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© 2002 American Society for Clinical Oncology
Endostatin: Are the 2 Years Up Yet?The Netherlands Cancer Institute, Amsterdam, the Netherlands
The University of Chicago, Cancer Research Center, Chicago, IL THERE HAS BEEN tremendous excitement among both the oncology community and the lay public regarding the potential for angiogenesis inhibitors, such as endostatin, climaxing on May 3, 1998, with a front page story by Gina Kolata in The New York Times. This article quoted Nobel Laureate James Watson as saying that endostatin would lead to a cure for cancer within 2 years.1,2 There is a strong rationale for the use of angiogenesis inhibitors. Tumors need blood vessels to expand in size and become clinically detectable. Angiogenesis is also essential for the process of metastasis, as micrometastases need blood supply for growth. The field of angiogenesis provides excellent handles for rationale design of drugs, because most elements of the algorithm for successful drug development are present: (1) clinical pathologic studies clearly demonstrated correlations between angiogenic factors and prognosis in a range of tumors, including breast, gastric, colorectal, non–small-cell lung cancer and melanoma3; (2) preclinical studies revealed that angiogenesis is a key pathway for tumor invasion, growth, and metastasis4,5; (3) critical pieces of the molecular puzzle of angiogenesis have recently been unraveled,6,7 which has lead to identification of a range of targets, and selection of candidate drugs for preclinical proof of concept studies8-12; (4) pharmacologic and toxicologic studies demonstrated that most tested compounds are safe and selectively target tumor vessels5,8,13; and (5) tumor responses were seen in clinical dose-finding studies with first-generation angiogenesis inhibitors, especially targeting the vascular endothelial growth factor (VEGF) pathway.3 But it is not at all that easy. Despite the fully loaded pipeline of powerful drug candidates ready for clinical testing, clinical scientists are faced with considerable uncertainties. Oncologists have limited familiarity with the development of anticancer drugs that have wide therapeutic windows and poorly validated biologic end points in dose-finding studies. Lack of knowledge about predictive markers for treatment outcome in early clinical studies hampers selection of the best dose and schedule for pivotal clinical trials. Desirable exposure levels in patients have to be based on preclinical pharmacokinetic and pharmacodynamic experiments, using artificial tumor models that poorly represent the biologic complexity of real life. We are also on the learning curve of understanding optimal clinical trial design, selecting strategies for effective combined-modality treatment, and unraveling mechanisms of clinical inactivity.14 It is a learning curve that we are familiar with from the past decades of development of effective chemotherapy. One of the promising candidate drugs is recombinant human endostatin (rhEndostatin). Endostatin is a 20-kd fragment of an endogenous extracellular matrix heparin sulfate proteoglycan of which the crystal structure has been elegantly elucidated.11,12 Antiangiogenesis activity results from a direct effect on endothelial cells, which has been established in Dr Folkman’s group, a pioneer in the field of antivascular research. In this issue of the Journal of Clinical Oncology, Eder et al15 report the first phase I study with rhEndostatin given as a short 20-minutes iv infusion once daily to patients with a range of advanced solid tumor types. The authors have addressed a number of the outlined difficulties in the development of angiogenesis-targeting drugs. The applied schedule of administration was selected from preclinical activity studies. The achieved exposure at the highest dose level of 240 mg/m2 per day was in the range of active levels as established in in vitro and tumor xenograft studies. The investigators applied dynamic contrast-enhanced magnetic resonance imaging to monitor biologic effect; however, there were no significant detectable changes in quantitative parameters after rhEndostatin administration. Urinary excretion levels of VEGF and basic fibroblast growth factor were not related to the dose of rhEndostatin and, therefore, not predictive of exposure or biologic effect. However, this relationship needs further validation in larger trials. Variable but linear pharmacokinetics were found, and clearance was not related to body-surface area. rhEndostatin was well tolerated and induced clinical benefit and hints of activity in three patients. The authors provide a number of plausible arguments as to why little activity was observed in this study. The dose and schedule may have been suboptimal, and late stage, bulky disease may not be responsive to rhEndostatin. Furthermore, heterogeneity in tumor types in this small cohort of 15 patients was very high, possibly masking activity in a subset of responsive tumors. Recently obtained results by Folkman’s group in preclinical models using a continuous exposure (continuous intravenous) schedule revealed higher activity, even at five-fold lower dose-levels, compared with twice-daily bolus injection.16 This scheme is logical and may result in clinical activity. The terminal half-life in mice is much shorter than in man, but the effect of scheduling on activity of rhEndostatin is still important to investigate. Also angiostatin was found to be more active when applied at a continuous exposure schedule.17 Of concern is the development of antibodies to rhEndostatin, and future studies should address whether they affect the active form of the protein. The second phase I study with rhEndostatin applying the same dosing schedule in 26 patients is presented by Herbst et al18 in this issue. Dose-levels up to 600 mg/m2/d were used. The results confirm that rhEndostatin is well tolerated and does not induce dose-limiting toxicity at these dose levels. Serum markers of angiogenic activity (VEGF, VCAM-1, E-selectin, and basic fibroblast growth factor) were highly variable and were not correlated to the exposure or activity of rhEndostatin. This confirms the need for the identification and validation of other predictive biomarkers in preclinical and clinical studies. Pharmacokinetic results were comparable with those obtained by Eder et al.15 Development of significant immunoreactivity was also common in this trial. Unfortunately, little antitumor activity was seen, similar to the other phase I study. Herbst et al19 have also determined other noninvasive and invasive biomarkers that may explore the biologic effect of rhEndostatin, results of which are also published in this issue of the Journal. These studies were mandated by the National Cancer Institute, the sponsor of this study, as part of their request for letters of intent to conduct phase I trials of rhEndostatin. Herbst et al were able to perform positron-emission tomography scanning for estimation of tumor blood flow and metabolism, using [15O]H2O and [18F]fluorodeoxyglucose as probes, respectively. They also had significant success in the acquisition of tumor biopsies at baseline and after 8 weeks of treatment to assess epithelial and tumor cell apoptosis. All 25 treated patients underwent tumor biopsy at baseline and 18 patients underwent follow-up biopsies. Seven patients went off study before a second biopsy was planned. The results reveal significant reduction in tumor blood flow and metabolism and increase in epithelial and tumor cell apoptosis. Disappointingly, there was no significant correlation between apoptosis and the rhEndostatin dose or with the area under the curve. Hence, the results are of little help in selecting the optimal dose of rhEndostatin in this schedule. Because there was no apparent relationship between these biologic markers and rhEndostatin exposure or dose, either the lowest dose was sufficient to achieve these changes in markers, or the changes have nothing to do with rhEndostatin. It is important to acknowledge that we have embarked on an expensive and invasive series of adventures with biologic markers, and we have only limited understanding of intraindividual and interindividual variability. We have demonstrated that we can conduct such studies (and convince patients with advanced cancer to give consent), but we have not yet demonstrated that such studies are worth the cost or the small but real risk to the patient in regard to serial biopsies. Additional prospective, multicenter studies with an appropriate number of patients and length of follow-up are needed to validate one of these, or other, novel prognostic markers. In these trials, the techniques should be thoroughly standardized and review of scans or pathology slides should be centralized.20 The phase I clinical trials with rhEndostatin are a logical extension of extensive preclinical testing. Clearly, the results are not what were predicted by some in 1998.1 The results of these important clinical trials will hopefully have a significant impact on the development strategy of future vascular targeting drugs. If there is an algorithm to success for antivascular drug development, how should we proceed from here? An important next step is to prove the principle that antivascular drugs can induce relevant tumor shrinkage. It is logical for this aim to select tumor types and patient populations in which significant correlations between angiogenic factors and prognosis have been demonstrated.3 Breast, prostate, and non–small-cell lung cancer may be good candidate tumor types, and early-stage disease may be the best testing condition. Trial design may need to be modified compared with traditional phase II studies because we do not know yet the duration of treatment required for antivascular drugs to produce an effect and whether the effect will be regression or growth inhibition (stable disease). When no relevant antitumor activity is seen in these trials one may seriously question the usefulness of development of these compounds as single agent or in combination therapy. According to current registration standards, a statistically significant and clinically meaningful survival benefit should be demonstrated in adequately powered pivotal trials. This makes sense also for this new class of anticancer drugs. Identification of noninvasive or secreted markers and thorough validation in large trials would help the field enormously and can support the complete clinical development from phase I to III trials. Trials in adjuvant disease are a logical extension of successful development of vascular targeting drugs in advanced disease, although such trials would be expensive and of relatively long duration. Considering the wide range of angiogenic growth factors that can be produced by tumors and the possible biologic heterogeneity of tumor-induced blood vessels, combinations of antiangiogenesis drugs may be more effective than single-agent treatment. Preclinical studies support this concept.21 In view of the complex biologic heterogeneity of tumors combinations of antivascular drugs and chemotherapy or radiotherapy are of great interest. Identification of genetic patterns of tumors by microarray analysis that predict responsiveness to antivascular therapy may guide these strategies. Elucidation of good prognosis and bad prognosis sets of genes in early breast cancer has recently demonstrated the enormous clinical value of genetic profiling of tumors.22 Support for the concept of chronic continuous exposure will fuel the development of orally available small molecules. All these are exciting steps on the way to the clinical application of novel targeted agents. REFERENCES 1. Kolata G: Two drugs eradicate tumors in mice. New York Times, May 3, 1998
2. Pentz RD, Flamm AL, Sugarman J, et al: Study of the media’s influence on prospective research participants’ understanding of and motivations for participation in a high-profile phase I trial. J Clin Oncol 20: 3785-3791, 2002 3. Fox SB, Gasparini G, Harris AL: Angiogenesis: pathological, prognostic, and growth-factor pathways and their link to trial design and anticancer drugs. Lancet Oncology 2: 278-289, 2001[CrossRef][Medline]
4. Folkman J: What is the evidence that tumors are angiogenesis dependent? J Natl Cancer Inst 82: 4-6, 1990 5. Boehm T, Folkman J, Browder T, et al: Angiogenetic therapy of experimental cancer does not induce acquired drug resistance. Nature 390: 404-407, 1997[CrossRef][Medline] 6. Hanahan D, Folkman J: Patterns of emerging mechanisms of angiogenetic switch during tumorigenesis. Cell 86: 353-364, 1996[CrossRef][Medline] 7. Davis S, Aldrich TH, Jones PF: Isolation of angiopoietin-1, a ligand for the TIE2 receptor, by secretion-trap expression cloning. Cell 87: 1153-1155, 1996[CrossRef][Medline] 8. O’Reilly MS, Boehm T, Shing Y, et al: Endostatin: An endogenous inhibitor of angiogenesis and tumor growth. Cell 88: 277-285, 1997[CrossRef][Medline] 9. Los M, Voest EE: The potential role of antivascular therapy in the adjuvant and neoadjuvant treatment of cancer. Semin Oncol 28: 93-105, 2001[CrossRef][Medline]
10. Halfter W, Dong S, Shurer B, et al: Collagen XVIII is a basement membrane heparin sulfate proteoglycan. J Biol Chem 273: 25404-25412, 1998 11. Dhanabal M, Volk R, Ramchandran R, et al: Cloning, expression and in vitro activity of human endostatin. Biochem Biophys Res Commun 258: 345-352, 1999[CrossRef][Medline] 12. Hohenester E, Sasaki T, Olsen BR, et al: Crystal structure of the angiogenesis inhibitor endostatin at 1.5 A resolution. EMBO J 17: 1656-1664, 1998[CrossRef][Medline] 13. Sim BK, MacDonald NJ, Gubish ER: Angiostatin and endostatin: Endogenous inhibitors of tumor growth. Cancer Metastasis Rev 19: 181-190, 2000[CrossRef][Medline] 14. Stadler WM, Ratain MJ: Development of target-based antineoplastic agents. Invest New Drugs 18: 7-16, 2000[CrossRef][Medline]
15. Eder JP Jr, Supko JG, Clark JW, 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
16. Kisker O, Becker ChM, 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
17. Drixler TA, Borel Rinkes IHM, Ritchie ED, et al: Continuous administration of angiostatin inhibits accelerated growth of colorectal liver metastases after partial hepatectomy. Cancer Res 60: 1761-1765, 2000
18. Herbst RS, Hess KR, Tran HT, et al: Phase I study of recombinant human endostatin in patients with advanced solid tumors. J Clin Oncol 20: 3792-3803, 2002
19. Herbst RS, Mullani NA, Davis DW, et al: Development of biologic markers of response and assessment of antiangiogenic activity in a clinical trial of human recombinant endostatin. J Clin Oncol 20: 3804-3814, 2002 20. Evelhoch J, Brown T, Chenevert T, et al: Consensus recommendation for acquisition of dynamic contrasted-enhanced MRI data in oncology. Http://cancer.gov/bip/dcemrilabst.htm
21. Yokoyama Y, Dhanabal M, Griffioen AW, et al: Synergy between angiostatin and endostatin: Inhibition of ovarian cancer growth. Cancer Res 60: 2190-2196, 2000 22. van‘t Veer LJ, Dai H, van de Vijver MJ, et al: Gene expression profiling predicts clinical outcome of breast cancer. Nature 415: 530-536, 2002[CrossRef][Medline]
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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