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Journal of Clinical Oncology, Vol 26, No 6 (February 20), 2008: pp. 919-924 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.14.1812 Phase I Clinical Trial of Cilengitide in Children With Refractory Brain Tumors: Pediatric Brain Tumor Consortium Study PBTC-012
From the Children's National Medical Center, Washington, DC; Dana-Farber Cancer Institute; Children's Hospital Boston, Boston, MA; Children's Hospital of Philadelphia, Philadelphia, PA; St Jude Children's Research Hospital; Pediatric Brain Tumor Consortium, Memphis, TN; Children's Hospital and Medical Center, Seattle, WA; and Children's Memorial Hospital, Chicago, IL Corresponding author: Tobey J. MacDonald, MD, Children's National Medical Center, 111 Michigan Ave, NW, Washington, DC 20010; e-mail: tmacdona{at}cnmc.org
Purpose A phase I trial of the antiangiogenesis agent cilengitide (EMD 121974), an alpha v beta 3,5 integrin antagonist, was performed to estimate the maximum-tolerated dose (MTD) and describe dose-limiting toxicities (DLTs) and the incidence and severity of other toxicities when administered to children with refractory brain tumors. Patients and Methods Thirty-one assessable patients received intravenous cilengitide over 1 hour twice a week for up to 52 weeks at dosages from 120 to 2,400 mg/m2. Serial blood and urine samples for clinical pharmacology studies were obtained in a subset of consenting patients. Results No DLTs were observed, and thus, the MTD was not estimated. Three of 13 patients at the dosage level of 2,400 mg/m2 experienced grade 3 or 4 intratumoral hemorrhage (ITH) possibly related to the study drug; however, two of the ITH events were asymptomatic and, by the current toxicity criteria, would be classified as grade 1. For patients treated at cilengitide 2,400 mg/m2, the 6-month cumulative incidence estimate of ITH is 23% (SE = 13%). No ITH was observed at 1,800 mg/m2. Three patients completed 1 year of protocol therapy; one patient with glioblastoma multiforme demonstrated complete response, and two patients had stable disease (SD). An additional patient had SD for more than 5 months. Conclusion The phase II dosage of intravenous cilengitide in children with refractory brain tumors is 1,800 mg/m2. A phase II trial to assess the efficacy of cilengitide therapy for children with refractory brain tumors is being developed by the Children's Oncology Group.
Angiogenesis, which is critical for tumor growth, is induced by tumor secretion of vascular growth factors that activate endothelial cell proliferation, survival, and maturation.1 A consequence of this activation is expression on endothelial cells of integrin receptors, whose presence is crucial for continued endothelial cell survival. The  vβ3 and vβ5 integrins are particularly important in angiogenesis and, therefore, represent logical targets for antiangiogenesis strategies to treat malignancies.2-5 These integrins allow endothelial cells to attach to the extracellular matrix through their ability to bind to arginine-glycine-aspartic acid (RGD) amino acid sequences found on matrix proteins.6,7 Thus, one approach to inhibiting angiogenesis is to use RGD-containing peptide antagonists.8 Specificity for the vβ3 and vβ5 receptors can be significantly enhanced by cyclizing RGD peptides. Cilengitide (EMD121974; Merck KGaA, Darmstadt, Germany), the inner salt of a cyclized RGD pentapeptide (cyclo-[Arg-Gly-Asp-DPhe-(NMeVal)]), is a potent and selective vβ3 and vβ5 antagonist.9-11 Cilengitide inhibits tumor growth in a dose-dependent manner in a variety of in vivo systems including athymic mice inoculated intracerebrally with human medulloblastoma and glioblastoma cells.12-17 Several phase I and II trials conducted in adult patients with advanced solid tumors have used cilengitide as a 1-hour infusion twice weekly (dosages: 30 to 1,600 mg/m2/d).18-21 The most frequently recorded toxicities were nausea and fatigue. Other mild toxicities include rash, pruritus, and vomiting. In these trials, neither significant hematologic toxicity nor evidence of cumulative toxicity was observed after repeated cilengitide administration. The phase I and II New Approaches to Brain Tumor Therapy (NABTT) 9911 study was a dose-finding study (120 to 2,400 mg/m2) for adults with recurrent malignant gliomas. Similar to the non-CNS studies, the majority of adverse events were mild to moderate, and a maximum-tolerated dose (MTD) was not reached.21 Results of pharmacokinetic studies have shown an average cilengitide systemic clearance between 2.0 and 3.9 L/h/m2 and a terminal half-life between 3 and 5 hours.19 Cilengitide renal clearance ranged from 0.9 to 3.4 L/h/m2, accounting for most of the systemic clearance.18 On the basis of these studies, a phase I dose-escalation trial of cilengitide twice weekly as a 1-hour infusion was conducted for the treatment of children with refractory CNS tumors. The primary aims were to determine the optimal dosage and dose-limiting toxicities (DLTs) and to characterize the pharmacokinetics and pharmacogenomics of cilengitide in children. A secondary aim was to assess tumor response using serial magnetic resonance imaging (MRI).
Patient Eligibility Patients  21 years of age with a primary CNS tumor that is recurrent or progressive and refractory to standard therapy, including benign CNS tumors (eg, low-grade glioma), were eligible. Karnofsky performance or Lansky score  50, life expectancy of more than 8 weeks, and normal organ function were required. The institutional review boards of each Pediatric Brain Tumor Consortium institution approved the protocol before initial patient enrollment, and continuing approval was maintained throughout the study. Patients or their legal guardians gave written informed consent, and assent was obtained as appropriate at the time of enrollment. Restrictions included no investigational agent within 2 weeks; no nitrosourea or myelosuppressive therapy within 6 or 4 weeks, respectively; no bone marrow transplantation within 6 months; no radiation therapy within 6 weeks; no craniospinal irradiation (> 24 Gy) or total-body irradiation within 3 months; and no local palliative irradiation within 2 weeks before study entry. Patients could not be receiving any other anticancer or experimental drug therapy, with the exception of corticosteroids.
Statistical Methods The CRM model was continually updated, and dosage escalation decisions were made as toxicity information became known for each patient. Subsequent dosage levels were determined to be the prespecified level closest to the CRM-estimated MTD without skipping a level that had been assigned to fewer than two assessable patients. The cumulative incidence functions of intratumoral hemorrhage (ITH), as measured from date on therapy to the earliest date of a competing event (disease progression or death), diagnosis of ITH, or last contact, were estimated by methods discussed in Kalbfleish and Prentice.24
Study Design Cilengitide dosing was started at 120 mg/m2, the starting dosage used in the NABTT trial. Dose escalations proceeded in subsequent patient cohorts until the MTD or the final dosage of 2,400 mg/m2 was reached (Table 1). Toxicities observed during the first 4 weeks of therapy were assessed to guide dose escalation. No intrapatient dosage escalation was allowed; however, de-escalation to the next lowest dosage level was permitted for specifically defined toxicities that occurred beyond the first 4 weeks of therapy. All patients were considered to have concluded protocol therapy at the completion of 1 year of treatment.
Toxicities were graded according to the National Cancer Institute Common Toxicity Criteria (version 2.0), and DLT was defined as any grade 3 or 4 nonhematologic toxicity (with the exclusion of grade 3 nausea and vomiting controlled with antiemetics and grade 3 transaminase [AST/ALT] elevation that returns to grade 1 within 7 days of stopping the drug), grade 3 or 4 thrombocytopenia, or grade 4 neutropenia that was considered at least possibly related to the investigational agent and occurring during the initial 4 weeks of therapy, regardless of expectedness.
Patient Evaluation
Pharmacokinetic Studies A two-compartment model was fitted to the cilengitide plasma concentrations using maximum likelihood estimation as implemented in ADAPT II.26 Parameters estimated included volume of the central compartment, elimination rate constant, and intercompartment rate constants. Systemic clearance, renal clearance, and beta half-life were calculated by standard equations, and the area under the concentration-time curve (AUC) from zero to 24 hours for cilengitide was calculated by integration of the simulated concentration-time data from model estimates.
Pharmacogenetic Studies
Patient Characteristics Between July 2003 and March 2005, 35 patients were enrolled onto the trial, of whom 33 started receiving the study drug and 31 were deemed assessable for toxicity over seven dosage levels ranging from 120 to 2,400 mg/m2 (Table 1). The study was completed in January 2006.
Toxicity
Antitumor Activity The best response demonstrated was one CR at 1,200 mg/m2 in a patient with recurrent GBM. This patient completed the 1-year protocol therapy and had sustained CR for more than 1 year with clinical improvement in symptoms. Three patients had SD for at least 22 weeks, including two patients who completed a year of protocol therapy. An additional three patients had stable neurologic examinations after the first two courses of treatment (8 weeks) and SD documented by the initial MRI but did not meet the criteria defined by the protocol for declaring SD of clinical benefit. The patients with documented SD by the initial response MRI include the following: one at 480 mg/m2 (medulloblastoma, SD for 8.4 weeks), one at 720 mg/m2 (fibrillary astrocytoma, SD for 8.4 weeks), and four at 2,400 mg/m2 (GBM, SD for 6.9 weeks; ependymoma, SD for 22.6 weeks; ependymoma, SD for 52 weeks; and optic pathway glioma, SD for 52.4 weeks; Table 3).
Pharmacokinetics Pharmacokinetic studies were collected on 22 consenting patients, but only 19 were assessable for pharmacokinetic modeling (eg, venous access problems, and so on). A representative cilengitide plasma concentration-time plot is shown in Figure 1. The median cilengitide plasma beta half-life and systemic clearance were 4.6 hours (range, 1.9 to 17.9 hours) and 4.7 L/h/m2 (range, 2.3 to 9.3 L/h/m2), respectively. The cilengitide renal clearance was determined in 10 patients, and the median was 2.9 L/h/m2 (range, 0.4 to 9.3 L/h/m2). The cilengitide AUC from zero to 24 hours and maximum concentration increased with dosage over the dosage range studied (Figs 2A and 2B). Using a compartmental modeling approach, we estimated that the cilengitide CSF penetration (AUCCSF to ACUplasma) was 1.2% for the patient with the indwelling Ommaya reservoir.
Lastly, we used the data from these 19 patients to create a limited sampling model for use in further clinical trials of cilengitide. To determine the optimal sampling times, we used a variation of D-optimality, which included the earlier described pharmacokinetic data. We also constrained the sampling scheme to three samples before 8 hours because of logistical considerations. This procedure produced the sampling method of 1, 3, and 6 hours after the end of the infusion. We tested the optimal sampling scheme along with several variations in our set of 19 patients. In all cases, the parameter estimates for the limited sampling model were obtained using maximum a posteriori probability estimator (ADAPT II). Accuracy was measured relative to the pharmacokinetic parameters determined using all plasma samples and showed that, for cilengitide, median clearance accuracy was 6% (range, 2% to 14%).
Pharmacogenetics
This is the first report of cilengitide administration in children. In this study restricted to pediatric patients with refractory brain tumors, no DLTs were observed, and thus, an MTD was not estimated. However, three serious adverse events of ITH were noted (two grade 3 and one grade 4), which were possibly related to the study drug. These adverse events occurred at the dosage level of 2,400 mg/m2 after the DLT observation period. The two grade 3 events were asymptomatic and would be considered grade 1 by the current Common Terminology Criteria of Adverse Events (version 3) criteria. The remaining patient had ITH in the setting of tumor progression. All patients who were receiving 2,400 mg/m2 of cilengitide at the time of the serious adverse events had their doses reduced to 1,800 mg/m2. No hemorrhages were observed in three patients receiving 1,800 mg/m2 and in the remaining nine patients who received 2,400 mg/m2. Therefore, it is concluded from this study that 1,800 mg/m2 is a safe dose in pediatric brain tumor patients without increased risk or overt evidence of ITH. To date, only one other study of cilengitide administration in patients with CNS tumors has been published, the NABTT-9911 study, a phase I/II trial of cilengitide for the treatment of recurrent malignant glioma in adults. In the NABTT study, which enrolled 51 patients over a dosage range identical to our study, no ITH was reported, an MTD was not estimated, and the majority of toxicities were mild to moderate. However, four DLTs were recorded (grade 3 thrombosis, grade 4 myalgia and arthralgia, and grade 3 thrombocytopenia), and one patient experienced grade 3 anorexia, hyperglycemia, hypokalemia, and hyponatremia.21 Cilengitide systemic and renal clearances in our pediatric population were similar to those observed in adults; however, we observed more interpatient variability.21 With the exception of two patients (half-lives of 14 and 17.9 hours), the terminal half-life values observed in our patient population were similar to those found in adult studies.21 Although characterized by wide interpatient variability, the cilengitide plasma concentrations increased as the cilengitide dosage increased. Patients treated at all dosage levels greater than 120 mg/m2 achieved plasma concentrations associated with growth inhibition in animal models.19 In the event that further cilengitide pharmacokinetic studies in phase II clinical trials are proposed or cilengitide dosage individualization is proposed, we developed and validated a limited sampling model for cilengitide. This model uses three sample time points to calculate cilengitide pharmacokinetic parameters accurately and without bias. Unpublished reports have suggested that cilengitide is a substrate for several ABC transporters, including ABCB1 or P-glycoprotein.18 This polymorphic efflux transport protein is present in many tissues in the body, including the brain, gut, liver, and kidney, and as such is responsible for the disposition of many compounds. However, an inconsistent relationship between ABCB1 genotype and pharmacokinetic phenotype has been reported for most drugs.29 In our small patient population studied for pharmacogenomics, we noted a suggestive relationship between ABCB1 genotype, specifically exon 26 C to T, and cilengitide systemic and renal clearance. It will be important to continue to study this relationship in larger patient populations. This will be especially true if a relationship between cilengitide plasma concentrations and effect (toxicity or efficacy) are noted because patients with the TT polymorphism could have an increased exposure to cilengitide. Finally, the responses demonstrated in our study are encouraging for preliminary evidence of activity of this agent against pediatric brain tumors. Similarly, five patients enrolled onto the NABTT-9911 study had an objective response to therapy, including two CRs and three PRs, and 16 patients experienced SD.21 Given our results, we conclude that phase II testing of cilengitide should be initiated for children with refractory brain tumors.
Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. 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. Employment or Leadership Position: None Consultant or Advisory Role: None Stock Ownership: None Honoraria: None Research Funding: Mark W. Kieran, Merck KGaA Expert Testimony: None Other Remuneration: None
Conception and design: Tobey J. MacDonald, Clinton F. Stewart, Mehmet Kocak, Richard G. Ellenbogen, Peter Phillips, Mark W. Kieran, James M. Boyett, Larry E. Kun Administrative support: James M. Boyett, Larry E. Kun Provision of study materials or patients: Stewart Goldman, Richard G. Ellenbogen, Peter Phillips, Deborah Lafond, Mark W. Kieran Collection and assembly of data: Tobey J. MacDonald, Clinton F. Stewart, Mehmet Kocak, Deborah Lafond, Tina Young Poussaint Data analysis and interpretation: Tobey J. MacDonald, Clinton F. Stewart, Mehmet Kocak, Tina Young Poussaint, James M. Boyett Manuscript writing: Tobey J. MacDonald, Clinton F. Stewart, Mehmet Kocak, Tina Young Poussaint, Mark W. Kieran, James M. Boyett, Larry E. Kun Final approval of manuscript: Tobey J. MacDonald, Clinton F. Stewart, Stewart Goldman, Richard G. Ellenbogen, Peter Phillips, Deborah Lafond, Mark W. Kieran, Larry E. Kun
We thank Stacye Richardson for protocol management support.
Supported in part by National Institutes of Health Grant No. U01 CA81457 for the Pediatric Brain Tumor Consortium and the American Lebanese Syrian Associated Charities. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Taga T, Suzuki A, Gonzalez-Gomes I, et al: Alpha v-Integrin antagonist EMD 121974 induces apoptosis in brain tumor cells growing on vitronectin and tenascin. Int J Cancer 98:690-697, 2002[CrossRef][Medline] 17. Mitjans F, Meyer T, Fittschen C, et al: In vivo therapy of malignant melanoma by means of antagonists of alphav integrins. Int J Cancer 87:716-723, 2000[CrossRef][Medline] 18. Merck KGaA: EMD 121974 Investigator's Brochure. Darmstadt, Germany, Merck KGaA, 2006 19. Eskens F, Dumez H, Verweij J, et al: Phase I and pharmacologic study of cilengitide (EMD 121974), an alphavbeta3 and alphavbeta5 integrin inhibitor that perturbs tumor angiogenesis in patients with solid tumors. Proc Am Soc Clin Oncol 19:206a, 2000 (abstr 801) 20. Holden SN, Morrow M, O'Bryant C, et al: Correlative biological assays used to guide dose escalation in a phase I study of the antiangiogenic alphaVbeta3 and alphaVbeta5 integrin antagonist EMD 121974 (EMD). Proc Am Soc Clin Oncol 21:28a, 2002 (abstr 110) 21. 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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
