A Phase I Clinical Study Comparing the Pharmacokinetics, Safety, and Immunogenicity of GB221 Injection and Trastuzumab (Herceptin®) in Healthy Chinese Adults.

BACKGROUND AND OBJECTIVE: GB221 is a recombinant humanized anti-HER2 monoclonal antibody. The purpose of this study was to evaluate the pharmacokinetic, safety, and immunogenicity of GB221 in healthy Chinese adults in comparison to trastuzumab (Herceptin®). METHODS: In this randomized, double-blind, parallel-group phase I clinical trial, 88 subjects were randomized 1:1 to receive a single intravenous infusion (90-100 min) of GB221 or trastuzumab (6 mg/kg). The primary pharmacokinetic parameters-maximum observed serum concentration (Cmax), area under the serum concentration-time curve from zero to the last quantifiable concentration at time t (AUC0-t), and area under the serum concentration-time curve from time zero to infinity (AUC0-∞)-of GB221 and trastuzumab were compared to establish whether the 90% confidence interval (CI) attained the 80-125% bioequivalence standard. Safety and immunogenicity were also evaluated. RESULTS: The GB221 group (n = 43) and the trastuzumab group (n = 44) showed similar pharmacokinetic characteristics. The geometric mean ratios (90% CI) of Cmax, AUC0-t, and AUC0-∞ between the two groups were 107.53% (102.25-113.07%), 108.31% (103.57-113.26%), and 108.34% (103.57-113.33%), respectively. The incidence of treatment-emergent adverse events (TEAEs) was 83.7% (36/43) of the subjects in the GB221 group and 95.5% (42/44) of the subjects in the trastuzumab group. No subjects withdrew from the trial due to TEAEs, and there were no occurrences of serious adverse events. All subjects tested negative for antidrug antibodies (ADA). CONCLUSION: GB221 demonstrated similar pharmacokinetics to trastuzumab and comparable safety and immunogenicity in healthy Chinese adults.

Nimotuzumab Plus Gemcitabine for K-Ras Wild-Type Locally Advanced or Metastatic Pancreatic Cancer.

PURPOSE: In a phase IIb trial of nimotuzumab plus gemcitabine, substantial clinical benefits were observed in patients with locally advanced or metastatic pancreatic cancer (PC). Therefore, we conducted a phase III clinical study to verify the efficacy and safety of this combination regimen in patients with K-Ras wild-type tumors (ClinicalTrials.gov identifier: NCT02395016). PATIENTS AND METHODS: Eligible patients were randomly assigned to receive nimotuzumab (400 mg once per week) or placebo followed by gemcitabine (1,000 mg/m2 on days 1, 8, and 15, once every 4 weeks) until disease progression or unacceptable toxicity. The primary end point was overall survival (OS) and the secondary end points were progression-free survival (PFS), response rates, and safety. RESULTS: A total of 480 patients were screened; 92 patients were enrolled and 82 patients with K-Ras wild-type tumors were eligible. In the full analysis set, the median OS was 10.9 versus 8.5 months, while the restricted mean survival time (RMST) was 18.05 versus 11.14 months for the investigational versus control arm (ratio of control v investigation = 0.62 [0.40-0.97]; P = .036). Median PFS was 4.2 versus 3.6 months in the investigational versus control arm (log-rank P = .04; hazard ratio, 0.60 [0.37-0.99]) and the restricted mean PFS time was 8.08 versus 4.76 months (RMST ratio, 0.58 [0.38-0.90]; P = .036). Both OS and PFS were longer in the nimotuzumab group than in the placebo group. The objective response rates and disease control rates were 7% versus 10% and 68% versus 63% for the investigational and control groups, respectively. The incidence of adverse events were comparable between the two groups. CONCLUSION: In patients with locally advanced or metastatic K-Ras wild-type PC, nimotuzumab plus gemcitabine significantly improved OS and PFS with a good safety profile.

Phase I, Randomized, Placebo-Controlled, Dose-Escalation Study of GB223, a Fully-Humanized Monoclonal Antibody to RANKL, in Healthy Chinese Adults.

BACKGROUND: GB223 is a novel, fully-humanized monoclonal antibody against the receptor activator of nuclear factor-kappa B ligand (RANKL). In this phase I study, the safety, tolerability, pharmacokinetics, pharmacodynamics, and immunogenicity of GB223 were investigated. PATIENTS AND METHODS: This was a randomized, double-blinded, placebo-controlled, single-dose escalation study conducted in 44 healthy Chinese adults. Participants were randomly assigned to receive a single subcutaneous injection dose of 7, 21, 63, 119, or 140 mg of GB223 (n = 34) or placebo (n = 10) and were followed up for 140-252 days. RESULTS: The results of noncompartmental analysis showed that GB223 was slowly absorbed after dosing, with a time to reach maximum concentration (Tmax) ranging from 5 to 11 days. Serum GB223 concentrations decreased slowly, with a long half-life ranging from 7.91 to 19.60 days. A two-compartment Michaelis-Menten model was found to best describe the pharmacokinetics of GB223, and the absorption rate of GB223 differed between males (0.0146 h-1) and females (0.0081 h-1). Serum C-terminal telopeptide of type I collagen decreased significantly postdose, and the inhibition lasted 42-168 days. No deaths or drug-related serious adverse events occurred. The most frequent adverse events were blood parathyroid hormone increased (94.1%), blood phosphorus decreased (67.6%) and blood calcium decreased (58.8%). In the GB223 group, 44.1% (15/34) of subjects were antidrug antibody positive after dosing. CONCLUSION: In this study, we demonstrated for the first time that a single subcutaneous injection of GB223, from 7 to 140 mg, is safe and well tolerated in healthy Chinese subjects. GB223 has a nonlinear pharmacokinetic profile, and sex was a potential covariate that may affect the absorption rate of GB223. CLINICAL TRIAL REGISTRATION: NCT04178044 and ChiCTR1800020338.

Difference in Efficacy and Safety of Anti-CD19 Chimeric Antigen Receptor T-Cell Therapy Containing 4-1BB and CD28 Co-Stimulatory Domains for B-Cell Acute Lymphoblastic Leukemia.

This study quantified the differences in the efficacy and safety of different stimulation domains of anti-CD19 chimeric antigen receptor (CAR) T therapy for B-cell acute lymphoblastic leukemia (B-ALL). Clinical trials related to anti-CD19 CAR T-cell therapy for B-ALL were searched in public databases from database inception to 13 November 2021. The differences in overall survival (OS) and progression-free survival (PFS) of B-ALL patients treated with anti-CAR T-cell therapy containing 4-1BB and CD28 co-stimulatory domains were compared by establishing a parametric survival function. The overall remission rate (ORR), the proportion of people with minimal residual disease (MRD)-negative complete remission (CR), the incidence of cytokine release syndrome (CRS), and the neurotoxicity across different co-stimulatory domains was assessed using a random-effects model. The correlation between the ORR, MRD-negative CR, PFS, and OS was tested. The results showed that the median OS of anti-CAR T-cell treatment containing 4-1BB and CD28 co-stimulatory domains was 15.0 months (95% CI: 11.0-20.0) and 8.5 months (95% CI: 5.0-14.0), and the median PFS was 7.0 months (95% CI: 4.0-11.5) and 3.0 months (95% CI: 1.5-7.0), respectively. Anti-CD19 CAR T-cells in the 4-1BB co-stimulatory domain showed superior benefits in patients who achieved ORR. The incidence of neurotoxicity was significantly higher in the CD28 co-stimulatory domain of anti-CD19 CAR T-cells than in the 4-1BB co-stimulatory domain. In addition, the ORR and MRD-negative CR were strongly correlated with OS and PFS, and PFS and OS were strongly correlated. The 4-1BB co-stimulatory domain suggested a better benefit-risk ratio than the CD28 co-stimulatory domain in B-ALL.

Pharmacokinetics, pharmacodynamics, safety, and immunogenicity of Gerilimzumab (GB224), a recombinant humanized interleukin-6 monoclonal antibody, in healthy Chinese adults: A randomized controlled dose-escalation study.

OBJECTIVES: This study aimed to investigate the safety, pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity of Gerilimzumab (GB224), a recombinant humanized IgG1λ monoclonal antibody against interleukin-6, in healthy Chinese adults. METHODS: Fifty-eight subjects were randomly assigned to receive a single subcutaneous dose of 2, 5, 10, 15, 20, 30 mg GB224 or placebo. Safety assessments were performed, and blood samples were collected for PK, PD, and immunogenicity analyses during a follow-up of 112 days. RESULTS: The most frequent adverse event was decreased fibrinogen (43.1%). GB224 was absorbed relatively fast with a median Tmax of 48 h (24-168 h) but eliminated slowly with a long mean half-life (839.38-981.63 h). Dose proportionality was shown to be in the dose range of 10-30 mg. A dose-dependent increase in serum interleukin-6 concentration from baseline was observed in the subjects receiving GB224. Only two subjects tested positive for antidrug antibodies after administration of GB224. CONCLUSION: GB224 had a well-tolerated safety profile, desirable PK, and a low immunogenicity following a single-dose subcutaneous administration in healthy Chinese subjects. These findings warrant further investigation.

Quantitative evaluation of therapy options for relapsed/refractory diffuse large B-cell lymphoma: A model-based meta-analysis.

New therapies for relapsed/refractory diffuse large B-cell lymphoma (r/rDLBCL) have emerged in recent years, but there have been no comprehensive quantitative comparisons of the efficacy of these therapies. In this study, the efficacy characteristics of 11 types of treatment strategy and 63 treatment regimens were compared by model based meta-analysis. We found that compared with monotherapy, association therapy had significant benefits in terms of overall survival (OS), progression-free survival (PFS), and objective response rate (ORR). However, whereas treatment regimens involving chemotherapy contributed to significant improvements in ORR and PFS, OS was not improved. In terms of treatment strategy, we identified chemotherapy in association with immunotherapy sequential autologous stem cell transplantation (ASCT), the association of two different types of immunotherapies, chemotherapy sequential ASCT, chemotherapy in association with immunotherapy, and chemotherapy in association with two types of immunotherapies as showing better efficacy. With respect to specific treatment regimens, we found that the following had better efficacy: rituximab in association with inotuzumab ozogamicin; rituximab in association with carmustine, etoposide, cytarabine, and melphalan sequential ASCT (R-BEAM+ASCT); lenalidomide in association with rituximab, etoposide, cisplatin, cytarabine, and methylprednisolone; iodine-131 tositumomab in association with BEAM sequential ASCT; and chemotherapy sequential chimeric antigen receptor T-cell immunotherapy, with median OS of 48.2, 34.2, 27.8, 25.8, and 25 months, respectively. Moreover, with respect to association therapy, there was a strong correlation between the 6-month PFS and 2-year OS. The findings of this study provide the necessary quantitative information for clinical practice and clinical trial design for the treatment of r/rDLBCL.

Quantitative comparison of the efficacies and safety profiles of three first-line non-platinum chemotherapy regimens for advanced non-small cell lung cancer.

Objectives: The purpose of this study was to quantify the efficacies and safety profiles of the three first-line non-platinum chemotherapy regimens recommended in the National Comprehensive Cancer Network guidelines. Materials and Methods: The PubMed and Cochrane Library databases were searched comprehensively, and clinical trials involving patients with advanced non-small cell lung cancer treated with one of three first-line non-platinum regimens (gemcitabine combined with vinorelbine, gemcitabine combined with docetaxel, or gemcitabine alone) were included in the analysis. A parametric proportional hazard survival model was established to analyze the time course of overall survival (OS). The objective response rate (ORR) and incidence rates of grade 3-4 adverse events (AEs) were summarized using a single-arm meta-analysis with a random-effects model. Results: Seventeen studies met the inclusion criteria. Age and performance status (PS) scores were significant predictors of OS. For each 10-years increase in age, mortality risk increased by 18.5%, and the mortality risk increased by 4% for every 10% increase in the proportion of patients with a PS score of 2. After correcting for the above factors, we found that the three first-line non-platinum chemotherapy regimens did not differ based on OS or toxicity. Conclusion: There was no significant difference in OS or toxicity among the three first-line non-platinum chemotherapy regimens. Age and PS scores were significant predictors of OS, and their heterogeneity across different studies should be considered in cross-study comparisons and sample size estimations when designing clinical trials.

Trend of drug clinical trials in mainland China from 2009 to 2020.

With the development of linnovative regulations on drug clinical trials in mainland China, the quantity and quality of drug clinical trials have gradually improved over the past decade. Based on the information of the clinical trials from the online drug clinical trial registration platform of National Medical Products Administration, we reviewed the data of drug clinical trials in mainland China from 2009 to 2020. A total of 8,593 clinical trials have been conducted during this period. The annual number of clinical trials has been increasing gradually, and peaked in 2017. There were 2,127, 1,051, 1,551, and 156 phases I, II, III, and IV clinical trials respectively. In addition, there were 3,441 bioequivalence studies. Trials for anti-tumor drugs ranked the highest (19.45%), followed by trials of drugs for infections and infestations (12.96%) and those for cardiovascular diseases (9.00%). Meanwhile the number of the clinical trial sites also increased annually. However, there were only 116 and 130 clinical trials of drugs for children and rare diseases respectively. The geographical distribution of the sites was uneven. This mapping review provides an overall look of clinical trials in China, which may be useful for domestic and international sponsors.

Long-Term Antipsychotic Effectiveness and Comparison of the Efficacy of Monotherapy and Polypharmacy in Schizophrenia: A 3-Years Follow-Up "Real World" Study in China.

Background: Discontinuation of antipsychotic treatment is a common problem in patients with schizophrenia and could reduce the effectiveness of treatment. Time to discontinuation (TTD) is one of the indicators of compliance and may also be an effective indicator of medication efficacy. The aim of the study was to compare the clinical effectiveness of quetiapine, olanzapine, risperidone, and aripiprazole in the real-world treatment of schizophrenia with 3-years follow-up. Method: A multi-center, open, cohort, prospective, real-world study was conducted. 706 patients were analyzed without intervention in medication selection and use, followed up for 3 years. Kaplan-Meier survival curves were used to draw the treatment discontinuation rates (TDR) curves at each time point. Cox proportional hazard regression model was used to assess the relative risk of TTD of antipsychotics. Results: There was a significant difference among monotherapy groups in all-cause antipsychotic treatment discontinuation (p = 0.0057). Among the four medications, the TDR of risperidone was the highest. Compared with polypharmacy, except for aripiprazole, the TDR of other three monotherapy medications were lower than that of polypharmacy, and olanzapine was statistically different (p = 0.0325). The cox regression analysis showed that after correction of Hochberg with multiple tests, only olanzapine had a relative risk lower than risperidone (p < 0.0083). Conclusions: The findings indicated that risperidone monotherapy and polypharmacy had the highest TDR and the shortest TTD. Olanzapine monotherapy had a relative risk lower than risperidone and was superior to polypharmacy.

Ethnicity evaluation of ferric pyrophosphate citrate among Asian and Non-Asian populations: a population pharmacokinetics analysis.

PURPOSE: To evaluate the potential ethnic differences of ferric pyrophosphate citrate (FPC, Triferic) in healthy subjects and patients with hemodialysis-dependent stage 5 chronic kidney disease (CKD-5HD) and identify covariates that may influence pharmacokinetics (PK) of FPC. METHODS: Data were collected from 2 Asian and 4 non-Asian clinical studies involving healthy subjects and CKD-5HD patients. Three population PK models were developed: M1 for intravenous (IV) administration of FPC in healthy subjects; M2 for dialysate administration of FPC in CKD-5HD patients; M3 for pre-dialyzer administration of FPC in CKD-5HD patients. All the models were fitted to concentration versus time data of FPC using the nonlinear mixed effect approach with the NONMEM® program. All statistical analyses were performed using SAS version 9.4. RESULTS: In total, 26 Asians and 65 non-Asians were included in the final model analysis database. Forty healthy subjects were administered FPC via intravenous (IV) route and 51 patients with CKD-5HD via dialysate (N = 50) and pre-dialyzer blood circuit administration (N = 51). The PK parameters of FPC IV were similar. The population PK model showed good parameter precision and reliability as shown by model evaluation, and no relevant influence of ethnicity on PK parameters was observed. In healthy subjects, the maximum observed plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) decreased with increase in lean body mass (LBM) and the average serum total iron at 6 h before the baseline period (Feav), whereas, in both patient populations, Cmax and AUC decreased with increase in LBM and decrease in Febaseline. Other factors such as gender, age, Feav, and ethnicity had no influence on PK exposures in patients. The influence of LBM on PK exposures in patients was smaller than that in healthy subjects (ratio of AUC0-24 for the 5th [68 kg] and 95th [45 kg] patient's LBM was almost 1). The influence of Feav and LBM on PK exposures was < 50%. CONCLUSION: The population pharmacokinetics model successfully described the PK parameters of FPC in healthy subjects and CKD-5HD patients and were comparable between Asian and non-Asian populations.

Modelling an evaluation of the efficacy and safety of gemcitabine combined with platinum in the treatment of non-small cell lung cancer.

WHAT IS KNOWN AND OBJECTIVES: Gemcitabine combined with platinum is currently the recommended first-line chemotherapy for advanced non-small cell lung cancer (NSCLC). This study aimed to quantitatively compare the efficacy and safety of gemcitabine-platinum combinations in the treatment of advanced NSCLC under different dosing regimens based on extensive literature data. METHODS: The PubMed and Cochrane Library databases were systematically searched for clinical trials in patients with NSCLC treated with a gemcitabine-platinum regimen. A parametric survival function was used to analyse the time course of overall survival (OS). The objective response rate (ORR) and the incidence of grade 3/4 adverse events were summarized using the random-effects model of a single-arm meta-analysis. RESULTS: The study included 63 arms from 47 publications, with a total sample size of 4344 patients for analysis. The model revealed that East Asians has a better survival benefit than non-East Asians, with a median OS of 16.4 (95% CI: 14.3-19.0) and 9.9 (95% CI: 8.1-12.4) months, respectively. Moreover, the OS of patients that underwent a 6-cycle treatment was significantly longer than those that had a 4-cycle treatment in non-East Asians, with a median OS of 10.2 (95% CI: 9.5-11.1) and 8.4 (95% CI: 7.7-9.3) months, respectively. However, the incidence of neutropenia, nausea and vomiting also increased after 6 cycles of treatment. When the dose of gemcitabine increased from 1000 mg/m2 to 1250 mg/m2 , the median OS was extended by approximately 1 month, but the incidence of grade 3/4 adverse reactions did not increase. WHAT IS NEW AND CONCLUSION: Race is an important factor affecting OS in the treatment of advanced NSCLC, which should be considered when conducting international multicentre clinical trials. Additionally, this study found that the OS increased with an increase in gemcitabine exposure, so it is necessary to construct an exposure-response model to obtain the best benefit-risk ratio for patients.

Whether Patients With Stage â ¡/â ¢ Colorectal Cancer Benefit From Adjuvant Chemotherapy: A Modeling Analysis of Literature Aggregate Data.

Objective: This study used model analysis to clarify the benefits and risks of postoperative adjuvant chemotherapy compared with surgery alone in patients with stage II/III colorectal cancer. Methods: Clinical trials involving patients with stage II/III colorectal cancer who underwent surgery alone or those who received post-surgical adjuvant chemotherapy were searched in the PubMed and embase databases. By establishing a survival model, the overall survival (OS) and disease-free survival (DFS) of patients who underwent surgery alone or postoperative adjuvant chemotherapy were quantitatively analyzed to compare the differences between the two. In addition, the incidence of grade 3/4 adverse reactions in the adjuvant chemotherapy group was analyzed using the random effects model in the single-arm meta-analysis. Results: A total of 34 studies containing 33,069 patients were included in the analysis. This study found that postoperative adjuvant chemotherapy can effectively improve the OS and DFS of patients with colorectal cancer. The median OS of the adjuvant chemotherapy group and the surgery-only group was 118.8 months (95% CI: 96.6, 146.6) and 74.6 months (95% CI: 57.8, 96.1) respectively; and median DFS was 86.3 months (95% CI: 67.6, 110.6) and 40.8 months (95% CI: 23.7, 69.6) in the adjuvant chemotherapy and surgery-only groups, respectively. Common grade 3/4 adverse reactions in the adjuvant chemotherapy group include diarrhea, stomatitis, leukopenia, and nausea or vomiting, with an incidence of approximately 3%-6%. Conclusion: Patients with mid-stage colorectal cancer can benefit significantly from postoperative adjuvant chemotherapy. This study provides the necessary quantitative information for decision-making regarding the benefits and risks of receiving adjuvant chemotherapy after resection in patients with colorectal cancer.

Quantitative Analysis of the Efficacy of PARP Inhibitors as Maintenance Therapy in Recurrent Ovarian Cancer.

Objective: This study aimed to establish a pharmacodynamic model and to screen reasonable covariates to quantitatively describe the efficacy of poly (ADP-ribose) polymerase inhibitors (PARPis) as maintenance treatment for recurrent ovarian cancer (ROC). Methods: The log normal hazard function model was established by using progression-free survival (PFS) data of 1,169 patients from published randomized trials on FDA-approved PARP inhibitors (olaparib, niraparib, and rucaparib). Monte Carlo simulation was used to compare PFS values in different scenarios, such as monotherapy (administered alone) and combination therapy (PARPis combined with chemo- or target-therapies), different biomarker statuses, and different PARP inhibitors. PFS was also estimated. Results: The study showed that the median PFS was 8.5 months with monotherapy and 16.0 months with combination therapy. The median PFS of patients with the BRCA mutation, BRCA wild-type, and HRD-positivity were 11.0, 7.5, and 9.0 months in monotherapy, respectively, and 23.0, 14.0 and 17.5 months, in combination therapy, respectively. In addition, the median PFS of olaparib, niraparib, and rucaparib monotherapy were about 9.5, 10.5, and 12.0 months, respectively, and about 19.0, 20.0, and 25 months, respectively, in combination therapy. The median PFS values in combination with cediranib, bevacizumab, and chemotherapy were approximately 17.0, 12.5 and 19.5 months, respectively. Conclusion: PARPi combination therapy is more effective as maintenance treatment for ROC than monotherapy, and the efficacy of PARPis in combination with chemotherapy is higher than that of the combination with antiangiogenic drugs. We found that the PFS of BRCA wild-type was similar to that of HRD-positive patients, and there was no significant difference in PFS between olaparib, niraparib, and rucaparib, which provides necessary quantitative information for the clinical practice of PARPis in the treatment of ROC.

Quantitative evaluation of drug efficacy in the treatment of myasthenia gravis.

OBJECTIVES: This study aimed to quantitatively evaluate placebo effect and drug efficacy characteristics and identify associated factors that affect quantitative myasthenia gravis (MG) score (QMGs) and MG activities of daily living score (MG-ADLs) in patients with MG. METHODS: Randomized placebo-controlled clinical trials were comprehensively searched in public databases (PubMed, EMBASE, and Cochrane Library databases).A model-based meta-analysis was developed to describe time-course about drug efficacy and placebo effect. RESULTS: Twelve articles including 13 trials (673 participants) that were eligible for this study evaluated four immunosuppressants (tacrolimus, cyclosporine, prednisone, and mycophenolate mofetil) and five targeted therapy drugs (eculizumab, belimumab, zilucoplan, efgartigimod, and iscalimab). The pharmacodynamic model showed that eculizumab had the highest efficacy in reducing QMGs scores (3.66 points), and efgartigimod had the highest efficacy in reducing MG-ADLs scores (1.97 points). The placebo effect of QMGs and MG-ADLs increased apparently with time and reached 52% and 90% of their maximum effect in 12 weeks, respectively. In addition, this study found that the activities of daily living ability increased with the increase of the proportion of patients undergoing thymectomy. CONCLUSION: This study analyzed the efficacy characteristics of nine drugs. The present findings provide necessary quantitative information for drug development of MG.

Factors affecting the efficacy and safety of docetaxel combined with platinum in the treatment of advanced non-small cell lung cancer.

BACKGROUND: This study aimed to quantitatively evaluate factors influencing the efficacy and safety of the docetaxel-platinum regimen to provide reliable information for optimizing chemotherapy regimens. RESEARCH DESIGN AND METHODS: A parametric survival function model was used to describe the time course of overall survival (OS) of patients with advanced non-small cell lung cancer (NSCLC) receiving a docetaxel-platinum regimen. A random-effects model in a single-arm meta-analysis was used to analyze the objective response rate and grade 3-4 adverse event rates based on various docetaxel-platinum regimens. RESULTS: The model revealed that the risk of death in East Asians was approximately 1.5-fold higher than that in non-East Asians, with a median OS of 13.7 (95% confidence interval [CI]: 12.8-14.7) months and 9.3 (95% CI: 7.7-11.1) months, respectively. No significant impact of different administration regimens on OS was found. However, when drug exposure increased, the incidence of grade 3-4 anemia or neutropenia significantly increased. CONCLUSIONS: The docetaxel-platinum regimen has different efficacies in the treatment of advanced NSCLC between East Asian and non-East Asian populations. A better benefit-risk ratio can be obtained with a lower exposure regimen of docetaxel combined with platinum.

The impacts of race and regimens on the efficacy and safety of paclitaxel and platinum combination treatment for patients with advanced non-small cell lung cancer.

PURPOSE: Paclitaxel-platinum chemotherapy is the first-line treatment for advanced non-small cell lung cancer (NSCLC) patients. This study quantitatively evaluated the factors influencing the efficacy and safety of the paclitaxel-platinum regimen to provide the necessary reference for the development of clinical practice and clinical trials. METHODS: A literature search was performed using public databases. The parametric survival function was used to analyze the overall survival (OS) time course of patients treated with the paclitaxel-platinum regimen. The random effects model in the single-arm meta-analysis was used to analyze the objective response rate (ORR) and the incidence of grade 3-4 adverse events (AEs) under the predefined subgroups according to race and the regimen. RESULTS: A total of 31 studies consisting of 3365 participants were included in the analysis. Race was the most important determinant of efficacy and safety in the paclitaxel-platinum regimen, with the median survival time and ORR in East Asians and non-East Asians being 12.2 months (95% CI: 10.5-14.4 months) and 37% (95% CI: 32-41%) and 8.4 months (95% CI: 6.5-11.0 months) and 28% (95% CI: 25-32%), respectively. The incidence of grade 3-4 AEs such as leukopenia and neutropenia was about three times higher in East Asians compared to non-East Asians. CONCLUSIONS: The efficacy and safety of the paclitaxel-platinum regimen can vary between East Asian and non-East Asian populations and between different treatment schedules. The results of this study can provide a reliable and precise external control for the future evaluation of new treatment options for advanced NSCLC.

Efficacy and safety of the long-acting fusion inhibitor albuvirtide in antiretroviral-experienced adults with human immunodeficiency virus-1: interim analysis of the randomized, controlled, phase 3, non-inferiority TALENT study.

BACKGROUND: Albuvirtide is a once-weekly injectable human immunodeficiency virus (HIV)-1 fusion inhibitor. We present interim data for a phase 3 trial assessing the safety and efficacy of albuvirtide plus lopinavir-ritonavir in HIV-1-infected adults already treated with antiretroviral drugs. METHODS: We carried out a 48-week, randomized, controlled, open-label non-inferiority trial at 12 sites in China. Adults on the World Health Organization (WHO)-recommended first-line treatment for >6 months with a plasma viral load >1000 copies/mL were enrolled and randomly assigned (1:1) to receive albuvirtide (once weekly) plus ritonavir-boosted lopinavir (ABT group) or the WHO-recommended second-line treatment (NRTI group). The primary endpoint was the proportion of patients with a plasma viral load below 50 copies/mL at 48 weeks. Non-inferiority was prespecified with a margin of 12%. RESULTS: At the time of analysis, week 24 data were available for 83 and 92 patients, and week 48 data were available for 46 and 50 patients in the albuvirtide and NRTI groups, respectively. At 48 weeks, 80.4% of patients in the ABT group and 66.0% of those in the NRTI group had HIV-1 RNA levels below 50 copies/mL, meeting the criteria for non-inferiority. For the per-protocol population, the superiority of albuvirtide over NRTI was demonstrated. The frequency of grade 3 to 4 adverse events was similar in the two groups; the most common adverse events were diarrhea, upper respiratory tract infections, and grade 3 to 4 increases in triglyceride concentration. Renal function was significantly more impaired at 12 weeks in the patients of the NRTI group who received tenofovir disoproxil fumarate than in those of the ABT group. CONCLUSIONS: The TALENT study is the first phase 3 trial of an injectable long-acting HIV drug. This interim analysis indicates that once-weekly albuvirtide in combination with ritonavir-boosted lopinavir is well tolerated and non-inferior to the WHO-recommended second-line regimen in patients with first-line treatment failure. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02369965; https://www.clinicaltrials.gov.Chinese Clinical Trial Registry No. ChiCTR-TRC-14004276; http://www.chictr.org.cn/enindex.aspx.

A randomized phase I clinical trial comparing the pharmacokinetic, safety, and immunogenicity of potential biosimilar recombinant human HER2 monoclonal antibody for injection and trastuzumab in healthy Chinese adults.

OBJECTIVES: Recombinant human HER2 monoclonal antibody for injection (AK-HER2) is a potential biosimilar of trastuzumab (Herceptin®). This phase Ⅰ study aimed to demonstrate the pharmacokinetic (PK) equivalence between AK-HER2 and trastuzumab in healthy volunteers. Besides, safety and immunogenicity were investigated. RESEARCH DESIGN AND METHODS: This was a randomized, double-blind phase Ⅰ trial in 96 healthy adults who received a single intravenous infusion of AK-HER2 or trastuzumab at 6 mg/kg. The primary PK endpoints were area under the serum concentration curve (AUC) from time 0 to the last time point (AUC0-t) and peak concentration in serum (Cmax). The PK bioequivalence was confirmed using the standard equivalence margins of 80%-125%. RESULTS: The PK profiles of AK-HER2 and trastuzumab displayed high similarity. The geometric mean ratios (90% confidence intervals) of primary PK endpoints were within 80%-125%. The C max and AUC 0-t of female subjects in the AK-HER2 group were greater than those of male subjects (P <0.05). No infusion-related reactions (IRRs) or anti-drug antibody-positivity was observed after dosing. CONCLUSIONS: AK-HER2 was demonstrated to have highly similar PK to trastuzumab in healthy Chinese adults. Both drugs showed comparable safety and immunogenicity using dexamethasone as premedication to prevent IRRs..

Safety and tolerability of a single dose T0001 in Chinese healthy adult volunteers: a first-in-human ascending dose study

T0001 is the first mutant of etanercept with a higher affinity to tumor necrosis factor α (TNF-α) than etanercept. In order to investigate the safety and tolerability of T0001, a study was carried out in healthy Chinese subjects. A first-in-human, dose escalation study was conducted in healthy Chinese subjects. Fifty-six subjects were divided into six dose cohorts (10 mg, 20 mg, 35 mg, 50 mg, 65 mg and 75 mg) to receive a single subcutaneous injection of T0001. Safety and tolerability assessment were based on the records of vital signs, physical examinations, clinical laboratory tests, 12-lead electrocardiograms and adverse events (AEs). All subjects were in good compliance and none withdraw due to AEs. No serious AEs occurred. A total of twenty-three AEs in sixteen subjects were recorded, and eighteen of these AEs were believed to be related to T0001. The most frequently reported AEs were injection site reactions and white blood cell count increase. All these AEs were of mild to moderate intensity and most of them recovered spontaneously within 14 days. In this study, no dose-limiting toxicity was observed, and the maximum tolerated dose was identified as 75 mg. T0001 was considered safe and generally well tolerated at doses up to 75 mg in healthy Chinese volunteers