Phase II Trial of the O 6-Alkylguanine DNA Alkyltransferase Inhibitor O 6-Benzylguanine and 1 , 3-Bis ( 2-Chloroethyl )-1-Nitrosourea in AdvancedMelanoma

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Author	Gajewski, Thomas F. Sosman, Jeffrey A. Gerson, Stanton L. Liu, Lili Dolan, Eileen M. Li-N, Shang Vokes, Everett E.
Copyright Year	2005
Abstract	Purpose: 1,3-Bis(2-chloroethyl)-1-nitrosourea (BCNU) induces DNA damage via a chloroethyl adduct at theO position of guanine, which can be repaired byO-alkylguanine DNA alkyltransferase (AGT) expressed in melanoma.We postulated that the addition of O benzylguanine (OBG), a potent inactivator of AGT, would improve the clinical response to BCNU inmelanoma. Experimental Design: Patients had measurable disease, adequate organ function, and a corrected Diffusing capacity of the lung for carbon monoxide (DLCO) of z70% predicted.They were accrued into two cohorts based on prior chemotherapy. OBG (120 mg/m) was administered i.v. followed by BCNU (40 mg/m) on an outpatient basis. Peripheral blood mononuclear cells (PBMC) were collected preand 18 hours post-OBG to analyze AGTdepletion. Treatment was every 6 weeks, and clinical response was assessed after every two cycles. Results: Forty-twopatients were enrolled, 22 of these patients were chemotherapy-naı̈ve. In the chemotherapy-naı̈ve cohort, there was a patient with a complete response (CR), 4 with stable disease (SD),13 with progressive disease (PD), and 4 nonevaluable patients; the median time to progressionwas80days and themedian survivalwas211days. In theprior-chemotherapycohort, there were no responses, 3 SD, 15 PD, and 2 nonevaluable patients; median time to progression was 54 days andmedian survival was120 days. AGTwas depleted from PBMC in the15 patients tested. Grades 3 to 4 myelosuppression was seen in 57% of patients; toxicities were similar between the two cohorts. Conclusions: OBG/BCNU was successfully administered on an outpatient basis and depleted AGT from PBMC. However, significant myelosuppressionwas observed and the clinical outcome wasnot improved. Alternativemechanisms of resistance tomelanoma cell deathneed tobe investigated. The incidence of malignant melanoma is steadily increasing. More than 59,000 new cases and >10,000 deaths were estimated in 2004 (up from 54,000 and 7,600, respectively, in 2003). Dacarbazine and interleukin 2 remain the only Food and Drug Administration–approved drugs for metastatic melanoma, each with response rates of f15%. Clearly, more effective therapeutic approaches are needed. Several alkylating agents are active in melanoma, including Temozolomide, cisplatin, and 1,3-bis(2chloroethyl)-1-nitrosourea (BCNU). However, the overall response rates are z15%, and combination chemotherapy has not been shown to be superior to the single agent dacarbazine (1). These results suggest that mechanisms of chemotherapy resistance are dominant in this disease, which has prompted continued research to uncover treatable mechanisms of melanoma escape from the actions of cytotoxic chemotherapy. It has been shown that BCNU induces its cytotoxic effect largely through the generation of a chlorethyl adduct at the Oposition of guanine in DNA that subsequently undergoes an intramolecular rearrangement to produce an unstable ethanoguanine intermediate, which subsequently reacts with cytosine on the opposite DNA strand (2, 3). An N-guanineN-cytosine-ethanol cross-link results. Development of the interstrand cross-links can be prevented by the DNA repair protein, O-alkylguanine DNA alkyltransferase (AGT), which removes the initial O-chloroethyl adduct or binds to the O portion of the ethanoguanine adduct. The first reaction removes the alkyl group leaving intact DNA, whereas the second reaction leaves a protein-DNA cross-link. Several recent studies have shown that AGT is expressed at high levels in melanoma (4), arguing that efficient repair of DNA damage induced by BCNU might be responsible for the low-level clinical activity observed. The use of compounds that deplete AGT activity can potentiate the cytotoxic effect of certain alkylating agents. Cancer Therapy: Clinical Authors’Affiliations: Department of Medicine, University of Chicago, Chicago, Illinois, Vanderbilt University, Nashville, Tennessee, and Case Comprehensive Cancer Center, CaseWestern Reserve University School of Medicine, Cleveland, Ohio Received1/10/05; revised 6/28/05; accepted 8/5/05. Grant support: NO1-CM-17102 and the University of Chicago Cancer Research Center. The costs of publication of this article were defrayed in part by the payment of page charges.This article must therefore be hereby marked advertisement in accordance with18 U.S.C. Section1734 solely to indicate this fact. Requests for reprints:Thomas F. Gajewski, Department of Medicine, University of Chicago, 5841South Maryland Avenue, MC2115, Chicago, IL 60637. Phone: 773-702-4601; Fax : 773-702-3163; E-mail : tgajewsk@medicine.bsd. uchicago.edu. F2005 American Association for Cancer Research. doi:10.1158/1078-0432.CCR-05-0060 www.aacrjournals.org Clin Cancer Res 2005;11(21) November1, 2005 7861 Research. on April 8, 2017. © 2005 American Association for Cancer clincancerres.aacrjournals.org Downloaded from One such agent is O-benzylguanine (OBG), which has been shown to potentiate the activity of BCNU in preclinical studies (5–11). Phase I studies defined the optimal dose of OBG for depletion of AGT activity in tumors at 120 mg/m (12, 13). The half-life of OBG was short, predominantly due to intracellular metabolism to the biologically active metabolite O-benzyl-8oxoguanine (14). The half-life of O-benzyl-8-oxoguanine was longer than that of OBG, and sustained levels at >200 ng/mL seemed to correlate with tumor AGT depletion. OBG alone was very well tolerated, with transient lymphopenia being the only drug-related side effect observed. A phase I study of the combination of OBG and BCNU was done in which the BCNU dose was started at 10 mg/m and escalated in combination with a fixed dose of OBG at 120 mg/m administered 1 hour prior. The maximally tolerated dose of BCNU was 33 to 40 mg/m when combined with OBG (13, 15). Dose-limiting toxicities were thrombocytopenia and neutropenia; no nonhematologic dose-limiting toxicities were observed. Based on these preclinical data, phase I results, and the high levels of AGT reported in melanoma, we undertook a phase II study of the combination of OBG and BCNU at 40 mg/m in patients with advanced melanoma who were either chemotherapy-naı̈ve or who had received previous chemotherapy.
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