TY - JOUR
T1 - A phase I trial of a guadecitabine (SGI-110) and irinotecan in metastatic colorectal cancer patients previously exposed to irinotecan
AU - Lee, Valerie
AU - Wang, Judy
AU - Zahurak, Marianna
AU - Gootjes, Elske
AU - Verheul, Henk M.
AU - Parkinson, Rose
AU - Kerner, Zachary
AU - Sharma, Anup
AU - Rosner, Gary
AU - De Jesus-Acosta, Ana
AU - Laheru, Daniel
AU - Le, Dung T.
AU - Oganesian, Aram
AU - Lilly, Ellen
AU - Brown, Thomas
AU - Jones, Peter
AU - Baylin, Stephen
AU - Ahuja, Nita
AU - Azad, Nilofer
N1 - Publisher Copyright:
© 2018 American Association for Cancer Research.
PY - 2018/12/15
Y1 - 2018/12/15
N2 - 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 patients with mCRC previously treated with irinotecan. Patients and Methods: In this 3þ3 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/m2 days 8 and 15 [dose level (DL) 1, guadecitabine 45 mg/m2; DL 1: guadecitabine 30 mg/m2; DL 1G: guadecitabine 30 mg/m2 with growth factor support (GFS); DL 1G: guadecitabine 45 mg/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 gastrointestinal cancers. Guadecitabine 45 mg/m2 and irinotecan 125 mg/m2 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.
AB - 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 patients with mCRC previously treated with irinotecan. Patients and Methods: In this 3þ3 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/m2 days 8 and 15 [dose level (DL) 1, guadecitabine 45 mg/m2; DL 1: guadecitabine 30 mg/m2; DL 1G: guadecitabine 30 mg/m2 with growth factor support (GFS); DL 1G: guadecitabine 45 mg/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 gastrointestinal cancers. Guadecitabine 45 mg/m2 and irinotecan 125 mg/m2 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.
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U2 - 10.1158/1078-0432.CCR-18-0421
DO - 10.1158/1078-0432.CCR-18-0421
M3 - Article
C2 - 30097434
AN - SCOPUS:85058448067
SN - 1078-0432
VL - 24
SP - 6160
EP - 6167
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 24
ER -