Phase II trial of the O6-alkylguanine DNA alkyltransferase inhibitor O6-benzylguanine and 1,3-bis(2-chloroethyl)-1-nitrosourea in advanced melanoma.
OBJECTIVE
1,3-Bis(2-chloroethyl)-1-nitrosourea (BCNU) induces DNA damage via a chloroethyl adduct at the O(6) position of guanine, which can be repaired by O(6)-alkylguanine DNA alkyltransferase (AGT) expressed in melanoma. We postulated that the addition of O(6) benzylguanine (O(6)BG), a potent inactivator of AGT, would improve the clinical response to BCNU in melanoma.


METHODS
Patients had measurable disease, adequate organ function, and a corrected Diffusing capacity of the lung for carbon monoxide (DLCO) of > or =70% predicted. They were accrued into two cohorts based on prior chemotherapy. O(6)BG (120 mg/m(2)) was administered i.v. followed by BCNU (40 mg/m(2)) on an outpatient basis. Peripheral blood mononuclear cells (PBMC) were collected pre- and 18 hours post-O(6)BG to analyze AGT depletion. Treatment was every 6 weeks, and clinical response was assessed after every two cycles.


RESULTS
Forty-two patients were enrolled, 22 of these patients were chemotherapy-naïve. In the chemotherapy-naïve 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 progression was 80 days and the median survival was 211 days. In the prior-chemotherapy cohort, there were no responses, 3 SD, 15 PD, and 2 nonevaluable patients; median time to progression was 54 days and median survival was 120 days. AGT was depleted from PBMC in the 15 patients tested. Grades 3 to 4 myelosuppression was seen in 57% of patients; toxicities were similar between the two cohorts.


CONCLUSIONS
O(6)BG/BCNU was successfully administered on an outpatient basis and depleted AGT from PBMC. However, significant myelosuppression was observed and the clinical outcome was not improved. Alternative mechanisms of resistance to melanoma cell death need to be investigated.
Gajewski
Thomas F
TF
Department of Medicine, University of Chicago, IL 60637, USA. tgajewsk@medicine.bsd.uchicago.edu
Sosman
Jeffrey
J
Gerson
Stanton L
SL
Liu
Lili
L
Dolan
Eileen
E
Lin
Shang
S
Vokes
Everett E
EE
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002248:Carbon Monoxide / Q000737:chemistry; D002330:Carmustine / Q000008:administration & dosage*; D015331:Cohort Studies; D018450:Disease Progression; D005260:Female; D006147:Guanine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000166:cytology; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000473:pathology; D008875:Middle Aged; D009362:Neoplasm Metastasis; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000037:antagonists & inhibitors*; D013997:Time Factors; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D018906:Antineoplastic Agents, Alkylating; C064976:O(6)-benzylguanine; D006147:Guanine; D002248:Carbon Monoxide; D019853:O(6)-Methylguanine-DNA Methyltransferase; D002330:Carmustine