Phase II study of dacarbazine for metastatic colorectal cancer with determined MGMT status.

3570 Background: O 6 -methylguanine-DNA-methyltransferase (MGMT) is a DNA repair protein that removes mutagenic and cytotoxic adducts from O 6 -guanine in DNA. Roughly 40% of colorectal cancers (CRCs) display MGMT deficiency due to promoter hypermethylation leading to silencing of the gene. Alkylating agents exert their antitumor activity by DNA methylation at the O 6 –guanine site, inducing base pair mismatch; therefore, activity of these compounds may be enhanced in CRCs lacking MGMT (Esteller, 2004; Pegg, 1990). Despite anecdotal reports about activity of dacarbazine in CRC (Shacham-Shmueli, 2011) no clinical trials assessed monotherapy with dacarbazine for metastatic CRC. Methods: We conducted a phase II study of dacarbazine in CRCs who had failed standard therapies (oxaliplatin, irinotecan, fluoropyrimidines and cetuximab or panitumumab if KRAS WT), PS=0-1, with adequate organ function, and measurable disease as per RECIST criteria assessed by CT scans at baseline and every 8 weeks. All patients had tumor tissue assessed for MGMT as promoter hypermethylation. Patients received dacarbazine 250 mg/m 2 i.v. d1-4, q21 until PD or untolerable toxicity (with a maximum of 6 cycles in case of SD). We employed a Simon, two-stage design to determinate if the ORR of dacarbazine treatment would be ≥ 10%. Secondary endpoints were association of response/resistance with loss of expression of MGMT, PFS and disease control rate. Results: In the first stage, from June 2011 to November 2011 we enrolled 40 pts (male 68%, median age 67 y [range 29-81], PS=0 50%, KRAS mut 55%). Pts received a median of 3 cycles [range 1-11]. Toxicities included (All Grades/Grade 3-4 %): fatigue (58/5), constipation (38/0), nausea/vomiting (35/0), anemia (20/2.5), platelet count decrease (10/5). 36 pts were evaluable for objective response. Overall, 2 pts (5%) achieved PR and 5 pts (12.5%) had SD. All pts with PR had tumors with MGMT promoter hypermethylation. Conclusions: Having exceeded the boundaries of futility (at least 2 objective responses in the first stage), the trial proceeds to the second stage, enrolling 28 more patients. Analysis of MGMT promoter hypermethylation and association with sensitivity/resistance is performed at the end of the second stage.