Alleviation of Papain-Induced Osteoarthritis by Recombinant Human Endostatin via Downregulation of Matrix Metalloproteinase-13, Interleukin-1 and Interleukin-6 in Rats

Osteoarthritis (OA) is a degenerative disease of joints commonly occurring in the elderly and middleaged people. This study aimed to investigate the effect of recombinant human endostatin (rhEndo) on OA and the levels of MMP-13, IL-1 and IL-6 in the synovial fluid in osteoarthritis rats. OA models were made by injecting 4% papain into the knee joint cavity of rats once every three days for three times. The models were then injected subcutaneously with rhEndo and examined six weeks later for the Mankin scores and levels of MMP-13, IL-1 and IL-6 using ELISA. Compared with control, the Mankin score as well as the levels of IL-1, IL-6 and MMP-13 were significantly increased in the models (0.30 vs. 5.80, 1.12 vs. 12.84 pg/ mL, 12.22 vs. 43.82 pg/ mL and 0.23 vs. 26.31 ng/ mL). Following treatment with 4 mg/kg rhEndo, the Mankin score in model decreased to 0.90, meanwhile, the levels of IL-1, IL-6 and MMP-13 decreased significantly to 0.79 pg/ mL, 2.89 pg/mL and 1.17 ng/mL, respectively, in a dose dependent manner. Therefore, rhEndo can alleviate osteoarthritis by reducing MMP-13, IL-1 and IL-6 expression in rats.

Efficacy and safety of recombinant human endostatin during peri-radiotherapy period in advanced non-small-cell lung cancer

Background: This study aimed to retrospectively investigate the efficacy and safety of recombinant human endostatin (Rh-endostatin) combined with radiotherapy in advanced non-small-cell lung cancer (NSCLC). Methods: Patients with unresectable stage III and IV NSCLC who treated with radiotherapy were enrolled. Patients who received Rh-endostatin infusion throughout the whole peri-radiotherapy period formed the Endostar group, and those who received no Rh-endostatin infusion were the control group. Results: The median progression-free survival was 8.0 and 4.4 months (hazard ratio: 0.53; 95% CI: 0.32–0.90; p = 0.019) and median overall survival was 40.0 and 13.1 months (hazard ratio: 0.53; 95% CI: 0.28–0.98; p = 0.045) for the Endostar and control groups, respectively. The Endostar group exhibited a numerically lower rate of radiation pneumonitis relapse, radiation pneumonitis death and pulmonary fibrosis. Conclusion: Rh-endostatin infusion throughout the peri-radiotherapy period enhanced radiosensitivity and showed better survival outcomes and a tendency toward fewer radiation-related pulmonary events in patients with NSCLC.

Chemotherapy Combined With Recombinant Human Endostatin (Endostar) Significantly Improves the Progression-Free Survival of Stage IV Soft Tissue Sarcomas

PurposeOur previously study showed that recombinant human endostatin (Endostar) combined with chemotherapy had significant activity to increase the mPFS in patients with advanced sarcomas with tolerable side effects. However, the small cohort size and short follow-up time made it difficult to screen sensitive sarcoma subtypes and determine whether there is an overall survival benefit. With the largest sarcoma cohort to our knowledge, we try to confirm the efficacy and safety of chemotherapy combined with Endostar in stage IV sarcomas, with the specific purpose of finding out the sensitive sarcoma types for this combined treatment.MethodsAfter the exclusion of ineligible patients, 156 patients with stage IV bone and soft tissue sarcomas were included in this study according to the inclusion criteria.ResultsBy the end of follow-up, the ORR was 10.7% (9/84) vs 1.4% (1/72) (p=0.041), the DCR was 26.2% (22/84) vs 5.6% (4/72) (p=0.001) in the combined group and chemotherapy group, respectively. The mPFS of combined group was significantly longer than the chemotherapy group (10.42 vs 6.87 months, p=0.003). The mOS were 26.84 months and 23.56 months, without significant difference (p= 0.481). In osteogenic sarcoma, there was no statistically significant difference in the mPFS between the two groups (p=0.59), while in the soft tissue sarcoma, the mPFS in the combined group was significantly higher than that of the chemotherapy group (11.27 vs 8.05 months, p=0.004). Specifically, undifferentiated polymorphic sarcoma (UPS) was the possible sarcoma subtypes that benefited from the combined therapy. For the 38 UPS patients (28 patients in the combined group and 10 patients in the chemotherapy group), the mPFS in the combined group was up to 14.88 months, while it was only 7.1 months in the chemotherapy group, with a significant difference (p=0.006). The most common adverse events in the combined group were myelosuppression, gastrointestinal reactions and abnormal liver function, without significant difference in two groups.ConclusionChemotherapy plus Endostar could prolong mPFS and improve ORR and DCR in patients with stage IV soft tissue sarcoma, suggesting that the combined therapy could improve the patient prognosis in soft tissue sarcomas, especially the UPS patients.

Clinical Study of Recombinant Human Endostatin Combined with Iressa in Targeted Treatment of Patients with Lung Adenocarcinoma with Pleural Metastasis

Objective: To evaluate and comprehensively analyze the clinical efficacy of recombinant human endostatin combined with Iressa targeted therapy in patients with pleural metastasis of lung adenocarcinoma. Methods: The interval of the selected study period span was from January 2017 to April 2021. The sample source of the study was 42 patients with lung adenocarcinoma admitted to hospital. The random number table method was used for study grouping, and they were further divided into study groups (n = 21, 14 cases with pleural metastasis) and control group (n=21, 13 cases with pleural metastasis), all patients received systemic chemotherapy with pemetrexed and cisplatin. Patients with pleural metastases in the control group were injected with 60 mg cisplatin into the thoracic cavity. Patients in the study group were treated with Iressa (gefitinib) targeted therapy if genetic testing showed epidermal growth factor receptor (EGRF) mutations, and patients with pleural metastases were treated with pleural metastasis with Endo (recombinant human endostatin YH-16) to control pleural effusion. Two sets of related indicators were compared and analyzed. Results: Comparing the short-term disease control rate, treatment effectiveness and long-term survival rate between the two groups shows that the study group has more advantages (P<0.05). In the comparison between the two groups of serum markers and related indicators, the study group has more advantages (P<0.05), whereas in the comparison between the two groups in the incidence of adverse reactions, there is no significant difference (P>0.05). Based on statistics of the recurrence rate of pleural fluid in the two groups, the study group is significantly lower than the control group (P<0.05). Conclusion: Recombinant human endostatin combined with Iressa targeted therapy for patients with lung adenocarcinoma with pleural metastasis has significant short-term and long-term effects without serious adverse reactions. It can be fully promoted in medical institutions at all levels.

Safety and efficacy of nivolumab plus recombinant human endostatin in previously treated advanced non-small cell lung cancer: A prospective and multicenter phase 2 trial.

e21079 Background: Although the administration of immune checkpoint inhibitors (ICIs) and antiangiogenic agents in advanced non–small-cell lung cancer (NSCLC) has been well established, evidence supporting the combination of immune checkpoint inhibitors plus antiangiogenic drugs in previous treatment patients with advanced NSCLC is insufficient. We aimed to investigate the efficacy and safety of nivolumab combined with recombinant human endostatin (rh-Endostatin) as second-line or later treatment for advanced NSCLC. Methods: In this prospective and multicentre phase 2 trial we enrolled patients with advanced NSCLC who had not responded to standardized first-line treatment regimen from two cancer centres in China. Eligible patients were those aged 18-75 years without ICIs in first-line treatment who received nivolumab (3mg/kg, intravenous drip, day 1) every 2 weeks and rh-Endostatin (30 mg, 24-hour continous intravenous infusion，day 1–7) every 4 weeks till disease progression or discontinuation. The primary end points were objective response rate and safety. This study is registered with Chinese Clinical Trial Registry, number ChiCTR1900023664. Results: A total of 35 patients (median age, 60 years; range, 37-72 years) received nivolumab and rh-Endostatin. Median previous treated line of eligible patients was 2 lines (range, 1-7 lines). Patients received a median of 2 cycles of therapy (range, 1-14 cycles). Eleven of 33 evaluable patients achieved confirmed partial response with an objective response rate of 33.3% (11/33, 95% confidence interval [CI]: 17.2% – 49.4%) and disease control rate of 60.6% (20/33,95%CI:43.9%–77.3%). Median follow-up was 8.2 months (range: 0.9 –17.1). Median progression-free survival was 7.1 months (95% CI: 1.2m–13.0m), median overall survival was not reached and the 6-month overall survival rate was 54.5% (95% CI:37.6%–71.4%). The predominant grade 1-2 adverse events were thyroiditis, arrhythmia, hypertension. The grade 3 treatment-related adverse events were pneumonitis (3/35, 8.6%), hypertension (1/35, 2.9%) and atrial fibrillation (1/35, 2.9%), respectively. No grade 4 or 5 treatment-related adverse events were observed. Conclusions: To the best of our knowledge, this is the first prospective study that assessed nivolumab combined with rh-Endostatin as second-line or later treatment in pretreated patients with advanced NSCLC. In view of its encouraging efficacy and safety profile, nivolumab plus rh-Endostatin represents a promising treatment regimen in this patient population. Clinical trial information: ChiCTR1900023664.

Recombinant human endostatin combined with chemotherapy for advanced squamous cell lung cancer: a meta-analysis

Background This paper aims to compare the efficacy and safety of recombinant human endostatin combined with chemotherapy in patients with squamous cell lung cancer (SqCLC). Methods We searched the Cochrane Library, PubMed, Embase, CNKI, Wanfang database, Metstr, VIP, and others and manually searched books and magazines until 2019 for articles about the efficacy and safety of recombinant human endostatin combined with chemotherapy in patients with SqCLC. A second search was conducted on the review literature. According to the criteria of the literature screen, the relevant randomized controlled trials (RCTs) and nonrandomized controlled trials (non-RCTs) of recombinant human endostatin combined with chemotherapy and chemotherapy alone in the treatment of SqCLC were included. After the data were extracted and analyzed, RevMan 5.3 software was used for meta-analysis for the outcome indicators. Then, heterogeneity tests and sensitivity analyses were carried out, and the publication bias of this study was tested in Stata 13.0 software. Six RCTs and eight non-RCTs were included. In total, 821 patients with SqCLC were included. Results The response rate (RR) was 2.12 (95% CI: 1.57–2.85, p < 0.00001). The disease control rate (DCR) was 2.38 (95% CI: 1.70–3.32, p < 0.00001). The difference between the two groups was statistically significant. Regarding safety, the incidence rates of the adverse reactions cardiotoxicity, leukopenia, thrombocytopenia, and gastrointestinal reactions were not significantly different between the two groups (OR = 1.70, 95% CI: 0.79–3.68; OR = 0.93, 95% CI: 0.61–1.42; OR = 1.08, 95% CI: 0.71–1.64; OR = 0.86, 95% CI: 0.56–1.30, respectively). Conclusion The combined treatment had a better therapeutic effect than chemotherapy alone. It did not increase the incidence of adverse reactions in the course of treatment.

Tolerance and Pharmacokinetics of Recombinant Human Endostatin Administered as Single-Dose or Multiple-Dose Infusions in Patients With Advanced Solid Tumors: A Phase I Clinical Trial

Objective: This study aimed to investigate the tolerance and pharmacokinetic characteristics of recombinant human endostatin (rh-endostatin) administered as single-dose or multiple-dose infusions in patients with advanced solid tumors. Methods: This phase I trial was designed as a single-center, single-arm, nonrandomized, open-label, dose-escalation study. The trial consisted of 2 parts: a single-dose part and a multiple-dose part, each with 3 dose comparison groups. Rh-endostatin was administered as an intravenous injection only once at a dose of 5 mg/m2, 7.5 mg/m2, or 10 mg/m2 in the single-dose part and as a daily intravenous injection for 14 days at the same doses in the multiple-dose part. The serum pharmacokinetics, toxicity and immunogenicity of rh-endostatin were evaluated. Results: Dose-limiting toxicity (DLT) was not observed in any group. A few patients developed cardiotoxicity, such as QT prolongation or narrow arrhythmia. Other adverse events were slight coagulation abnormalities and haematological abnormalities. For rh-endostatin doses of 5 mg/m2, 7.5 mg/m2, and 10 mg/m2, the mean Cmax values in the single-dose part were 344 ± 38.7 ng/mL, 524 ± 157 ng/mL, and 800 ± 201 ng/mL, respectively, and the average AUC0−t values were 3290 ± 3790 ng•h/mL, 4940 ± 4380 ng•h/mL, and 5050 ± 3980 ng•h/mL, respectively. The Cmax ss values of the 3 doses in the multiple-dose part were 575 ± 270 ng/mL, 531 ± 106 ng/mL, and 864 ± 166 ng/mL, respectively, and the AUC0−τ values were 3610 ± 1040 ng•h/mL, 3290 ± 1090 ng•h/mL, and 5180 ± 1210 ng•h/mL, respectively. The Cmax of a single-dose regimen showed linear kinetic characteristics. The patients in the single-dose group were negative for serum antibodies against rh-endostatin, while one patient in the multiple-dose group was positive. Conclusions: Rh-endostatin as a daily intravenous injection for 14 days in patients with advanced solid tumors is safe and well tolerated, without DLT, at doses of 5 mg/m2, 7.5 mg/m2, and 10 mg/m2. Serum antibodies against rh-endostatin were very low after multiple infusions. For phase II trials, the recommended rh-endostatin dose is 10 mg/m2 as a daily intravenous injection for 14 days.