 1 (phase 1b) objective was determination of an SC atezolizumab dose yielding a serum trough concentration (Ctrough) comparable with IV. Patients enrolled in 3 cohorts received SC atezolizumab 1800 mg (thigh) once (cohort 1), 1200 mg (thigh) every 2 weeks for 3 cycles (cohort 2), or 1800 mg (abdomen) every 3 weeks cycle 1, then cycles 2 and 3 (thigh) every 3 weeks (cohort 3). In subsequent cycles, IV atezolizumab 1200 mg every 3 weeks was administered until loss of clinical benefit. SC atezolizumab 1800 mg every 3 weeks and 1200 mg every 2 weeks provided similar Ctrough and area under the curve values in cycle 1 to the corresponding IV atezolizumab reference, was well tolerated, and exhibited a safety profile consistent with the established IV formulation. Exposure following SC injection in the abdomen was lower (20%, 28%, and 27% for Ctrough, maximum concentration, and area under the concentration‐time curve from time 0 to day 21, respectively) than in the thigh. Part 1 SC and IV PK data were analyzed using a population PK modeling approach, followed by simulations. Part 2 (phase 3) will now be initiated to demonstrate that SC atezolizumab PK exposure is not lower than that of IV.

#50: Vancomycin Doses and Trough Concentrations in Pediatric Patients

Abstract Background Vancomycin serum trough concentrations are monitored to reduce nephrotoxicity and optimize therapeutic efficacy. Vancomycin pharmacokinetics and trough levels used in pediatric patients are extrapolated from the adult population. The pediatric dosing strategies are empirical and there is limited evidence to suggest that these doses result in the recommended steady-state trough concentrations. The objective of the study was to determine the association between vancomycin dosing regimens and trough concentrations levels of 10 to 20 μg/mL in pediatric patients with complicated infections. Methods Retrospective cohort, 505 trough vancomycin serum concentrations of patients of 1 month to 18 years from hospital wards and the Intensive Care Unit of the Instituto Nacional de Salud del Niño San Borja during December 2015 to April 2019. It included only the first vancomycin trough level measured 30 minutes before the fourth doses and serum trough concentrations of 10 to 20 μg/mL were considered as therapeutic levels. A multinomial logistic regression model to estimate the relative risk ratio (RRR) with a 95% confidence interval was used, the comparator group was therapeutic vancomycin levels and it was adjusted by glomerular filtration rate, age group, hospital room, dose interval, and weight. Results Five hundred and five vancomycin dosages were analyzed. Infants and children were 43.12% and 39.22%, respectively, 45.17% were women. 56.77% had a high glomerular filtration rate and only 28.02% of the patients obtained therapeutic trough levels of vancomycin. The RRR of having sub-therapeutic levels in patients with low glomerular filtration rates compared with normal filtration rates was 0.31 (P = 0.049) and the RRR of having sub-therapeutic levels in patients from 2 to 12 years compared with patients under 2 years old was 2.38 (P = 0.007). There was no difference in having therapeutic levels using doses equal or greater than 60 mg/kg/day vs. less than 40 mg/kg/day comparing sub-therapeutic levels (P = 0.655) and supratherapeutic levels (P = 0.264). Conclusions The empirical vancomycin regimens used in pediatric patients did not reach the recommended therapeutic trough levels of 10 to 20 μg/mL. Patients of 2 to 12 years and low glomerular filtration rates were associated to have sub-therapeutic trough levels.

Target Attainment and Clinical Efficacy for Vancomycin in Neonates: Systematic Review.

Vancomycin is commonly used as a treatment for neonatal infections. However, there is a lack of consensus establishing the optimal vancomycin therapeutic regimen and defining the most appropriate PK/PD parameter correlated with the efficacy. A recent guideline recommends AUC–guided therapeutic dosing in treating serious infections in neonates. However, in clinical practice, trough serum concentrations are commonly used as a surrogate PKPD index for AUC24. Despite this, target serum concentrations in a neonatal population remain poorly defined. The objective is to describe the relationship between therapeutic regimens and the achievement of clinical or pharmacokinetic outcomes in the neonatal population. The review was carried out following PRISMA guidelines. A bibliographic search was manually performed for studies published on PubMed and EMBASE. Clinical efficacy and/or target attainment and the safety of vancomycin treatment were evaluated through obtaining serum concentrations. A total of 476 articles were identified, of which 20 met the inclusion criteria. All of them evaluated the target attainment, but only two assessed the clinical efficacy. The enormous variability concerning target serum concentrations is noteworthy, which translates into a difficulty in determining which therapeutic regimen achieves the best results. Moreover, there are few studies that analyze clinical efficacy results obtained after reaching predefined trough serum concentrations, this information being essential for clinical practice.

Vedolizumab Tissue Concentration Correlates to Mucosal Inflammation and Objective Treatment Response in Inflammatory Bowel Disease.

BackgroundThe association between vedolizumab (VDZ) exposure and treatment response is unclear and seems insufficiently explained by serum levels. The aim of this study was to assess the correlation between VDZ concentrations in serum and intestinal tissue and their association with mucosal inflammation and response to VDZ.MethodsThis prospective study included 37 adult patients with inflammatory bowel disease with endoscopic inflammation at baseline who started VDZ. At week 16, serum and biopsies were collected for VDZ measurement by enzyme-linked immunosorbent assay. Nonlinear mixed-effects modeling was used to calculate serum trough concentrations and to assess intestinal tissue concentrations. Validated clinical and endoscopic scores were used to define clinical and endoscopic response and remission, and fecal calprotectin levels were used to assess biochemical response. Histologic remission was determined by the Nancy score.ResultsA positive correlation was observed between VDZ concentrations in serum and tissue (r2 = 0.83; P < 0.0001). High mucosal rather than serum VDZ levels correlated with a reduced endoscopic (P = 0.06) grade of mucosal inflammation. Furthermore, patients with a positive biochemical and endoscopic outcome had higher tissue levels of VDZ than patients without biochemical and endoscopic response (P < 0.01 and P = 0.04, respectively).ConclusionsTissue levels of VDZ may provide a better marker than serum levels for mucosal inflammation and objective treatment outcome at week 16. The potential of VDZ tissue levels for therapeutic drug monitoring in inflammatory bowel disease warrants further exploration.

Software to predict the right dose for vancomycin in a clinical environment-A commentary on: Personalised dosing of vancomycin: A prospective and retrospective comparative quasi-experimental study by Luqman Vali et al.

Software to predict the right dose for vancomycin in a clinical environment-A commentary on: Personalised dosing of vancomycin: A prospective and retrospective comparative quasi-experimental study by Luqman Vali et al.

Usefulness and Potential Pitfalls of Long-Acting Growth Hormone Analogs.

Daily recombinant human GH (rhGH) is currently approved for use in children and adults with GH deficiency (GHD) in many countries with relatively few side-effects. Nevertheless, daily injections can be painful and distressing for some patients, often resulting in non-adherence and reduction of treatment outcomes. This has prompted the development of numerous long-acting GH (LAGH) analogs that allow for decreased injection frequency, ranging from weekly, bi-weekly to monthly. These LAGH analogs are attractive as they may theoretically offer increased patient acceptance, tolerability, and therapeutic flexibility. Conversely, there may also be pitfalls to these LAGH analogs, including an unphysiological GH profile and differing molecular structures that pose potential clinical issues in terms of dose initiation, therapeutic monitoring, incidence and duration of side-effects, and long-term safety. Furthermore, fluctuations of peak and trough serum GH and IGF-I levels and variations in therapeutic efficacy may depend on the technology used to prolong GH action. Previous studies of some LAGH analogs have demonstrated non-inferiority compared to daily rhGH in terms of increased growth velocity and improved body composition in children and adults with GHD, respectively, with no significant unanticipated adverse events. Currently, two LAGH analogs are marketed in Asia, one recently approved in the United States, another previously approved but not marketed in Europe, and several others proceeding through various stages of clinical development. Nevertheless, several practical questions still remain, including possible differences in dose initiation between naïve and switch-over patients, methodology of dose adjustment/s, timing of measuring serum IGF-I levels, safety, durability of efficacy and cost-effectiveness. Long-term surveillance of safety and efficacy of LAGH analogs are needed to answer these important questions.

Effectiveness and Safety of Nonmedical Switch From Adalimumab Originator to SB5 Biosimilar in Patients With Inflammatory Bowel Diseases: Twelve-Month Follow-Up From the TABLET Registry

Few data are currently available about SB5 in inflammatory bowel diseases (IBD). The aim of this study was to assess the effectiveness and safety of SB5 in a cohort of patients with IBD in stable remission switched from the adalimumab (ADA) originator and in a cohort of patients with IBD naïve to ADA. We prospectively enrolled patients with IBD who started ADA treatment with SB5 (naïve cohort) and those who underwent a nonmedical switch from the ADA originator to SB5 (switching cohort). Clinical remission and safety were assessed at baseline and at 3, 6, and 12 months. In addition, in a small cohort of patients who were switched, we assessed the ADA serum trough levels and antidrug antibodies at baseline, 3, and 6 months. In the naïve cohort, the overall remission rate at 12 months was 60.42%, whereas in the switching cohort it was 89.02%. Fifty-three (36.3%) patients experienced an adverse event, and injection site pain was the most common; it was significantly more frequent in the switching cohort (P = 0.001). No differences were found in terms of ADA serum trough levels at baseline, 3, and 6 months after switching. No patient developed antidrug antibodies after the switch. We found that SB5 seemed effective and safe in IBD, both in the naïve cohort and in the switching cohort. Further studies are needed to confirm these data in terms of mucosal healing.

Efficacy and safety of biosimilar CT-P17 versus reference adalimumab in subjects with rheumatoid arthritis: 24-week results from a randomized study

BackgroundTo demonstrate equivalent efficacy of the proposed high-concentration (100 mg/ml), citrate-free adalimumab biosimilar CT-P17 to European Union-approved adalimumab (EU-adalimumab) in subjects with active rheumatoid arthritis (RA).MethodsThis randomized, double-blind phase III study (ClinicalTrials.gov, NCT03789292) randomized (1:1) subjects with active RA at 52 centers to receive CT-P17 or EU-adalimumab 40 mg subcutaneously every 2 weeks until week 52. Results to week 24 are reported here. The primary endpoint was 20% improvement by American College of Rheumatology criteria (ACR20) response rate at week 24. Equivalence was concluded if the corresponding confidence intervals (CIs) for the estimate of treatment difference were within predefined equivalence margins: − 15 to 15% (95% CI; European Medicines Agency assumption); − 12 to 15% (90% CI; Food and Drug Administration assumption). Additional efficacy, pharmacokinetic, usability, safety, and immunogenicity endpoints were evaluated.Results648 subjects were randomized (324 CT-P17; 324 EU-adalimumab). The ACR20 response rate at week 24 was 82.7% (n = 268/324) in both groups (intention-to-treat population). The 95% CI (− 5.94 to 5.94) and 90% CI (− 4.98 to 4.98) were within predefined equivalence margins for both assumptions and equivalent efficacy was concluded. Additional endpoints and overall safety were comparable between groups. Mean trough serum concentrations of CT-P17 were slightly higher than those of EU-adalimumab. Immunogenicity was slightly lower numerically for the CT-P17 group than for the EU-adalimumab group.ConclusionsCT-P17 and EU-adalimumab have equivalent efficacy and comparable safety and immunogenicity in subjects with active RA. Overall safety of CT-P17 is consistent with the known safety profile of reference adalimumab.Trial registrationClinicalTrials.gov, NCT03789292. Registered 28 December 2018—retrospectively registered.

Vedolizumab Concentrations in Breast Milk: Results from a Prospective, Postmarketing, Milk-Only Lactation Study in Nursing Mothers with Inflammatory Bowel Disease.

Background and ObjectivesThe safety of inflammatory bowel disease medications during lactation is of significant relevance to women of childbearing potential. Available data regarding the transfer of biologic agents for inflammatory bowel disease via breast milk are limited to case reports. The objective of this prospective postmarketing lactation study was to assess vedolizumab concentrations in breast milk from lactating vedolizumab-treated women with inflammatory bowel disease.MethodsBreast milk was serially collected throughout the dosing interval from 11 patients receiving established intravenous vedolizumab 300-mg maintenance therapy every 8, 6, or 4 weeks. Maternal safety was also assessed.ResultsVedolizumab was detectable in ~90% of milk samples collected from all patients. Following the day 1 dose, vedolizumab milk concentrations increased with a median of 3–4 days to peak concentration, and subsequently decreased exponentially. For the nine patients receiving vedolizumab every 8 weeks, the average relative infant dose was 20.9%. Using a mean trough serum concentration of 11.2 µg/mL from historical studies, the ratio of mean vedolizumab milk-to-serum concentration was ~ 0.4 to 2.2%, consistent with published data on vedolizumab and other monoclonal antibody therapeutics for inflammatory bowel disease. The maternal safety profile was similar to that observed in previous vedolizumab studies. Published vedolizumab studies also showed no adverse findings for infants breastfed by vedolizumab-treated mothers.ConclusionsVedolizumab was present in human breast milk at a low level. The decision to use vedolizumab should balance the benefit of therapy to the mother and the potential risks to the infant.Trial RegistrationClinicalTrials.gov, NCT02559713; registered 24 September, 2015.

A phase 2 study of E6011, an anti-Fractalkine monoclonal antibody, in patients with rheumatoid arthritis inadequately responding to biological disease-modifying antirheumatic drugs

Objectives To evaluate the safety and efficacy of E6011, a novel humanized anti-fractalkine monoclonal antibody, in patients with active rheumatoid arthritis (RA) with an inadequate response to biological disease-modifying antirheumatic drugs (DMARDs). Methods Active RA patients inadequately responding to biological DMARDs were randomly assigned to placebo or E6011 400-mg group at a 1:1 ratio, and administered E6011 at weeks 0, 1, 2, and subsequently every 2 weeks. Primary endpoint was American College of Rheumatology (ACR)20 response at week 12. Results Of 64, 33 received placebo, 31 received E6011 400-mg. The ACR20 response rate at week 12 (non-responder imputation) was 27.3% and 22.6% in the placebo and E6011 groups, respectively. ACR50, ACR70 response rates at week 12 were 3.0%, 0% in the placebo and 9.7%, 3.2% in the E6011 group. Exploratory PK exposure analysis revealed that the effect of E6011 tended to be clearer in patients with higher serum trough E6011 concentration. E6011 was well tolerated with no notable safety concerns. Conclusions E6011 400-mg was well tolerated but had no clear efficacy at week 12 in RA patients with inadequate response to biologics. Further investigations are warranted to determine the optimal clinical dose and evaluation period for E6011.

Phase I dose-escalation study of MCLA-158, a first-in-class bispecific antibody targeting EGFR and LGR5, in metastatic colorectal cancer (CRC).

62 Background: The WNT and EGFR signaling pathways are oncogenic and mitogenic drivers in CRC and other cancers. MCLA-158 is an ADCC enhanced human IgG1 cLC bispecific antibody identified from functional screening of CRC patient (pt)-derived organoids (PDO). MCLA-158 exposure leads to EGFR degradation in LGR5+ cancer and exhibits potent growth inhibition of RASmut and wt CRC PDOs, while minimal inhibition is observed in non-tumoral PDOs. Blockade of metastasis initiation was seen in preclinical in vivo models. MCLA-158 also demonstrated tumor regression or stasis in esophageal squamous (6/6) and gastric adenocarcinoma (6/8) PDX models selected for LGR5 and EGFR expression. Methods: Metastatic CRC pts progressing after oxaliplatin, irinotecan and fluoropyrimidines, and EGFR monoclonal antibodies if RASwt, received MCLA-158 IV every 2 weeks (q2w; 4-week cycle) in a phase I study. Safety, efficacy (per RECIST 1.1), PK and ADA were assessed. WNT and EGFR pathway components were evaluated in tumor tissue. EGFR pathway mutations (ctDNA) and soluble EGFR (sEGFR) were assessed in blood. PDOs were derived from baseline biopsies and assessed for MCLA-158 responsiveness. Results: As of 7 September 2020, 33 pts were treated over 11 dose levels (5 to 1500 mg, flat dose). At enrollment, median age was 58 years (range 35-76), ECOG PS 0/1:22/11, and 15 pts were RASmut. Pts had a median of 3 metastatic sites (range 1-12) with a median of 4 prior lines of therapy (range 1-10). A median of 2 MCLA-158 cycles (range 1-6) were administered. No dose limiting toxicity occurred. Infusion-related reactions were the most common AEs (67% of pts), occurred mostly in cycle 1 (21/22 pts), and were manageable. Other common related AEs included rash acneiform (36%), diarrhea (15%), pyrexia (9%) and asthenia/fatigue (9%). Related AEs were mostly mild or moderate; G3 related AEs were IRRs (4 pts; 12%), diarrhea and hypophosphatemia (1 pt each). The RP2D (1500 mg) was selected based on safety, PK and receptor occupancy prediction. MCLA-158 exhibited target-mediated clearance with proportional PK from 750 mg (t1/2 ~80 h at 1500 mg). Low ADA titers were seen in 3/23 pts, with no effect on PK. Target saturation is predicted at steady state serum trough levels. No clinical responses were observed during dose escalation. No/low baseline tumor EGFR expression (0-1+ IHC) was observed in 17/30 pts and non-elevated sEGFR levels ( &lt; 4 ng/mL) in 18/22 pts. More than 1 activating mutation in EGFR signaling pathway genes were identified in ctDNA from 10/20 pts. 1/4 PDOs had &gt; 30% growth inhibition with MCLA-158 ex vivo. MCLA-158 activity on PDOs correlated negatively with the presence of EGFR pathway resistance-mutations. Conclusions: Dual EGFR/LRG5 blockade with MCLA-158 was well tolerated, and the RP2D was 1500 mg IV q2w. Enrollment of pts with gastric and other non-CRC cancers at the RP2D continues in the expansion phase. Clinical trial information: NCT03526835.

Evaluation of a thrice weekly administration of teicoplanin in the outpatient setting: a retrospective observational multicentre study

IntroductionThe glycopeptide teicoplanin is commonly utilized to facilitate outpatient parenteral antimicrobial therapy (OPAT). Licensed for once daily maintenance dosing, teicoplanin’s long half-life allows for less frequent dosing (e.g. thrice weekly) following successful loading. This service evaluation reviews the safety and effectiveness of a novel thrice weekly teicoplanin dosing regimen.MethodsA retrospective, observational study was conducted at Chelsea and Westminster Hospital (March 2018 to July 2020), evaluating trough serum teicoplanin concentrations for patients receiving >5 days of teicoplanin in the OPAT setting. Teicoplanin dosing and administration (once daily versus thrice weekly), clinical outcomes and therapeutic levels were analysed for all patients. The project was registered with clinical governance locally.ResultsA total of 82 patients treated with teicoplanin in the OPAT service were included; 53/82 receiving thrice weekly and 29/82 receiving once daily dosing. Mean teicoplanin trough levels were similar in both groups (26.2 mg/L and 25.8 mg/L in once daily and thrice weekly groups, P = 0.8895). High clinical success rates were recorded in both groups (25/29 [86.2%] versus 50/53 [94.3%]). No correlation with clinical outcomes and initial teicoplanin serum levels was identified. Normal renal function (>90 mL/min) was associated with lower teicoplanin serum concentrations (mean [±SD] 21.4 mg/L [±10.1] versus 29.7 mg/L [±14], P = 0.0178) in the thrice weekly dosed group but not with the once daily dosed group (mean [±SD] 28.2 mg/L [±9.4] versus 23.7 mg/L [±9.9], P = 0.2201).ConclusionsThis study supports thrice weekly teicoplanin as a convenient and effective OPAT for administration in the OPAT setting. Therapeutic drug monitoring is advised to adjust for intra-patient variability.