Mass Balance, Metabolic Pathways, Absolute Bioavailability, And Pharmacokinetics of Giredestrant In Healthy Subjects.

Giredestrant is a potent and selective small molecule estrogen receptor degrader. The objectives of this study were to assess the absolute bioavailability (aBA) of giredestrant and to determine the mass balance, routes of elimination and metabolite profile of [14C]giredestrant. In Part 1 (mass balance), a single 30.8 mg oral dose of [14C]giredestrant (105 µCi) was administered to women of non-childbearing potential (WNCBP, n = 6). The mean recovery of total radioactivity (TR) in excreta was 77.0%, with 68.0% of the dose excreted in feces and 9.04% excreted in urine over a 42-day sample collection period. The majority of the circulating radioactivity (56.8%) in plasma was associated with giredestrant. Giredestrant was extensively metabolized with giredestrant representing only 20.0% and 1.90% of the dose in feces and urine, respectively. All metabolites in feces resulted from oxidative metabolism and represented 44.7% of the dose. In Part 2 (absolute bioavailability, aBA), WNCBP (n = 10) received an oral (30 mg capsule) or intravenous (30 mg solution) dose of giredestrant. The aBA of giredestrant after oral administration was 58.7%. Following the intravenous dose, giredestrant had a plasma clearance and volume of distribution of 5.31 L/h and 266 L, respectively. In summary, giredestrant was well tolerated, rapidly absorbed, and showed moderate oral bioavailability with low recovery of the dose as parent drug in excreta. Oxidative metabolism followed by excretion in feces was identified as the major route of elimination of giredestrant. Significance Statement This study provides definitive insight into the absorption, distribution, metabolism, and excretion of giredestrant in humans. The results show that giredestrant exhibits low clearance, high volume of distribution, and moderate oral bioavailability in humans. In addition, the data show that oxidative metabolism followed by excretion in feces is the primary elimination route of giredestrant in humans. These results will be used to further inform the clinical development of giredestrant.

Efficacy of customized crown-level position jig in measuring peri-implant crestal bone level on periapical radiographs: An in vitro study.

Background/purpose: Accuracy of using implant length on periapical radiographs as calibration reference for measurements has not been verified. This study aimed to verify the measurements of peri-implant crestal bone level (piCBL) on periapical radiographs taken by the paralleling technique and using the implant length for calibration; and to propose a customized crownlevel position (CLP) jig to improve the measurement accuracy of piCBL. Materials and methods: A typodont installed an implant and a screw-retained crown at maxillary central incisor was used. To simulate piCBL, a metal post was placed near the implant at the same height of implant platform. The CLP jig was designed and 3-dimensionally printed out to allow implant projected orthogonally on periapical film. Thirty periapical radiographs were taken using paralleling technique with and without the jig by three examiners. The implant axis and implant length on radiographs were acquired by image segmentation. The discrepancy of piCBL determination (ΔD) from these measurements were compared and further analyzed when using the implant length for calibration. Results: The piCBL measurement errors were smaller when the jig was used for all examiners (P < 0.001). The inter-rater differences were insignificant. After calibration, ΔD with and without jig were 0.09 (0.07-0.11) and 0.43 (0.38-0.49) mm, respectively. Conclusion: Conventional long-cone paralleling technique using true implant length for calibration demonstrated imprecise piCBL measurement on periapical radiographs. Transferring the implant axis to the CLP jig allowed orthogonal projection of radiography which provided reliable measurements of piCBL with an accuracy of less than 0.1 mm.

UGT1A4 Polymorphism is not Associated with a Clinically Relevant Change in Giredestrant Exposure.

PURPOSE: Giredestrant is a potent, orally bioavailable, small-molecule selective estrogen receptor antagonist and degrader (SERD) that is being developed for the treatment of patients with estrogen receptor (ER)-positive breast cancer. In vitro, giredestrant was primarily metabolized by UGT1A4. The goal of this study was to investigate if UGT1A4 polymorphism had a clinically relevant impact on giredestrant exposure. METHODS: Genotyping and pharmacokinetic data were obtained from 118 and 61 patients in two clinical studies, GO39932 [NCT03332797] and acelERA Breast Cancer [NCT04576455], respectively. RESULTS: The overall allelic frequencies of UGT1A4*2 and UGT1A4*3 were 3.3% and 11%, respectively. Giredestrant exposure was consistent between patients with wild-type UGT1A4 and UGT1A4*2 and *3 polymorphisms, with no clinically relevant difference observed. In addition, haplotype analysis indicated that no other UGT1A4 variants were significantly associated with giredestrant exposure. CONCLUSION: Therefore, this study indicates that UGT1A4 polymorphism status is unlikely a clinically relevant factor to impact giredestrant exposure and giredestrant can be administered at the same dose level regardless of patients' UGT1A4 polymorphism status.

Optimizing Early-stage Clinical Pharmacology Evaluation to Accelerate Clinical Development of Giredestrant in Advanced Breast Cancer.

PURPOSE: We describe the clinical pharmacology characterization of giredestrant in a first-in-human study. EXPERIMENTAL DESIGN: This phase Ia/Ib dose-escalation/-expansion study (NCT03332797) evaluated the safety, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of giredestrant in estrogen receptor-positive HER2-negative locally advanced/metastatic breast cancer. The single-agent dose-escalation stage evaluated giredestrant 10, 30, 90, or 250 mg once daily. The dose-expansion stage evaluated single-agent giredestrant at 30, 100, and 250 mg once daily. Dose-escalation and -expansion phases also evaluated giredestrant 100 mg combined with palbociclib 125 mg. RESULTS: Following single-dose oral administration, giredestrant was rapidly absorbed and generally showed a dose-proportional increase in exposure at doses ranging from 10 to 250 mg. At the 30 mg clinical dose, maximum plasma concentration was 266 ng/mL (50.1%) and area under the concentration-time curve from 0 to 24 hours at steady state was 4,320 ng·hour/mL (59.4%). Minimal giredestrant concentrations were detected in urine, indicating that renal excretion is unlikely to be a major elimination route for giredestrant. Mean concentration of 4beta-hydroxycholesterol showed no apparent increase over time at both the clinical dose (30 mg) and a supratherapeutic dose (90 mg), suggesting that giredestrant may have low CYP3A induction potential in humans. No clinically relevant drug-drug interaction was observed between giredestrant and palbociclib. Giredestrant exposure was not affected by food and was generally consistent between White and Asian patients. CONCLUSIONS: This study illustrates how the integration of clinical pharmacology considerations into early-phase clinical trials can inform the design of pivotal studies and accelerate oncology drug development. SIGNIFICANCE: This work illustrates how comprehensive clinical pharmacology characterization can be integrated into first-in-human studies in oncology. It also demonstrates the value of understanding clinical pharmacology attributes to inform eligibility, concomitant medications, and combination dosing and to directly influence late-stage trial design and accelerate development.

Long-term evaluation of peri-implant keratinized mucosa stability after free epithelialized graft and keratinized mucosa shifting procedures: A retrospective study up to 13 years.

OBJECTIVES: This study aimed to assess the risk of less than 2 mm keratinized mucosa (KM) width occurrence after free epithelialized graft (FEG) and keratinized mucosa shifting (KMS) procedures using survival analysis. In addition, KM dimensional changes were evaluated. MATERIALS AND METHODS: This study included 76 implants in 36 patients with insufficient KM (<2 mm). The implants underwent either FEG or KMS procedures. The mid-buccal KM width was measured from surgery to the end of a one 13-year follow-up period. RESULTS: Mean follow-up durations were 9.2 ± 3.9 years for FEG and 6.3 ± 4.2 years for KMS. Two implants in FEG and nine implants in KMS exhibited a KM width of less than 2 mm during follow-up. The hazard ratios for KMS compared to FEG were 6.48 (crude) and 6.54 (adjusted), both statistically significant (p < .05). The incidence rate of KMS (4.06%) was higher than that of FEG (0.63%), with an average incidence time of 3.38 years for KMS and 8.82 years for FEG post-surgery. FEG showed a significant shrinkage within 6 months (33% ± 22%), whereas KMS demonstrated a gradual decrease over 13 years (34% ± 25%). FEG exhibited significantly greater width change than KMS during a 5-year follow-up (p < .05). CONCLUSIONS: FEG and KMS enhanced PIKM but exhibited different long-term reduction patterns. FEG demonstrated rapid shrinkage, while KMS displayed gradual and continuous reduction. Moreover, KMS presented a higher risk and incidence of KM width less than 2 mm compared to FEG.

Concentration QTc analysis of giredestrant: Overcoming QT/heart rate confounding in the presence of drug-induced heart rate changes.

Concentration-QTc (C-QTc) analysis has become a common approach for evaluating proarrhythmic risk and delayed cardiac repolarization of oncology drug candidates. Significant heart rate (HR) change has been associated with certain classes of oncology drugs and can result in over- or underestimation of the true QT prolongation risk. Because oncology early clinical trials typically lack a placebo control arm or time-matched, treatment-free baseline electrocardiogram collection, significant HR change brings additional challenges to C-QTc analysis in the oncology setting. In this work, a spline-based correction method (QTcSPL) was explored to mitigate the impact of HR changes in giredestrant C-QTc analysis. Giredestrant is a selective estrogen receptor degrader being developed for the treatment of patients with estrogen receptor-positive (ER+) breast cancer. A dose-related HR decrease has been observed in patients under giredestrant treatment, with significant reductions (>10 bpm) observed at supratherapeutic doses. The QTcSPL method demonstrated superior functionality to reduce the correlation between QTc and HR as compared with the Fridericia correction (QTcF). The effect of giredestrant exposure on QTc was evaluated at the clinical dose of 30 mg and supratherapeutic dose of 100 mg based on a prespecified linear mixed effect model. The upper 90% confidence interval of ΔQTcSPL and ΔQTcF were below the 10 ms at both clinical and supratherapeutic exposures, suggesting giredestrant has a low risk of QT prolongation at clinically relevant concentrations. This work demonstrated the use case of QTcSPL to address HR confounding challenges in the context of oncology drug development for the first time.

Real-world data prognostic model of overall survival in patients with advanced NSCLC receiving anti-PD-1/PD-L1 immune checkpoint inhibitors as second-line monotherapy.

BACKGROUND AND AIM: The objective of this retrospective, observational, noninterventional cohort study was to investigate prognostic factors of overall survival (OS) in patients with advanced non-small cell lung cancer (aNSCLC) and to develop a novel prognostic model. METHODS: A total of 4049 patients with aNSCLC diagnosed between January 2011 and February 2020 who received atezolizumab, nivolumab, or pembrolizumab as second-line monotherapy were selected from a real-world deidentified database to build the cohort. Patients could not have received first-line treatment with clinical study drug(s) nor immune checkpoint inhibitors including anti-programmed cell death 1 (PD-1)/programmed death-ligand 1 (PD-L1), and anti-cytotoxic T-lymphocyte-associated protein 4 therapies. RESULTS: Patients had a median age of 69 years; 45% were female, 75% White, 70% had stage IV at initial diagnosis, and 70% had nonsquamous histology. A Cox proportional hazards model with lasso regularization was used to build a prognostic model for OS using 18 baseline demographic and clinical factors based on the real-world data cohort. The risk-increasing prognostic factors were abnormally low albumin and chloride levels, Eastern Cooperative Oncology Group performance status score ≥ 2, and abnormally high levels of alkaline phosphatase and white blood cells. The risk-decreasing prognostic factors were PD-L1 positivity, longer time from advanced diagnosis to start of first-line therapy, and higher systolic blood pressure. The performance of the model was validated using data from the OAK trial, and the c-index for the OAK trial validation cohort was 0.65 and 0.67 for the real-world data cohort. CONCLUSIONS: Based on baseline demographic and clinical factors from a real-world setting, this prognostic model was developed to discriminate the risk of death in patients with aNSCLC treated with checkpoint inhibitors as second-line monotherapy, and it performed well in the real-world data and clinical trial cohorts.

Latest generation estrogen receptor degraders for the treatment of hormone receptor-positive breast cancer.

INTRODUCTION: The selective estrogen receptor degrader (SERD) and full receptor antagonist provides an important therapeutic option for hormone receptor (HR)-positive breast cancer. Endocrine therapies include tamoxifen, a selective estrogen receptor modulator (SERM), that exhibits receptor agonist and antagonist activity, and aromatase inhibitors that block estrogen biosynthesis but which demonstrate acquired resistance. Fulvestrant, the only currently approved SERD, is limited by poor drug-like properties. A key focus for improving disease management has been development of oral SERDs with optimized target occupancy and potency and superior clinical efficacy. AREAS COVERED: Using PubMed, clinicaltrials.gov, and congress websites, this review explored the preclinical development and clinical pharmacokinetics from early phase clinical studies (2015 or later) of novel oral SERDs, including giredestrant, amcenestrant, camizestrant, elacestrant, and rintodestrant. EXPERT OPINION: Numerous oral SERDs are in clinical development, aiming to form the core endocrine therapy for HR-positive breast cancer. Through property- and structure-based drug design of estrogen receptor-binding, antagonism, degradation, anti-proliferation, and pharmacokinetic properties, these SERDs have distinct profiles which impact clinical dosing, efficacy, and safety. Assuming preliminary safety and activity data are confirmed in phase 3 trials, these promising agents could further improve the management, outcomes, and quality of life in HR-positive breast cancer.

Influence of maxillary antrolith on the clinical outcome of implants placed simultaneously with osteotome sinus floor elevation: A retrospective radiographic study.

BACKGROUND: Large antroliths and those located adjacent to the sinus floor can affect clinical interventions and increase the difficulty of implant placement performed simultaneously with osteotome sinus floor elevation surgery. PURPOSE: This retrospective study investigated the clinical outcomes of implants placed simultaneously with osteotome sinus floor elevation subjacent to maxillary antroliths. MATERIAL AND METHODS: Twenty implants inserted subjacent to or intruding into the antrolith after sinus floor elevation were evaluated in 18 patients. Cone-beam computed tomography (CBCT) was used to measure antrolith size and membrane thickness at sites of osteotome sinus floor elevation. Periapical radiographs were used to assess the height of grafted bone. Generalized estimating equation (GEE) analysis was performed to correlate the occurrence of antroliths with patient background characteristics and dental outcomes, based on a sample population of 239, among whom 33 presented antroliths. RESULTS: The 20 implants remained clinically stable over a mean follow-up period of 42.4 months. The mean thickness of the sinus membrane at osteotome sites was 5.4 ± 3.3 mm. None of the cases presented sinus membrane perforation or sinus symptoms following osteotome intervention. The mean gain in the height of grafted sinus bone was 4.0 ± 1.4 mm at the last follow-up. The occurrence of antroliths was higher among females and the elderly (>49 years old). The multivariable GEE analysis showed that the adjusted odds ratio for the occurrence of antroliths with root canal fillings was significantly lower than those without root canal fillings (odds ratio = 0.33; 95% confidence interval = 0.11-0.96). CONCLUSION: Our findings indicate that osteotome sinus floor elevation is a surgical procedure with a risk <17%. Thorough planning based on CBCT and careful management during surgery can eliminate the negative effects of antroliths on implant performance.

Differences in parent-perceived and patient-reported quality of life among young adult burn patients: A prospective longitudinal study.

PURPOSE: This study examines the differences in parent-perceived and patient-reported quality of life (QoL) among young adult burn patients three years after injury and the factors affecting these differences. METHOD: The sample comprised 35 burn patients from the Formosa Fun Coast Water Park dust explosion and their parents. The study was conducted from June 2016 to August 2018. We used self-report questionnaires to collect socio-demographic data, the adapted Chinese version of the Burn Specific Health Scale-Brief, and the Impact of Events Scale for Burn. RESULTS: The analysis indicated that simple abilities recovered the fastest, while body image recovered the slowest. The variation trends of these factors were similar but parents' scores were lower than patients' scores. Parents' post-traumatic stress disorder (PTSD) scores were higher than that of patients, but were not statistically significant. Parents' gender and PTSD levels and patients' burn area affected differences in parent-perceived QoL among patients. PTSD levels were significantly higher among mothers. CONCLUSIONS: For parents, PTSD is a common response to their children experiencing burn injuries. Parents' observations of warning signs enable early medical intervention. Establishing a family-centered care plan, providing psychological support for both parents and patients, and forming a continuous care system with efficient communication can support patients' return to society.

Tumor Time-Course Predicts Overall Survival in Non-Small Cell Lung Cancer Patients Treated with Atezolizumab: Dependency on Follow-Up Time.

The large heterogeneity in response to immune checkpoint inhibitors is driving the exploration of predictive biomarkers to identify patients who will respond to such treatment. We extended our previously suggested modeling framework of atezolizumab pharmacokinetics, IL18, and tumor size (TS) dynamics, to also include overall survival (OS). Baseline and model-derived variables were explored as predictors of OS in 88 patients with non-small cell lung cancer treated with atezolizumab. To investigate the impact of follow-up length on the inclusion of predictors of OS, four different censoring strategies were applied. The time-course of TS change was the most significant predictor in all scenarios, whereas IL18 was not significant. Identified predictors of OS were similar regardless of censoring strategy, although OS was underpredicted when patients were censored 5 months after last dose. The study demonstrated that the tumor-time course-OS relationship could be identified based on early phase I data.

The Formosa Fun Coast water park dust explosion accident: Three-year cohort study to track changes and analyze the influencing factors of burn survivors' quality of life.

Nearly 500 people were injured in the dust explosion at the Formosa Fun Coast water park in 2015, making it the accident with the largest number of burn victims in Taiwan. Severe burn injuries are often accompanied by long-term impacts on physical, psychological, social, occupational, and aesthetic wellness. Survivors usually require several years or even decades of medical rehabilitation and psychological counseling, which inevitably affect their quality of life (QoL). The purpose of this study was to assess the changes in the QoL and the risk of posttraumatic stress disorder (PTSD) among the survivors of the 2015 dust explosion at the Formosa Fun Coast water park and discuss the potential influencing factors. Data were collected from the burn victims using a self-administered sociodemographic and injury characteristics questionnaire, the adapted Chinese version of the Burn Specific Health Scale-Brief (ACV BSHS-B), and the Impact of Event Scale for Burns (IESB). IBM-SPSS (Version 21.0) was used for the statistical analysis of the data. A total of 81 patients were enrolled in this study from July 2016 to August 2018. The study results revealed that gender, employment status after the burn injury, marital status, injury area, and the presence of facial burns greatly affected survivors' QoL three years following the injury. Survivors' simple abilities (Mean: 3.91 out of 4 on average, SD: .21) showed the best recovery and improved significantly over time. Employment (Mean: 2.33, SD: .98) and body image (Mean: 1.94, SD: .95) were considered the most influential factors on QoL, with no significant improvement over the three years. Moderate to severe pain, itching, and sleep problems caused by the dust explosion still affected 29.2%, 46.6%, and 58.1% of survivors after three years, respectively. Survivors with more severe symptoms had worse QoL and a higher risk of PTSD. The burn accident affected not only the injured individuals but also their entire families. In order to help injured individuals reintegrate into society and maintain better overall health, our study suggested providing family-based healthcare plans and necessary follow-up visits in a timely manner.

On the misincorporation of nucleotides opposite mutagenic cyclic 1,N2-propanoguanine: A computational investigation.

The misincorporation properties of exocyclic DNA adduct, cyclic 1,N2-propanoguanine with nucleobases have been investigated using DFT and DFT-D methods. Number of possible and stable mispairing conformations of cyclic 1,N2-propanoguanine with A,T,G and C have been considered for our investigation. The single point energy calculations have been carried out at the M06/6-311++G**, ωB97XD/6-311++G** and MP2/6-311++G** levels on corresponding optimized geometries. The reaction enthalpy values were employed at the M06/6-31 + G* and ωB97XD/6-31 + G* levels. The energies have been compared among the cyclic 1,N2-propanoguanine adduct with nucleobases to find the most stable conformer. The CPCM model was utilized on account of solvent phase and overall polarizability. The computed binding energies follow the order as CPr-Gua-G(2)(-23.2 kcal/mol) > CPr-Gua-C(1) (-16.1 kcal/mol) > CPr-Gua-A(2)(-10.6 kcal/mol) > CPr-Gua-T(2)(-9.6 kcal/mol) in the gas phase at M06 level, which indicates the guanine and cytosine are favorable for mispairing with the cyclic 1,N2-propanoguanine adduct. The obtained results using computational tools are in good agreement with the experimental observation.

Combining expression of GPC3 in tumors and CD16 on NK cells from peripheral blood to identify patients responding to codrituzumab.

BACKGROUND: Codrituzumab, a monoclonal antibody targeting an oncofetal protein glypican-3 (GPC3) expressed on cell surface of hepatocellular carcinoma (HCC) induces antibody-dependent cellular cytotoxicity (ADCC) and inhibits tumor growth in preclinical studies. Based on this mechanism, tumor GPC3 expression and CD16 expression on NK cells, which are the effector cells of ADCC, were investigated to correlate with codrituzumab's clinical efficacy in patients with advanced HCC. RESULTS: Joint analyses of the two biomarkers revealed that both high levels of GPC3 and CD16 were required for patients to benefit from codrituzumab; lack of either one of them would lead to a loss of the therapeutic effect. CONCLUSIONS: These results suggest the combination of tumor GPC3 expression and CD16 expression on NK cells from peripheral blood at baseline as a composite biomarker to select HCC patients for codrituzumab. IMPACT: The conclusion warrants a future study in an HCC population with both high GPC3 expression and high levels of CD16 at baseline to establish codrituzumab's therapeutic benefit in HCC. METHODS: Data from a phase II clinical trial of codrituzumab were used for the analyses. GPC3 expression in baseline tumor biopsies was determined by immunohistochemistry (IHC) analysis, and baseline CD16 expression on NK cells were quantified by peripheral blood lymphocyte immunophenotyping. According to high or low expression of GPC3 and CD16, different patient subgroups were formed; for each subgroup, overall survival of patients having high codrituzumab exposure was compared to that of patients receiving placebo.

Time-to-event modelling of effect of codrituzumab on overall survival in patients with hepatocellular carcinoma.

AIMS: Codrituzumab (GC33) is a recombinant, humanized mAb that binds to glypican-3 (GPC3), an oncofetal protein highly expressed in hepatocellular carcinoma (HCC). This investigation aimed to identify clinically relevant factors that may affect the overall survival (OS) in HCC patients treated with codrituzumab and to quantitatively annotate their effects. METHODS: Codrituzumab exposure was estimated by a population pharmacokinetics model with a nonlinear elimination pathway. Analysis of OS was performed using a time-to-event model in 181 patients with advanced HCC. The model was tested with the addition of various covariates, including levels of immune biomarkers, such as CD16 (measured in terms of molecules of equivalent soluble fluorophore; CD16MESF ) and CD4, codrituzumab exposure and potential prognostic biomarkers of HCC such as baseline tumour size and soluble GPC3. RESULTS: The time-to-event model estimated a prolonged OS (>3 months) in patients with codrituzumab exposure of ≥230 µg ml-1 and high CD16MESF level (>5.26 × 105 MESF at least). The Weibull model was selected as the base hazard model. The baseline tumour size was included in the hazard model as a parameter independent of the drug effect. A logistic model was applied to explain the effects of drug exposure and CD16MESF level. CONCLUSIONS: The final model indicates that adequate drug exposure plus a favourable immune environment are associated with prolonged OS. This quantitative model should be further validated with emerging data so as to guide study design in future clinical trials.

Malignant choroidal melanoma with suspected vitreous seeding - A case report.

Retinal perforation with vitreous seeding is an uncommon condition of treatment-naïve choroidal malignant melanoma. We reported a 52-year-old male who had a pigmented tumor protruding from choroid of his right eye. He had only black shadow sensation for 4 months then a rapid deterioration of vision. Fundus examination showed vitreous haze with many pigmented materials. B-scan ultrasonography revealed a mass with low internal reflectivity and vitreous opacity. The eyeball was enucleated and a stage IIIA melanoma was confirmed by the pathologist. No local recurrences or metastases were found during 31-month follow-up. Although vitreous seeding may indicate rapid tumor growth, early enucleation may insure a better prognosis.

Clinical pharmacology of tocilizumab for the treatment of polyarticular-course juvenile idiopathic arthritis.

INTRODUCTION: The efficacy and safety of tocilizumab (TCZ), a humanized anti-interleukin-6 receptor (IL-6R) monoclonal antibody, in patients with polyarticular-course juvenile idiopathic arthritis (pJIA) were demonstrated in clinical trials. Area covered: A literature search was undertaken in the public domain from 1995 to 2016. Data included in the regulatory submission leading to approval of TCZ for the treatment of pJIA in the European Union, United States, and Japan were also presented. TCZ 10 mg/kg in patients weighing <30 kg provided pharmacokinetic exposure comparable to that of TCZ 8 mg/kg for patients ≥30 kg. Pharmacodynamic (C-reactive protein, erythrocyte sedimentation rate, IL-6, and soluble IL-6R) and efficacy outcomes were comparable between TCZ 10 mg/kg in patients <30 kg and TCZ 8 mg/kg in patients ≥30 kg. Proportions of patients achieving JIA ACR 30/50/70/90 responses at week 16 increased with higher exposure (mean±SD Cmin from quartile 1 to quartile 4: 0.02 ± 0.047, 0.98 ± 0.707, 5.00 ± 1.73, and 16.54 ± 7.74 µg/mL; n = 42). The adverse event rate did not increase with increased exposure. Data support weight-based dosing regimens. Expert commentary: Biologics have improved outcomes for patients with pJIA with inadequate response to conventional therapy. TCZ will likely become an increasingly important treatment option for the management of pJIA.

Phase Ib study of codrituzumab in combination with sorafenib in patients with non-curable advanced hepatocellular carcinoma (HCC).

PURPOSE: Codrituzumab, a humanized antibody against glypican-3, is highly expressed in HCC. A phase I study evaluated the combination with sorafenib in HCC. PATIENTS AND METHODS: In a 3 + 3 design, codrituzumab was given intravenously in various doses with sorafenib 400 mg twice daily to patients with advanced HCC, age ≥18, ECOG 0-1, Child-Pugh A and B7, adequate organ functions, and no prior systemic therapy, with tumor assessment by RECIST 1.0 and safety by CTCAE 3.0. PK and pre, during, and post-therapy 124I radiolabeled codrituzumab PET scan imaging were performed. RESULTS: 41 patients were enrolled: 2.5 mg/kg weekly (qw) (12), 5 mg/kg qw (12), 10 mg/kg qw (3), 1600 mg every 2 weeks (q2w) (6), and 1600 mg qw (7). Two drug limiting toxicities occurred: grade 3 hyponatremia at 5 mg/kg and grade 3 hyponatremia and hyperglycemia at 1600 mg q2w. Adverse events occurred in 80% of patients, including at least one ≥grade 3: ten (25%) increased AST, three (7.5%) increased ALT, and ten (25%) increased lipase. There were no responses and nine (25.7%) had stable disease. PK C max and AUCt of codrituzumab and sorafenib were comparable to single-agent data. Thirteen out of 14 patients showed 124I radiolabeled codrituzumab uptake in tumor. In all three patients who underwent a post-progression PET, glypican-3 remained expressed. CONCLUSION: Codrituzumab plus sorafenib were tolerated at 1600 mg q2w and 400 mg bid, respectively, with no responses. Codrituzumab exerts selective distribution to HCC cells, and GPC3 does not show any down-regulation post-progression (NCT00976170).

Randomized phase II placebo controlled study of codrituzumab in previously treated patients with advanced hepatocellular carcinoma.

BACKGROUND & AIMS: Codrituzumab, a humanized monoclonal antibody against Glypican-3 (GPC3) that is expressed in hepatocellular carcinoma (HCC), interacts with CD16/FcγRIIIa and triggers antibody-dependent cytotoxicity. Codrituzumab was studied vs. placebo in a randomized phase II trial in advanced HCC patients who had failed prior systemic therapy. METHODS: Patients with advanced HCC who had failed prior systemic therapy, ⩾18years, Eastern cooperative oncology group (ECOG) 0-1, Child-Pugh A were randomized 2:1 to biweekly codrituzumab 1600mg vs. placebo. Patients were stratified based on GPC3 immunohistochemical expression: 2+/3+, 1+, and 0. Primary endpoint was progression free survival. Secondary endpoints include overall survival (OS), tolerability, pharmacokinetics, and an exploratory endpoint in biomarkers analysis. RESULTS: 185 patients were enrolled: 125 received codrituzumab and 60 placebo: Median age 64/63, 85/75% male, 46/42% Asian, ECOG 0 65/63%, 74/77% having vascular invasion and/or extra-hepatic metastasis. 84%/70% had prior sorafenib. Drug exposure was 98.4% of planned dose, with an identical adverse events profile between the 2 groups. The median progression free survival and overall survival in the codrituzumab vs. placebo groups in months were: 2.6 vs. 1.5 (hazard ratios 0.97, p=0.87), and 8.7 vs. 10 (hazard ratios 0.96, p=0.82). Projected Ctrough at cycle 3day 1 based exposure, high CD16/FcγRIIIa on peripheral immune cells, and GPC3 expression in the tumor, were all associated with prolonged progression free survival and overall survival. CONCLUSIONS: Codrituzumab did not show clinical benefit in this previously treated HCC population. Whether higher codrituzumab drug exposure or the use of CD16 and GPC3 as potential biomarkers would improve outcome remain unanswered questions. LAY SUMMARY: Codrituzumab is a manufactured antibody against a liver cancer protein called glypican-3. In this clinical trial, codrituzumab was not found be effective against liver cancer. It was suggested though that a higher dose of codrituzumab or selecting patients with high level of glypican-3 or its mediator CD16 might improve outcome. CLINICAL TRIAL REGISTRATION: This trial is registered at Clinicaltrials.gov (NCT01507168).

ΔNp63α Transcriptionally Regulates the Expression of CTEN That Is Associated with Prostate Cell Adhesion.

p63 is a member of the p53 transcription factor family and a linchpin of epithelial development and homeostasis. p63 drives the expression of many target genes involved in cell survival, adhesion, migration and cancer. In this study, we identify C-terminal tensin-like (CTEN) molecule as a downstream target of ΔNp63α, the predominant p63 isoform expressed in epithelium. CTEN belongs to the tensin family and is mainly localized to focal adhesions, which mediate many biological events such as cell adhesion, migration, proliferation and gene expression. Our study demonstrate that ΔNp63 and CTEN are both highly expressed in normal prostate epithelial cells and are down-regulated in prostate cancer. In addition, reduced expression of CTEN and ΔNp63 is correlated with prostate cancer progression from primary tumors to metastatic lesions. Silencing of ΔNp63 leads to decreased mRNA and protein levels of CTEN. ΔNp63α induces transcriptional activity of the CTEN promoter and a 140-bp fragment upstream of the transcription initiation site is the minimal promoter region required for activation. A putative binding site for p63 is located between -61 and -36 within the CTEN promoter and mutations of the critical nucleotides in this region abolish ΔNp63α-induced promoter activity. The direct interaction of ΔNp63α with the CTEN promoter was demonstrated using a chromatin immunoprecipitation (ChIP) assay. Moreover, impaired cell adhesion caused by ΔNp63α depletion is rescued by over-expression of CTEN, suggesting that CTEN is a downstream effector of ΔNp63α-mediated cell adhesion. In summary, our findings demonstrate that ΔNp63α functions as a trans-activation factor of CTEN promoter and regulates cell adhesion through modulating CTEN. Our study further contributes to the potential regulatory mechanisms of CTEN in prostate cancer progression.