A Phase I Trial of a Guadecitabine (SGI-110) and Irinotecan in Metastatic Colorectal Cancer Patients Previously Exposed to Irinotecan

Abstract

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 patients with mCRC previously treated with irinotecan. In this 3+3 dose-escalation study, patients with mCRC previously exposed to irinotecan received guadecitabine days 1 to 5 of a 28-day cycle and irinotecan 125 mg/m days 8 and 15 [dose level (DL) 1, guadecitabine 45 mg/m; DL -1: guadecitabine 30 mg/m; DL -1G: guadecitabine 30 mg/m with growth factor support (GFS); DL 1G: guadecitabine 45 mg/m with GFS]. 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. We report the first study of chemo-priming with epigenetic therapy in gastrointestinal cancers. Guadecitabine 45 mg/m and irinotecan 125 mg/m with GFS was safe and tolerable in patients with mCRC, with early indication of benefit. These data have provided the basis for an ongoing phase II randomized, multicenter trial.

Guadecitabine Plus Ipilimumab in Unresectable Melanoma: The NIBIT-M4 Clinical Trial

“…Of note, exposure to decitabine generated from guadecitabine, as assessed by AUC inf , was lower in our study than that observed in ovarian cancer (38) and hepatocellular carcinoma (36), but was comparable with exposure previously reported for myeloid malignancies (35) and colorectal cancer (37).…”

“…No AEs other than those typically reported with guadecitabine (35) or ipilimumab (11) monotherapy were observed, including no unexpected or potentially additive toxicities, thus supporting the feasibility of the explored therapeutic sequence at all doses of guadecitabine investigated. In contrast, severe myelosuppression was reported in several other studies of guadecitabine in solid tumors (36)(37)(38), leading to lower MTDs of 30-45 mg/m 2 /day. In the ovary and colorectal studies (37,38), coadministration of guadecitabine with myelosuppressive chemotherapy undoubtedly affected overall tolerability, suggesting additive toxicity, unlike our results using the combination of guadecitabine and checkpoint blockade.…”

“…In contrast, severe myelosuppression was reported in several other studies of guadecitabine in solid tumors (36)(37)(38), leading to lower MTDs of 30-45 mg/m 2 /day. In the ovary and colorectal studies (37,38), coadministration of guadecitabine with myelosuppressive chemotherapy undoubtedly affected overall tolerability, suggesting additive toxicity, unlike our results using the combination of guadecitabine and checkpoint blockade.…”

Modulation of the Endothelin System in Colorectal Cancer Liver Metastasis: Influence of Epigenetic Mechanisms?

“…Patients with metastatic colorectal cancer eventually develop imbalances in promotor methylation, which can result e.g., in reduced expression of tumor suppressor genes and in resistance to chemotherapy. Hypomethylating agents can reverse this resistance mechanism by promotor demethylation and subsequent gene expression reactivation (Lee et al, 2018). In fact, tumor suppressor genes were found re-expressed by DNA methyltransferase enzyme inhibitors (DNMTi) in colorectal cancer cell lines (Bosch et al, 2016).…”

“…Hypomethylating agents (HMAs) were approved for treatment of hematologic malignancies, but with little success in solid tumors (Azad et al, 2017;Lee et al, 2018). EGFR promoter hypermethylation in colorectal cancer has been found associated with patient resistance to anti-EGFR therapies (Jueliger et al, 2016).…”