A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy of Paclitaxel-Carboplatin Alone or with Endostar for Advanced Non-small Cell Lung Cancer

Shanghai Chest Hospital, Shanghai, China.
Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer (Impact Factor: 5.28). 06/2011; 6(6):1104-9. DOI: 10.1097/JTO.0b013e3182166b6b
Source: PubMed


Recombinant human endostatin is a novel inhibitor of tumor angiogenesis that acts specifically on neovascular endothelial cells. Studies have shown that endostar plus vinorelbine-cisplatin chemotherapy could improve objective response rates (ORR) and overall survival (OS) of advanced non-small cell lung cancer (NSCLC) patients. This study is to explore the clinical efficacy of endostar plus paclitaxel-carboplatin (TC) in advanced NSCLC patients.
A phase II, multicenter, randomized, double-blind, placebo-controlled study was carried out. Patients were randomly assigned to the treatment (TC + endostar) or the control group (TC + placebo). The efficacy was evaluated at the end of each cycle. Follow-up continued until disease progression or death.
A total of 126 patients were enrolled, of whom 122 were evaluable, with 61 in each group. ORR was 39.3% in the treatment group versus 23.0% in the control group (p = 0.078), and the disease control rate was 90.2% versus 67.2% (p = 0.004), respectively. The median progression-free survival (PFS) was 7.1 versus 6.3 months (p = 0.522) in the treatment and control groups, the 24-week rate of PFS was 78% versus 59% (p = 0.017), and the median OS was 17.6 versus 15.8 months (p = 0.696), respectively. There were no significant differences, either in the incidence of adverse events or serious adverse events, between the two groups.
In previously untreated, advanced NSCLC patients, treatment with TC plus endostar seemed to improve ORR. However, the differences in PFS or OS between the two groups were not statistically significant. Treatment with TC plus endostar exhibited a good safety profile.

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    • "Dicycloplatin is a novel platinum derivative synthesized in China. In this study, we found that the efficacy of dicycloplatin was similar to that of carboplatin when combined with paclitaxel, with a response rate of about 30% in each arm, which was similar to the reports of previous studies [18–22] (Table II). Disease control rates were also comparable between D + P and C + P arms. "
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    ABSTRACT: Introduction The aim of this study was to compare the efficacy and toxicity of dicycloplatin plus paclitaxel with those of carboplatin plus paclitaxel as first-line treatment for patients with advanced non-small-cell lung cancer (NSCLC). Material and methods In this study, 240 NSCLC patients with stage IIIB (with pleural effusion) and stage IV disease were randomly assigned (1: 1) to receive dicycloplatin 450 mg/m2 or carboplatin AUC = 5, in combination with paclitaxel 175 mg/m2 (D + P or C + P) every 3 weeks for up to 4 to 6 cycles. The primary endpoint was response rate. Secondary endpoints included progression-free survival (PFS), overall survival (OS) and adverse events. Results The response rates for the D + P and C + P arm were 36.44% and 30.51%, respectively (p = 0.33). The median PFS was 5.6 months in the D + P arm and 4.7 months in the C + P arm (p = 0.31). The median OS was 14.9 months for D + P and 12.9 months for C + P (p = 0.37). Adverse events in the two arms were well balanced. The most common grade 3/4 adverse event was hematologic toxicity. Conclusions Patients treated with D + P had similar response and survival rates to those treated with C + P, and toxicities of both treatments were generally tolerable.
    Full-text · Article · Aug 2014 · Archives of Medical Science
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    • "human endostatin with a nine amino acid sequence at the N-terminus (MGGSHHHHH), expressed by E. coli, was approved by the CFDA for good clinical responses (Cui et al., 2013; Han et al., 2011). To explain this difference, we analyzed the structure of P. pastoris-expressed and E. coli-expressed endostatin, and found that almost 93% of P. pastoris-expressed endostatin was truncated and lost its zinc binding capacity. "
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    ABSTRACT: PEGylated recombinant human endostatin (M2ES) exhibited prolonged serum half-life and enhanced antitumor activity when compared with endostatin. A non-clinical study was performed to evaluate the toxicokinetics and safety of M2ES in rhesus monkeys. After intravenous (IV) infusions of M2ES at a dose level of 3, 10, and 30 mg/kg in rhesus monkeys, the concentration-time curves of M2ES were best fitted to a non-compartment model, and area under the curve (AUC) was positively correlated with the dosage. M2ES had a tendency to accumulate in vivo following successive IV infusions. Serum anti-M2ES IgG antibodies were generated quickly during IV administration, and the antibody level in serum did not significantly decrease after four-week recovery period. Animals administered IV infusions twice weekly (M2ES at 10 or 30 mg/kg body weight per day) for 3 months developed mild or moderate vacuolation of proximal tubule epithelial cell in proximal convoluted tubule of kidney, but this adverse-effect was reversible. In summary, M2ES was well tolerated and did not cause any serious toxicity. These pre-clinical safety data contribute to the initiation of the ongoing clinical study.
    Full-text · Article · Jan 2014 · Regulatory Toxicology and Pharmacology
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    • "Rh-endostatin not only increased tumor response rate, but also significantly improved the overall survival (OS) without increasing the adverse effects. In another multicenter, randomized, double-blind, placebo-controlled study published in 2011, treatment with paclitaxel and carboplatin (TC) plus rh-endostatin improved ORR in patients with advanced NSCLC and exhibited a good safety profile, although the differences in progression free survival (PFS) or OS were not statistically significant from TC alone [6]. "
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    ABSTRACT: Recombinant human endostatin (rh-endostatin) is a novel antiangiogenesis drug developed in China. Previous experiments have shown that rh-endostatin can inhibit the proliferation and migration of endothelial cells and some types of tumor cells. In this study, we evaluated the efficacy and safety profiles of combination therapy of rh-endostatin and neoadjuvant chemotherapy for breast cancer patients in a prospective, randomized, controlled, phase II trial. Sixty-eight patients with core-biopsy confirmed breast cancer were allocated randomly to two groups to receive 3 cycles of intravenous administration of either neoadjuvant DE (docetaxel: 75 mg/m2, d1, epirubicin: 75 mg/m2, d1, every 3 weeks), or neoadjuvant DE combined with rh-endostatin (7.5 mg/m2, d1-d14, every 3 weeks). The primary end point was clinical response based upon Response Evaluation Criteria in Solid Tumors, and the secondary end point was safety and quality of life. All patients were assessable for toxicity and 64 (94.2%) were assessable for efficacy evaluation. The objective response rate was 67.7% for chemotherapy (n = 31) and 90.9% for rh-endostatin plus chemotherapy (n = 33) (P = 0.021). A retrospective subset analysis revealed that rh-endostatin was more effective in premenopausal patients and patients with ECOG score of zero (P = 0.002 and P = 0.049, respectively). Five patients in the rh-endostatin plus chemotherapy arm achieved pathologic complete response compared with 2 in the chemotherapy arm (P = 0.428). No significant difference was identified in quality of life score and side effects (P > 0.05). The combination of rh-endostatin with chemotherapy produced a higher tumor response rate without increasing toxicity in breast cancer patients. Trial registration Identifier, NCT00604435
    Full-text · Article · May 2013 · BMC Cancer
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