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

Valerie Lee, Judy Wang, Marianna Zahurak, Elske Gootjes, Henk M. Verheul, Rose Parkinson, Zachary Kerner, Anup Sharma, Gary Rosner, Ana De Jesus-Acosta, Daniel Laheru, Dung Le, Aram Oganesian, Ellen Lilly, Thomas Brown, Peter Jones, Stephen B Baylin, Nita Ahuja, Nilofer Azad

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)6160-6167
Number of pages8
JournalClinical Cancer Research
Volume24
Issue number24
DOIs
StatePublished - Dec 15 2018

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irinotecan
Colorectal Neoplasms
Intercellular Signaling Peptides and Proteins
Fever
Gastrointestinal Neoplasms
SGI-110
Leukopenia
Gene Silencing
Neutropenia
Dehydration

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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A phase I trial of a guadecitabine (SGI-110) and irinotecan in metastatic colorectal cancer patients previously exposed to irinotecan. / Lee, Valerie; Wang, Judy; Zahurak, Marianna; Gootjes, Elske; Verheul, Henk M.; Parkinson, Rose; Kerner, Zachary; Sharma, Anup; Rosner, Gary; De Jesus-Acosta, Ana; Laheru, Daniel; Le, Dung; Oganesian, Aram; Lilly, Ellen; Brown, Thomas; Jones, Peter; Baylin, Stephen B; Ahuja, Nita; Azad, Nilofer.

In: Clinical Cancer Research, Vol. 24, No. 24, 15.12.2018, p. 6160-6167.

Research output: Contribution to journalArticle

Lee, Valerie ; Wang, Judy ; Zahurak, Marianna ; Gootjes, Elske ; Verheul, Henk M. ; Parkinson, Rose ; Kerner, Zachary ; Sharma, Anup ; Rosner, Gary ; De Jesus-Acosta, Ana ; Laheru, Daniel ; Le, Dung ; Oganesian, Aram ; Lilly, Ellen ; Brown, Thomas ; Jones, Peter ; Baylin, Stephen B ; Ahuja, Nita ; Azad, Nilofer. / A phase I trial of a guadecitabine (SGI-110) and irinotecan in metastatic colorectal cancer patients previously exposed to irinotecan. In: Clinical Cancer Research. 2018 ; Vol. 24, No. 24. pp. 6160-6167.
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abstract = "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 3{\th}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/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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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

AU - Oganesian, Aram

AU - Lilly, Ellen

AU - Brown, Thomas

AU - Jones, Peter

AU - Baylin, Stephen B

AU - Ahuja, Nita

AU - Azad, Nilofer

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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