In:
Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 31, No. 15_suppl ( 2013-05-20), p. 3581-3581
Abstract:
3581 Background: O 6 -methylguanine-DNA-methyltransferase (MGMT) is a DNA repair protein removing mutagenic and cytotoxic adducts from O 6 -guanine in DNA. Approximately 40% of colorectal cancers (CRCs) display MGMT deficiency due to promoter hypermethylation leading to silencing of the gene. Alkylating agents, such as dacarbazine, exert their antitumor activity by DNA methylation at the O 6 –guanine site, inducing base pair mismatch, therefore activity of dacarbazine could be enhanced in CRCs lacking MGMT. We conducted a phase II study with dacarbazine in CRCs who had failed standard therapies (oxaliplatin, irinotecan, fluoropyrimidines, and cetuximab or panitumumab if KRAS wild type). Methods: All patients had tumor tissue assessed for MGMT as promoter hypermethylation in double-blind for treatment outcome. Patients received dacarbazine 250 mg/m 2 i.v. qd for 4 consecutive days q21 until PD or intolerable toxicity. We employed a Simon two-stage design to determinate if the ORR would be ≥ 10%. Secondary endpoints included association of response, PFS and disease control rate with MGMT status. Results: Sixty-eight patients were enrolled from May 2011 to March 2012. Patients received a median of 3 cycles of dacarbazine [range 1-12]. Grade 3-4 toxicities included: fatigue (41%), nausea/vomiting (29%), constipation (25%), platelet count decrease (19%), anemia (18%). Overall, 2 patients (3%) achieved partial response (PR) and 8 patients (12%) had stable disease (SD). Disease control rate (PR+SD) was significantly associated with MGMT promoter hypermethylation in the corresponding tumors. Conclusions: Objective clinical responses to dacarbazine in metastatic CRC patients are confined to those tumors harbouring epigenetic inactivation of the DNA repair enzyme MGMT. Clinical trial information: 2011-002080-21.
Type of Medium:
Online Resource
ISSN:
0732-183X
,
1527-7755
DOI:
10.1200/jco.2013.31.15_suppl.3581
Language:
English
Publisher:
American Society of Clinical Oncology (ASCO)
Publication Date:
2013
detail.hit.zdb_id:
2005181-5
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