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. 2013 May 14;21(7):1456–1463. doi: 10.1038/mt.2013.79

A Phase II, Randomized, Double-blind, Placebo-controlled Multicenter Trial of Endostar in Patients With Metastatic Melanoma

Chuanliang Cui 1, Lili Mao 1, Zhihong Chi 1, Lu Si 1, Xinan Sheng 1, Yan Kong 1, Siming Li 1, Bin Lian 1, Kangsheng Gu 2, Min Tao 3, Xin Song 4, Tongyu Lin 5, Xiubao Ren 6, Shukui Qin 7, Jun Guo 1,*
PMCID: PMC3702105  PMID: 23670576

Abstract

Endostatin is a potent endogenous angiogenic inhibitor with implicated antitumor activity. However, efficacy of recombinant human endostatin (rhES) in clinical trials is controversial, and application of rhES in treatment of metastatic melanoma awaits further investigations. This phase II trial evaluated the efficacy and safety of a soluble and stable rhES (Endostar) plus dacarbazine in patients with metastatic melanomas that contains no mutations in c-kit and BRAF genes. A total of 110 patients received placebo plus dacarbazine (250 mg/m2, n = 54) or Endostar (7.5 mg/m2) plus dacarbazine (250 mg/m2, n = 56). The primary end points were progression-free survival (PFS) and overall survival (OS). Median PFS in the Endostar plus dacarbazine arm was 4.5 months versus 1.5 months in the placebo plus dacarbazine arm (hazard ratio (HR) = 0.578; P = 0.013). There were statistically significant improvements in OS (median, 12.0 months versus 8.0 months; HR, 0.522; P = 0.005) in favor of the Endostar plus dacarbazine arm. The regimen was generally well tolerated and had a manageable toxicity profile. Our trial suggests that Endostar plus dacarbazine is well tolerated in patients with metastatic melanoma harboring no genetic mutations popular for targeted therapy and yields a significant improvement in PFS and OS.

Introduction

Metastatic melanoma is a devastating disease, with an expected 2-year survival rate of 10–20%.1,2,3 Dacarbazine is the most commonly used cytotoxic chemotherapeutic agent, associated with median progression-free survival (PFS) ranged from 1.5 to 1.9 months, and overall survival (OS) ranged from 5.6 to 7.8 months.1,2,3 However, most of dacarbazine-based therapies have yielded poor improvements in respect to either PFS or OS, as compared with dacarbazine alone.4 Two recent trials using Vemurafenib (PLX4032, a potent inhibitor of mutated BRAF) and Ipilimumab (a fully human IgG1 monoclonal antibody blocking cytotoxic T lymphocyte–associated antigen 4) respectively have shown improved PFS or OS in patients with metastatic melanoma,5,6 thus suggesting that potential molecular targeted therapies (or combination with chemotherapies) should be further tested in these patients. However, standard treatments for patients with melanoma harboring no popular genetic mutations (i.e., c-kit, BRAF, or PTEN) need further investigations.

Malignant melanoma is a highly angiogenic tumor type, and antiangiogenesis has been a potential strategy in melanoma treatment.4 Vascular endothelial growth factor (VEGF) is strongly expressed in melanoma and seems to play an important role in disease progression.4,7,8 Current antiangiogenic therapies have focused on VEGF-VEGF receptor (VEGFR), among which bevacizumab (Avastin), a monoclonal antibody that selectively binds to VEGF and blocks receptor binding, has been most extensively tested in various cancers.4,9 Several large randomized clinical trials in various indications, such as colon cancer, breast cancer, non-small–cell lung cancer (NSCLC), glioblastoma, renal cancer, ovarian cancer, and prostate cancer, have demonstrated that when combined with chemotherapy or targeted therapies, bevacizumab prolongs PFS and/or OS.10,11,12,13,14,15,16 Several trials have tested the efficacy and safety of bevacizumab (or in combination) in metastatic melanoma.17,18,19,20,21 However, all these trials have not yielded improvements in PFS or OS. The most recent phase II trial of bevacizumab, carboplatin plus paclitaxel showed that the addition of bevacizumab could not significantly improve PFS and OS in metastatic melanoma despite that the addition of bevacizumab could increase the PFS, OS, and overall response rate (RR) to some extent.17 Therefore, other antiangiogenic strategy should be alternatively selected and tested in metastatic melanoma.

Endostatin, a representative of endogenous angiogenesis inhibitors, is the 20 kDa internal fragment of the c-terminus of collagen XVIII.22 Since its discovery in 1997, the inhibitory effects of endostatin on endothelial cell proliferation, angiogenesis and tumor growth have been validated in various murine tumor models and xenografts of human tumors.22,23,24,25,26,27 Genetic evidence has been provided for endostatin, showing that endostatin is an endogenous angiogenesis inhibitor and a tumor suppressor.28 Due to its broad spectrum of targets and its minimal toxic side effects in human, endostatin has been rapidly pushed into clinical treatments of cancer.29,30,31 However, the recombinant endostatin showed minor antitumor activity. One trial in metastatic melanoma of rhES plus IFN-α2b also did not show antitumor response.32 Endostar, a novel recombinant human endostatin purified from Escherichia coli with an additional nine-amino acid sequence and forming another histidine tag structure for the convenience of solubility and purification,33 was approved by the State Food and Drug Administration of China in 2005 for the treatment of NSCLC.34,35 Endostar in combination with chemotherapy (vinorelbine plus cisplatin) prolonged the time to tumor progression and improved RR and clinical benefit rate with a favorable toxic profile in advanced NSCLC in phase III clinical trial in China.34 Despite the reasons for the contrasting activity of Endostar in China versus recombinant endostatin in US and Europe have not been clarified, further trials of Endostar in other cancers (e.g., melanoma) are worthy of being expected and conducted.

We conducted a randomized phase II study in patients with previously untreated metastatic melanoma to characterize the efficacy and safety of Endostar when combined with dacarbazine. The primary end points were PFS and OS. Secondary end points included objective RR, disease control rate, and adverse effects.

Results

Patients and treatments

A total of 114 patients with histologically, cytologically, or radiologically confirmed metastatic melanoma were screened and randomly assigned between the two treatment arms. Among these patients, three patients in placebo group (two of them bear c-kit mutation and thus were enrolled to imatinib trial; and one patient had no measurable lesions (multi-lesions in the lung)) and one patient (bearing c-kit mutation and thus enrolled in imatinib trial) in Endostar group were finally excluded from the treatments. The detailed patient disposition is shown in Figure 1. The baseline characteristics of the patients who were finally allocated in the trial (54 patients in the placebo arm and 56 patients in the Endostar arm) were balanced between the two groups (Table 1), especially for the major prognostic factors including stage and serum lactate dehydrogenase level. Acral melanoma and mucosal melanoma were the most common subtypes in both of two groups compared with clinical trials of Caucasians because of the clear demographic and ethnic disparity. No patients withdrew from the allocated intervention.

Figure 1.

Figure 1

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CONSORT diagram.

Table 1. Baseline patient demographics and clinical characteristics.

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Three patients in both arms only received one cycle of treatment due to disease progression. A total of 16 patients (29.6%) in the placebo arm and 25 patients (44.6%) in the Endostar arm received ≥4 cycles of treatments. The median treatment cycles in placebo arm (range: 1–10 cycles) and Endostar arm (range: 1–12 cycles) were both two cycles.

Efficacy

Efficacy analyses were performed on the intention-to-treat population. Two patients (3.7%) in placebo arm and five patients (8.9%) in Endostar arm showed partial response (P = 0.464). The disease control rate in the placebo arm (33.3%, 18 (2 partial response + 16 SD)/54) was not significantly lower than that in the Endostar arm (53.6%, 30 (5 partial response + 25 SD)/56; P = 0.051, Table 2), favoring a non-significant trend toward a higher disease control rate in the Endostar group.

Table 2. Efficacy results.

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A total of 88 patients (45 in placebo arm and 43 in Endostar arm) experienced disease progression or had died at the cutoff date in November 2011. The median PFS for the placebo arm was 1.5 months (95% CI = 1.3–1.7) and 4.5 months (95% CI = 1.7–7.3) for the Endostar arm, resulting in an estimated hazard ratio (HR) of 0.578 (Endostar plus dacarbazine/placebo plus dacarbazine; P = 0.013; Table 2, and Figure 2a). The estimated median OS was 8.0 months (95% CI = 7.1–8.9) for the placebo arm and 12.0 months (95% CI = 9.7–14.3) for the Endostar arm (Table 2, and Figure 2b), resulting in an estimated HR of 0.522 (Endostar plus dacarbazine/placebo plus dacarbazine; P = 0.005). Among patients showing increased lactate dehydrogenase levels, combination of Endostar also significantly improve both PFS and OS (Figure 3a,b). These data suggest that Endostar plus dacarbazine significantly improved the PFS and OS of patients with metastatic melanoma.

Figure 2.

Figure 2

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Kaplan–Meier estimated survival for all patients by treatment groups. (a) progression-free survival and (b) overall survival for all patients. CI, confidence interval; D, dacarbazine; E, Endostar; HR, hazard ratio; OS, overall survival; P, placebo; PFS, progression-free survival.

Figure 3.

Figure 3

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Kaplan–Meier estimated survival for patients with poor prognosis by treatment groups. (a) progression-free survival and (b) overall survival for patients with elevated serum lactate dehydrogenase levels. CI, confidence interval; D, dacarbazine; E, Endostar; HR, hazard ratio; LDH, lactate dehydrogenase; OS, overall survival; P, placebo; PFS, progression-free survival.

Unstratified exploratory subgroup analyses of both PFS and OS were performed (Figure 4). Among patients with M1c staging (n = 30), combination with Endostar led to a 63% reduction in risk of progression (HR = 0.37; 95% CI = 0.13–1.05; Figure 4a). Among patients with the age ≥60 years (n = 28) and patients with mucosal melanoma (n = 16), combination with Endostar led to 75% (HR = 0.25; 95% CI = 0.094–0.671) and 93% (HR = 0.07; 95% CI = 0.009–0.632) reduction in risk of death respectively (Figure 4b). For patients with elevated lactate dehydrogenase levels (n = 26), combination with Endostar led to a 68% reduction in risk of progression (HR = 0.32; 95% CI = 0.119–0.872) and a 83% reduction in risk of death (HR = 0.17; 95% CI = 0.060–0.510; Figure 4). However, risk of death (HR = 1.02; 95% CI = 0.305–3.434) and progression (HR = 1.15; 95% CI = 0.394–3.484) were both increased for patients with melanomas on skin with chronic sun-induced damage (CSD) treated with Endostar plus dacarbazine (n = 17).

Figure 4.

Figure 4

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Analysis of progression-free survival and overall survival by subgroups for all randomly assigned patients. (a) Progression-free survival (PFS); (b) overall survival (OS). CI, confidence interval; CSD, melanomas on skin with chronic sun-induced damage; NCSD, melanomas on skin without chronic sun-induced damage; ULN, upper limit of the normal range; UP, melanoma of unknown primary.

Adverse events

The safety analysis included all patients who underwent randomization and received at least one dose of the assigned study drug (110 patients). The adverse events reported in the safety population are listed in Table 3. Many patients had more than one adverse event; however, adverse events were generally mild to moderate in severity and easily managed by dose interruption or supportive medical treatment. No treatment-related deaths were recorded. A total of 169 adverse events (87 in placebo group and 82 in Endostar group) were recorded. No grade 3/4 toxicities were observed in Endostar arm, and three grade 3/4 events were observed in the placebo arm (Table 3). Combination of Endostar led to an increase in hepatic toxicity (increase in alanine aminotransferase; 28.7% (25/87) in placebo arm versus 56.1% (46/82) in Endostar arm), but did not add to the other toxicity profile of dacarbazine. And there's no new-onset cases of hypertension which was usually associated with antiangiogenesis therapeutics. Considering that Endostar did not increase the events of grade 3/4 toxicity, the Endostar plus dacarbazine regimen was safe and well tolerated in patients with metastatic melanoma.

Table 3. Adverse events.

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Discussion

Although dacarbazine is the most commonly used cytotoxic chemotherapeutic agent, prior clinical trials investigating dacarbazine and dacarbazine containing regimens in the treatment of advanced melanoma have demonstrated minimal to modest antitumor activity.1,2,3,4 This trial was designed to assess whether Endostar could potentiate the efficacy of dacarbazine in the treatment of metastatic melanoma without genetic mutations in c-kit or BRAF genes. Our trial shows that Endostar in combination with dacarbazine can significantly improve the PFS and OS of patients with metastatic melanoma, thus reaching our primary endpoints. Combination with Endostar increased the PFS from 1.5 to 4.5 months and the OS from 8.0 to 12.0 months as compared with dacarbazine alone, significantly improving the efficacy of dacarbazine-based chemotherapy. The encouraging results of our trial thus warrant a larger phase III study in patients with metastatic melanoma.

Targeted therapies using kinase inhibitors or monoclonal antibodies may represent the major proceedings in the treatment of metastatic melanoma. Treatment of patients with metastatic melanoma bearing BRAF V600E mutation with Vemurafenib could significantly improve the OS and PFS as compared with dacarbazine.5 Our own and other's trial of imatinib in the treatment of metastatic melanoma also demonstrated significant activity among subset of patients containing c-kit mutations.36,37 Recently, clinical trials using immunomodulatory agents such as anti-CTLA4 monoclonal antibody or trymosin α1 have shown improvements in OS for patients with metastatic melanoma as compared with dacarbazine-based chemotherapy.6,38 Sorafenib, an inhibitor of Raf kinase, can also improve the efficacy of dacarbazine in patients with advanced melanoma.39 In our trial, dacarbazine plus placebo treatment led to a median PFS of 1.5 months and an OS of 8.0 months, which was comparable with the previous studies of dacarbazine-based regimen.1,2,3 However, the objective RRs in both arms (3.7 and 8.9% respectively) were lower than those reported in several dacarbazine-associated phase II and III trials (ranging from 5 to 15%) and one representative meta-analysis,1,2,3,40–42 which may be due to differences in the melanoma subtypes of enrolled patients since more than 50% of patients in our trial were acral or mucosal melanomas. Significantly, combination of Endostar led to a 48% reduction in risk of progression and a 42% reduction in risk of death in patients with metastatic melanoma. Therefore, Endostar may represent a novel promising agent for metastatic melanoma and is worthy of further larger trials in the future. Additionally, the patients enrolled in the current trial contained no mutations in KRAS, NRAS, BRAF, and c-kit genes that may be potential targets for targeted therapies, suggesting that Endostar plus dacarbazine regimen may be a first-line chemotherapy regimen for patients that were unsuitable for kinase inhibitors–based targeted therapy.

Antiangiogenic therapy is an important strategy in the treatment of melanoma.4,9 One representative drug is bevacizumab that specifically targets VEGF. Despite that several large randomized phase III trials in various indications have demonstrated that when combined with chemotherapy or targeted therapies, bevacizumab prolongs PFS and OS,10,11,12,13,14,15,16 recent trials of bevacizumab in combination with chemotherapy have not yielded encouraging outcomes.17 The BEAM trial (bevacizumab in combination with carboplatin plus paclitaxel) showed that combination of bevacizumab could not significantly improve OS of patients with advanced melanoma. Most recently, a multicenter phase II trial using bevacizumab plus temozolomide (a dacarbazine analogue) shows that the median PFS and OS were 4.2 and 9.6 months respectively.19 In our trial, the PFS and OS were both significantly improved by combination with Endostar as compared with dacarbazine alone, suggesting that Endostar may be more efficient than bevacizumab in metastatic melanoma, and be comparable with the efficiency of bevacizumab in other cancers. Notably, bevacizumab treatment always results in severe grade 3/4 adverse events (i.e., neutropenia)17,18,19,20,21 whereas Endostar did not lead to additional toxicity. Therefore, our data suggest that Endostar is a safe and efficient choice for patients with metastatic melanoma when antiangiogenic regimens were considered.

Endostatin is an endogenous inhibitor of endothelial cell growth and a tumor suppressor.22,28 Preclinical studies have shown that recombinant endostatin shows antitumor activity in both mouse tumor models and xenografts of human tumors.22,23,24,25,26,27 Phase I clinical trials of human recombinant endostatin have shown that it is safe and can induce measurable effects on tumor blood flow, metabolism and apoptosis of endothelial and tumor cells.29,30,31 However, in most of the trials, no clinical responses were observed.29,30,31,32 Despite that several reasons for the poor efficacy of recombinant human endostatin have been provided (i.e., solubility and activity of the purified protein), previous trials did not encourage further trials using recombinant human endostatin. Endostar is a modified form of endogenous endostatin, with better solubility and stability.33 In China, Endostar has been approved to be used in the treatment of advanced NSCLC in combination with vinorelbine and cisplatin.34,35 The addition of Endostar results in significantly and clinically meaningful improvement in RR, median time to tumor progression, and clinical benefit rate in patients with advanced NSCLC.34 However, the efficacy of Endostar in treatment of metastatic melanoma has not been tested. Our trial suggests that Endostar, in combination with dacarbazine, is efficient in previously untreated patients with metastatic melanoma, which is different to the effects of recombinant human endostatin and can lead to improved PFS and OS. For patients with progressive diseases in both arms, the pacilitaxel plus carboplatin regimen was usually prescribed, which could not significantly affect the OS between the two arms (data not shown). Therefore, Endostar, instead of recombinant human endostatin, should be considered as a choice for patients with metastatic melanoma in addition to the patients with NSCLC. The efficacy of Endostar reported here may be apparently but partially due to the improved solubility and stability of Endostar as compared with the conventional rhES used in previous trials.29,30,31,32 As an endogenous angiogenic inhibitor, endostatin could inhibit VEGF, metalloproteinases, integrins, c-myc, cyclin D1, and even Wnt signaling,43,44 which indicated that Endostar may demonstrate a broader spectrum than bevacizumab, and thus may be more effective in antiangiogenic therapy of melanoma. More studies are required for full understanding of the mechanisms of Endostar.

In addition, unstratified exploratory subgroup analyses suggested that combination of Endostar could not reduce the risk of either death and progression of patients with CSD type of melanoma, which may contribute to the poor effects of recombinant human endostatin in patients with melanoma since CSD melanoma is a major subtype in Caucasians while acral melanoma and mucosal melanoma are more frequent in Asians.45,46 Therefore, Endostar may be more preferred by patients with acral or mucosal melanomas while attentions should be paid for patients with CSD type of melanoma. However, the numbers of patients with CSD in our trial is small (a total of 17 in two arms). So, only after further trials in other populations with larger sample size, proper interpretation of the efficacy of Endostar in melanoma could be made.

In conclusion, our trial has tested the efficacy and safety of Endostar in the treatment of previously untreated patients with metastatic melanoma. Our data demonstrated that combination of Endostar could significantly improve the PFS and OS as compared with dacarbazine alone, and did not add additional toxicity to dacarbazine. Therefore, Endostar may represent a novel antiangiogenic drug that should be considered for patients with melanoma unsuitable for kinase inhibitor-based or monoclonal antibody-based therapy. The detailed mechanisms for the efficacy of Endostar in treatment of metastatic melanoma may be an important focus of ongoing research. Whether Endostar could increase the clinical response of other systemic regimens (i.e., IFN-α, IL-2, kinase inhibitors, and monoclonal antibodies) may need further studies.

Materials and Methods

Patients. A total of 114 patients received screening for this trial and 110 of them were enrolled and eligible for clinical evaluation. The inclusion criteria included the provision of written informed consent, an age of 18–75, metastatic melanomas (with at least one of the metastatic lesions ≥1 cm in diameter) confirmed histologically, clinically, and radiologically, Karnofsky performance status score ≥70, life expectancy of 3 months or longer, lesions assessable as defined by the Response Evaluation Criteria in Solid Tumors (RECIST), and adequate hepatic, renal, and hematological functions. Key exclusion criteria included prior history of systemic chemotherapy; mutations in KRAS, NRAS, BRAF, or c-kit genes; acute infection or uncontrolled chronic infection; history of serious heart disease (e.g., congestive heart failure, uncontrolled high risk arrhythmias, unstable angina or myocardial infarction, serious valvular vitium of the heart, and resistant hypertension); known metastatic disease in the brain or a second tumor type; history of abnormal psychology; hypersensitivity to dacarbazine; and pregnant or lactation women.

Study design and treatment. The study was supported by Simcere Pharmaceutical (Jiangsu, China), which provided the study drug Endostar. The trial was designed jointly by the senior academic authors and the sponsor. The protocol was approved by the institutional review boards of all the participated centers and was conducted in accordance with the ethical principles originating from the Declaration of Helsinki and with Good Clinical Practice as defined by the International Conference on Harmonization.

This randomized, double-blind, placebo-controlled, multicenter, phase II study (http://www.clinicaltrials.gov; identifier: NCT00813449) was conducted at seven centers in China between December 2008 (first patient first visit) and November 2011 (data cutoff date). After providing informed consent, patients were randomly assigned in an allocation ratio of 1:1 to the placebo plus dacarbazine arm or the Endostar plus dacarbazine arm. Simple stratified randomization with permuted blocks of size 2 was used to create a prospective randomization schedule. Random assignment of patients was performed by designated personnel at each participating site in a double-blind fashion such that the investigator and patient did not know the treatment assignment.

Patients in both arms received dacarbazine 250 mg/m2 by intravenous infusion on days 1–5 of a 21-day treatment cycle for up to a maximum of 12 cycles. Endostar (7.5 mg/m2) or placebo was administered intravenously once daily within 3–4 hours on days 1–14 of a 21-day treatment cycle for up to a maximum of 12 cycles. Patients continued to receive therapy during the treatment period until unacceptable toxicity, tumor progression, or death occurred.

Assessment of response and adverse effects. Response assessments consisted of complete history and physical examinations every week, complete blood counts and serum chemistry every week, and CT scan of the thorax and abdomen/pelvis every 6 weeks. Response of disease was assessed and confirmed by two investigators using RECIST 1.047, and were required to be confirmed by follow-up CT in 4 weeks after initial assessment. Other tests such as MRI of the brain or PET/CT scans were obtained if clinically indicated, and their results were allowed for evaluating response.

Adverse effects were graded and recorded according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 3.048.

Statistical analyses. The primary endpoints of the study were PFS and OS. PFS was defined from the time of treatment initiation until clinically evident disease progression or death due to other cause. OS was defined from the time of initiation of treatment to the date of death due to any cause. Secondary end points included objective RR, disease control rate, and safety. Time to event distributions was estimated using the Kaplan–Meier method and differences were evaluated by the log-rank test.

Using historical data, a median PFS of 1.9 months was assumed for the placebo plus dacarbazine arm. The planned duration of accrual was 1 year, and the planned follow-up time was 1.5 years. A sample size of 92 patients was designed to provide the study with 80% power to detect an improvement of 1.6 months in the median PFS of the patients in the endostar plus dacarbazine arm with a type I error of 0.05. Considering dropout rate, the sample size planned was 120 patients, with 60 patients in each group.

All patients randomly assigned to treatment (intent to treat population) were included in the primary efficacy analysis by using SPSS 13.0 software. For analysis of efficacy outcomes, a two-sided significance level of 0.05 was used. PFS was compared using the log-rank test, and two-sided 95% CI was calculated for median PFS. The HR and 95% CI of the HR were calculated. OS was analyzed using the same methods, and the estimated probability of OS rate at 1, 2, and 3 years was calculated based on the Kaplan–Meier estimates. HR was also calculated for each subset of patients. Best RR was compared using Fisher's exact test.

Acknowledgments

We thank the staff of the Department of Pathology in Peking University Cancer Hospital & Institute. This work was supported by grants from the Program for New Century Excellent Talents in University (985-2-085-113), the National Natural Science Foundation of China (30973483), and the Simcere Pharmaceutical Co. in China. The authors declared no conflict of interest.

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