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Journal of Clinical Oncology, Vol 24, No 22 (August 1), 2006: pp. 3555-3561 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.05.6762 Phase II Study of Recombinant Human Endostatin in Patients With Advanced Neuroendocrine Tumors
From the Department of Medical Oncology, Dana-Farber Cancer Institute; Harvard Medical School; Department of Hematology/Oncology, Massachusetts General Hospital; Channing Laboratory, Brigham and Women's Hospital, Boston, MA; University of California at San Francisco Comprehensive Cancer Center, San Francisco, CA; and Entremed Inc, Rockville, MD Address reprint requests to Matthew H. Kulke, MD, Department of Medical Oncology, Dana-Farber Cancer Institute, 44 Binney St, Boston, MA 02115; e-mail: matthew_kulke{at}dfci.harvard.edu
PURPOSE: Endostatin is a 20-kd proteolytic fragment of collagen XVIII that, in preclinical studies, has been shown to have antiangiogenic and antitumor activity. Both preclinical and human phase I studies of recombinant human endostatin (rhEndostatin) suggested activity in neuroendocrine tumors, which are known to be hypervascular. We therefore performed a multicenter phase II study of rhEndostatin in patients with carcinoid or pancreatic neuroendocrine tumors. PATIENTS AND METHODS: Forty-two patients with advanced pancreatic endocrine tumors or carcinoid tumors were treated with rhEndostatin administered as a bid subcutaneous injection at a starting dose of 60 mg/m2/d. Steady-state trough levels were obtained after 6 weeks of therapy; patients who did not achieve a target therapeutic level of 300 ng/mL underwent dose escalation to 90 mg/m2/d. Patients were observed for evidence of toxicity, response, and survival. RESULTS: rhEndostatin was associated with minimal toxicity. However, among 40 patients assessable for radiologic response, none experienced partial response to therapy, as defined by WHO criteria. The median steady-state trough level achieved after dose escalation was 331 ng/mL, within the postulated therapeutic range. CONCLUSION: Treatment with rhEndostatin did not result in significant tumor regression in patients with advanced neuroendocrine tumors.
Endostatin is one of a number of endogenous peptides that inhibit the migration and proliferation of vascular endothelial cells.1 Structural studies have demonstrated that endostatin is a 20-kd fragment derived from the carboxy-terminal region of collagen XVIII, a proteoglycan that is a major constituent of blood vessels throughout the body.2 Endostatin initially was isolated from a murine hemangioendothelioma cell line, and was subsequently shown to inhibit tumor angiogenesis and cause tumor regression in carcinogen-induced mammary tumors, mouse xenografts, and transgenic mice.1,3-5 Initially, three separate phase I studies of recombinant human endostatin (rhEndostatin) in humans were undertaken, in which patients with advanced cancer were treated at doses ranging from 15 to 600 mg/m2/d without evidence of dose-limiting toxicity.6-8 In these studies, rhEndostatin was administered as a daily intravenous bolus injection, after which serum concentrations of rhEndostatin declined rapidly. Preclinical studies in mouse xenografts suggested that the administration of endostatin as a continuous infusion is associated with higher rates of tumor growth inhibition, at lower overall doses, than required with bolus injections.9 Therefore, in a fourth phase I human study, both continuous intravenous infusion and bid subcutaneous administration of rhEndostatin were evaluated at doses ranging from 3.75 to 120 mg/m2/d.10 This study demonstrated that both the intravenous and subcutaneous modes of administration resulted in steady-state serum concentrations in the range (200 to 300 ng/mL) predicted to induce antitumor effects. A total of 94 patients received treatment in the first four phase I endostatin studies.6-8,10 Although no formal radiologic partial responses were observed in these studies using standard response criteria, minor tumor responses were observed in a patient with melanoma, a patient with synovial cell carcinoma, and one patient with advanced, metastatic pancreatic neuroendocrine tumor. The pancreatic neuroendocrine tumor patient experienced maximum tumor reduction of 17%, which lasted for more than 11 months. The fact that neuroendocrine tumors are highly vascular further supported the continued evaluation of rhEndostatin in this patient population, as did the observation that endostatin treatment was associated with 60% tumor shrinkage in a transgenic mouse pancreatic endocrine tumor model.4,11 We performed a multicenter phase II study of rhEndostatin in patients with advanced neuroendocrine tumors. Because of their similar histologic and clinical characteristics, patients with both pancreatic neuroendocrine and carcinoid tumors were enrolled. rhEndostatin was administered subcutaneously, using a bid dosing schedule, at a starting dose of 60 mg/m2 daily without scheduled treatment breaks. Steady-state trough levels of rhEndostatin were monitored, and patients who had not achieved a target therapeutic steady-state trough level of 300 ng/mL underwent dose escalation to 90 mg/m2. Patients were observed for evidence of toxicity, biochemical response, radiologic response, and survival.
Patient Population All patients had histologically documented, metastatic neuroendocrine tumors, excluding small-cell carcinoma. Measurable disease, as defined by WHO criteria was required. Prior treatment with systemic chemotherapy or an investigational agent (except rhEndostatin) was allowed if patients had discontinued prior therapy at least 4 weeks before study enrollment. Patients receiving octreotide were allowed to continue therapy at stable doses throughout study treatment. Additional inclusion criteria included: Eastern Cooperative Oncology Group status of 0 or 1, AST and ALT less than 5x the upper limit of normal, total bilirubin less than 2.0 mg/dL, serum creatinine  2.0 mg/dL, WBC  3,000/mL, absolute neutrophil count 1,000/µL, and platelets 100,000/µL. Exclusion criteria included clinically apparent CNS metastases or carcinomatous meningitis, myocardial infarction or angina pectoris in the 6 months before study treatment, major surgery within 2 weeks, concurrent treatment with heparin, pregnancy, or lactation. Patients from Dana-Farber Cancer Institute (Boston, MA), Massachusetts General Hospital (Boston, MA), the Beth Israel Deaconess Medical Center (Boston, MA), or the University of California, San Francisco Comprehensive Cancer Center (San Francisco, CA) were eligible for enrollment. All patients provided informed consent as required by the institutional review boards of the respective institutions.
Treatment Program Dose adjustments were made after completion of the second 4-week treatment cycle, based on tumor response and serum pharmacokinetics in each patient. If the tumor was stable or had not responded, and if the cycle 2, day 15 blood sample indicated that the serum levels of rhEndostatin protein had not achieved a steady-state trough level of 300 ng/mL, then the dose for that patient was escalated to 45 mg/m2 bid (90 mg/m2/d). No additional dose escalations or reductions were performed over the course of the study. Patients discontinued therapy in the event of grade 3 or greater nonhematologic toxicity, if they experienced a grade 4 hematologic toxicity that did not resolve in 14 days, if they missed more than 14 consecutive days of rhEndostatin treatment, if they became pregnant, if they chose to terminate study participation, or at the discretion of the investigator. Radiologic assessments of response with computed tomography or magnetic resonance scan were made at baseline and after every two cycles (8 weeks) of study therapy. Radiologic response was classified according to the WHO criteria. Complete response required total resolution of all detectable disease lasting for at least 4 weeks. Partial response required a decrease of more than 50% in the sum of the products of the largest perpendicular diameters of all measurable lesions, persisting for at least 4 weeks, without progression of any nonmeasurable sites and without the appearance of new sites of disease. Progressive disease included an increase of 25% or more in the sum of the products of the largest perpendicular diameters of one or more measurable lesions, the development of new lesions, or progression of nonmeasurable but assessable sites of disease. Stable disease was defined as having neither sufficient shrinkage to qualify for partial response nor sufficient increase to qualify for progressive disease. Serum chromogranin A (CGA), 24-hour collections of urinary 5-hydroxyindoleacetic acid (5-HIAA), and urinary levels of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) were measured at baseline and after each cycle of therapy. CGA and 5-HIAA were measured using standard clinical assays. VEGF and bFGF were measured using the Quantikine human VEGF and Quantikine high-sensitivity human bFGF enzyme-linked immunosorbent assay kits (R&D Systems Inc, Minneapolis, MN). CGA or 5-HIAA responses were defined as a decrease from baseline of at least 50% on two consecutive measurements in patients who had elevated baseline levels (defined as CGA > 36.4 ng/mL or 5-HIAA > 6 mg/24 hours).
Statistical Considerations
Patient Characteristics A total of 42 patients were entered onto the study at the four participating centers. Baseline characteristics of the patients are shown in Table 1. Patients had a median age of 55 years, 55% were male, and the median time from their original diagnosis was 49.5 months. Fifty-three percent of the cohort had metastatic carcinoid tumors, and 47% had metastatic pancreatic endocrine tumors. In nearly all patients (90%) the tumor was histologically described as well differentiated; only 10% had moderately or poorly differentiated neuroendocrine tumors. The majority (64%) had received some form of prior therapy other than surgery; prior treatments included systemic chemotherapy, interferon alfa, and embolization of hepatic metastases.
Pharmacokinetic Data and Dose Escalation Forty-two patients received treatment for a median of 6.4 months (range, 10 days to 45 months). All patients initiated therapy at a dose of 60 mg/m2 daily. Serial endostatin levels were measured in five study patients at baseline and during the first 24 hours after administration of the first dose of 30 mg/m2 on day 1, and after administration of the morning dose of 30 mg/m2 on day 28. The median baseline level of endostatin protein in these five patients was 33 ng/mL, reflecting endogenous endostatin levels. Median endostatin levels increased to a peak of 66 ng/mL 12 hours after initial administration (Fig 1A) and decreased back to baseline levels (37 ng/mL) at 24 hours. The median endostatin concentration before dosing on day 28 was 179 ng/mL. The endostatin concentration increased to a maximum level of 241 ng/mL before decreasing to 123 ng/mL 12 hours after administration (Fig 1B).
The median endostatin level for the entire patient cohort during cycle 2, before dose escalation, was 259 ng/mL, which was below the target endostatin steady-state trough level of 300 ng/mL (Fig 1C). Twenty-two (52%) patients were found to have subtherapeutic trough levels, and underwent subsequent dose escalation to the 90 mg/m2/d dose level. Following this dose escalation, the median monthly endostatin concentrations for cycles 3 to 12 in the study cohort ranged from 241 to 583 ng/mL, with a median level of 331 ng/mL.
Toxicity
Biochemical and Symptomatic Response to Therapy Thirty-one patients had elevated CGA levels at baseline (> 36.4 ng/mL) and were assessable for CGA response, defined as a more than 50% decrease in serum levels from baseline on two consecutive measurements. Two patients (6%) experienced CGA responses; both patients had stable disease as their best radiologic response to therapy. Twenty patients had elevated baseline levels of urinary 5-HIAA (> 6 mg/24 hours) and were assessable for 5-HIAA responses; none responded. Consistent with the rarity of biochemical responses, resolution of hormonally mediated symptoms was uncommon during treatment. Before initiating treatment with rhEndostatin, 17 patients reported symptoms of flushing, 21 reported diarrhea, and 18 reported fatigue. After treatment initiation, no patients experienced resolution of flushing symptoms, two patients (9.5%) experienced resolution of their diarrhea, and one patient (5%) experienced resolution of fatigue. Urinary VEGF and bFGF levels were measured at baseline and after each cycle of therapy in 26 of the 28 patients treated at the Dana-Farber Cancer Institute and Massachusetts General Hospital sites. The median baseline urinary bFGF level was 1,792.5 pg/L (range, < 1,000 to 11,653 pg/L), and the median baseline urinary VEGF level was 86.5 ng/mL (range, 35 to 581 ng/mL). No consistent changes in urinary VEGF or bFGF concentrations were observed in these patients during study therapy.
Efficacy
To better assess whether the high incidence of stable disease in the study reflected treatment effect or the natural tumor growth rate of the enrolled patients, patients were evaluated retrospectively for reported disease progression before study enrollment. Twenty-one (95%) of 22 assessable patients were reported to have stable disease for at least 2 months before study enrollment, and 11 (48%) of 23 were reported to have stable disease for at least 6 months before study enrollment. The most common reason for discontinuation of study treatment was disease progression (20 patients; 48%). Other reasons for treatment discontinuation included adverse events (four patients; 10%) and death (one patient; 2%). Seventeen patients (41%) either withdrew consent for additional treatment or discontinued for other, unspecified reasons. The median progression-free survival time was 5.8 months (range, 1.9 to 13.5 months) for patients with pancreatic endocrine tumors and 7.6 months (range, 5.3 to 19.2 months) for patients with carcinoid tumors. The median overall survival was 17.2 months (range, 8.1 to 27.2 months) for patients with pancreatic endocrine tumors and 22.6 months (range, 17.8 to > 27.4 months) for patients with carcinoid tumors (Figs 2 and 3).
Our study demonstrates that the administration of rhEndostatin is associated with minimal toxicity when administered during a prolonged period to patients with advanced neuroendocrine tumors. However, treatment with rhEndostatin was not associated with significant antitumor activity as measured by traditional response criteria. No patients achieved a partial or complete radiologic response, biochemical (CGA) responses were observed in only 6% of assessable patients, and less than 10% of patients reported resolution of hormonally mediated tumor-related symptoms. One limitation of our study is the lack of firm data regarding the optimal therapeutic dose of rhEndostatin. The target steady-state level of rhEndostatin for this study was based primarily on studies using tumor xenografts, suggesting that steady-state levels of 200 to 300 ng/mL are required for tumor regression.9 Subsequent studies have suggested that the dose-response curve of rhEndostatin is biphasic, and that administration of higher doses of endostatin is not associated with further enhancement of antitumor activity.12 Steady-state trough levels after the administration of the initial 60 mg/m2/d starting dose in our study were below the target therapeutic range of 300 ng/mL. After dose escalation to 90 mg/m2/d, the median steady-state trough level was 331 ng/mL, which closely approximated the target therapeutic dose. Notably, the pancreatic neuroendocrine tumor patient who experienced a minor tumor response in an earlier phase I study had received intravenous bolus doses of 30 mg/m2 daily, which were well below the dosing levels used in the present study.7
The precise mechanisms of the reported antiangiogenic and antitumor activity of endostatin have not yet been characterized fully. Endostatin contains a heparin-binding motif, and may exert some of its antiangiogenic effects through interactions with the heparan sulfate proteoglycans glypican-1 and -4.13 Binding of endostatin to Several investigators have suggested that angiogenesis inhibitors may be cytostatic rather than cytotoxic, and that strategies other than evaluation of radiologic tumor regression may be necessary to assess their potential efficacy.18 The majority (80%) of patients in this study experienced stable disease as their best response to therapy. However, this observation may reflect the naturally indolent nature of their disease. In 22 study patients for whom prior progression could be assessed, 95% had stable disease for at least 2 months before study enrollment. The incidence of stable disease for at least 6 months before study enrollment in a similar subgroup of 23 patients was 48%, a figure that may explain the relatively long time to tumor progression observed in patients with either carcinoid (7.6 months) or pancreatic neuroendocrine tumors (5.6 months) during study treatment. In contrast to the results observed in this study, modest antitumor activity has been observed recently after the treatment of neuroendocrine tumors with specific VEGF pathway inhibitors. In a preliminary report, the tyrosine kinase inhibitor sunitinib, which inhibits phosphorylation of VEGF receptor, platelet-derived growth factor receptor, c-Kit, and the product of RET proto-oncogene, was associated with an overall radiologic response rate of 9% in a 102-patient phase II study of carcinoid and pancreatic endocrine tumors.19 In a randomized phase II study, treatment with the monoclonal anti-VEGF antibody bevacizumab was associated with radiologic tumor responses in three of 18 (16%) patients with carcinoid tumors.20 A number of cytotoxic agents have also been shown previously to have activity in neuroendocrine tumors. The combination of streptozocin and fluorouracil has been associated with overall response rates of 16% to 21% in carcinoid tumors, and in pancreatic neuroendocrine tumors, the three-drug combination of streptozocin, fluorouracil, and doxorubicin has been associated with an overall response rate of 39%.21-23 Regimens containing dacarbazine or its oral analog, temozolomide, have been associated with objective response rates of 8% to 16% in patients with advanced carcinoid tumors and 33% to 45% in patients with pancreatic neuroendocrine tumors.24,25 Whether the addition of angiogenesis inhibitors to currently available cytotoxic regimens will enhance their efficacy is not yet known. In conclusion, treatment with rhEndostatin did not result in significant tumor or biochemical regression in patients with advanced neuroendocrine tumors, nor was it associated with clear evidence of a cytostatic effect. Other angiogenesis inhibitors seem to have more activity in this disease.
Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Dollar Amount Codes (A) $10,000 (B) $10,000-99,999 (C) $100,000 (N/R) Not Required
We thank Taylor S. Spear for assistance in manuscript preparation.
Supported by Entremed Inc. Supported in part by National Institutes of Health Grants No. K23 CA 093401 and K30 HL04095, and gifts from Raymond and Beverly Sackler, the Caring for Carcinoid Foundation, and the Stephen and Caroline Kaufer Fund for Neuroendocrine Tumor Research (M.H.K.). Presented in part at the 39th Annual Meeting of the American Society of Clinical Oncology, May 31-June 3, 2003, Chicago, IL. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Eder J, Supko J, Clark J, et al: Phase I clinical trial of recombinant human endostatin administered as a short intravenous infusion repeated daily. J Clin Oncol 20:3772-3784, 2002 8. Thomas J, Arzoomanian R, Albierti D, et al: Phase I pharmacokinetic and pharmacodynamic study of recombinant human endostatin in patients with advanced solid tumors. J Clin Oncol 21:223-231, 2003 9. Kisker O, Becker C, Prox D, et al: Continuous administration of endostatin by intraperitoneally implanted osmotic pump improves the efficacy and potency of therapy in a mouse xenograft tumor model. Cancer Res 61:7669-7674, 2001 10. Hansma A, Broxterman H, vanderHorst I, et al: Recombinant human endostatin administered as a 28-day continuous intravenous infusion, followed by daily subcutaneous injections: A phase I and pharmacokinetic study in patients with advanced cancer. Ann Oncol 16:1695-1701, 2005 11. Terris B, Scoazec J, Rubbia L: Expression of vascular endothelial growth factor in digestive neuroendocrine tumors. Histopathology 32:133-138, 1998[CrossRef][Medline] 12. Celik I, Surucu O, Dietz C, et al: Therapeutic efficacy of endostatin exhibits a biphasic dose-response curve. Cancer Res 65:11044-11050, 2005 13. Olsson AK, Johansson I, Akerud H, et al: The minimal active domain of endostatin is a heparin-binding motif that mediates inhibition of tumor vascularization. Cancer Res 64:9012-9017, 2004 14. Wickstrom SA, Alitalo K, Keski-Oja J: Endostatin associates with integrin alpha5beta1 and caveolin-1, and activates Src via a tyrosyl phosphatase-dependent pathway in human endothelial cells. Cancer Res 62:5580-5589, 2002 15. Wickstrom SA, Veikkola T, Rehn M, et al: Endostatin-induced modulation of plasminogen activation with concomitant loss of focal adhesions and actin stress fibers in cultured human endothelial cells. Cancer Res 61:6511-6516, 2001 16. Sudhakar A, Sugimoto H, Yang C, et al: Human tumstatin and human endostatin exhibit distinct antiangiogenic activities mediated by alpha v beta 3 and alpha 5 beta 1 integrins. Proc Natl Acad Sci U S A 100:4766-4771, 2003 17. Abdollahi A, Hlatky L, Huber PE: Endostatin: The logic of antiangiogenic therapy. Drug Resist Updat 8:59-74, 2005[CrossRef][Medline] 18. Shaheen R, Davis D, Liu W, et al: Antiangiogenic therapy targeting the tyrosine kinase receptor for vascular endothelial growth factor inhibits the growth of colon cancer liver metastases and induces tumor and endothelial cell apoptosis. Cancer Res 59:5412-5416, 1999 19. Kulke M, Lenz H, Meropol N, et al: A phase 2 study to evaluate the efficacy and safety of SU11248 in patients (pts) with unresectable neuroendocrine tumors (NETS). J Clin Oncol 23:310s, 2005 (suppl; abstr 4008) 20. Yao J, Ng C, Hoff P, et al: Improved progression free survival (PFS) and rapid, sustained decrease in tumor perfusion among patients with advanced carcinoid treated with bevacizumab. J Clin Oncol 23:309s, 2005 (suppl; abstr 4007) 21. Sun W, Lipsitz S, Catalano P, et al: Phase II/III study of doxorubicin with fluorouracil compared with streptozocin with fluorouracil or dacarbazine in the treatment of advanced carcinoid tumors: Eastern Cooperative Oncology Group Study E1281. J Clin Oncol 23:4897-4904, 2005 22. Engstrom P, Lavin P, Moertel C, et al: Streptozocin plus fluorouracil versus doxorubicin therapy for metastatic carcinoid tumor. J Clin Oncol 2:1255-1259, 1984[Abstract] 23. Kouvaraki M, Ajani J, Hoff P, et al: Fluorouracil, doxorubicin, and streptozocin in the treatment of patients with locally advanced and metastatic pancreatic endocrine carcinomas. J Clin Oncol 22:4762-4771, 2004 24. Ramanathan RK, Cnaan A, Hahn RG, et al: Phase II trial of dacarbazine (DTIC) in advanced pancreatic islet cell carcinoma: Study of the Eastern Cooperative Oncology Group E6282. Ann Oncol 12:1139-1143, 2001 25. Kulke MH, Stuart K, Enzinger PC, et al: Phase II study of temozolomide and thalidomide in patients with metastatic neuroendocrine tumors. J Clin Oncol 24:401-406, 2006 Submitted January 11, 2006; accepted May 18, 2006. This article has been cited by other articles:
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
= .05. Progression-free survival and overall survival estimates were calculated using Kaplan-Meier methodology. Toxicity and complications of treatment were based on reports of adverse events, physical examinations, and laboratory measurements. For pharmacokinetic analysis, serum concentration-time profiles were analyzed. 
