A phase I trial of a guadecitabine (SGI-110) and irinotecan in metastatic colorectal cancer patients previously exposed to irinotecan.

PURPOSE: Chemotherapeutic resistance eventually develops in all patients with metastatic colorectal cancer (mCRC). Gene silencing through promoter demethylation is one potential reversible mechanism of resistance with administration of hypomethylating agents. We evaluated the safety and tolerability of guadecitabine and irinotecan in mCRC patients previously treated with irinotecan.

EXPERIMENTAL DESIGN: In this 3+3 dose-escalation study, mCRC patients previously exposed to irinotecan received guadecitabine days 1-5 of a 28 day cycle and irinotecan 125mg/m2 days 8 and 15 [dose level (DL) 1, guadecitabine 45mg/m2; DL -1: guadecitabine 30mg/m2; DL -1G: guadecitabine 30mg/m2 with growth factor support (GFS); DL 1G: guadecitabine 45mg/m2 with GFS.

RESULTS: Twenty-two patients were treated across four DLs. Dose-limiting toxicities were neutropenic fever (DL 1 and -1G), biliary drain infection (DL -1), colonic obstruction (DL -1), and severe dehydration (DL 1G). Most common toxicities were neutropenia (82% any grade, 77% Grade 3/4), neutropenic fever (23%), leukopenia (73% any grade, 50% Grade 3/4), and injection site reactions (64% total, 0% Grade 3/4). Patients received a median of 4.5 cycles of treatment; 12/17 evaluable patients had stable disease as best response, with one having initial disease progression but subsequently durable partial response. Circulating tumor DNA showed decrease in global demethylation by LINE-1 after treatment.

CONCLUSIONS: We report the first study of chemo-priming with epigenetic therapy in GI cancers. Guadecitabine 45 mg/m2 and irinotecan 125mg/m2 with GFS was safe and tolerable in mCRC patients, with early indication of benefit. These data have provided the basis for an ongoing phase II randomized, multicenter trial.