Abstract CT017: A phase I study of guadecitabine (GUA) combined with irinotecan (IRI) in previously treated metastatic colorectal cancer (mCRC) patients
Authors: Lee Valerie , Wang Judy , El Khoueiry Anthony , Verheul Henk , Gootjes Elske , Sharma Anup , Kerner Zachary , Jones Peter , Baylin Stephen , Lilly Ellen , Ahuja Nita , Brown Thomas , Azad Nilofer 
Published: July 2016

Abstract
Background: Treatment of IRI-resistant CRC lines with a DNA methyltransferase inhibitor (DNMTi) can induce IRI re-sensitization. We theorized that combination of next generation DNMTi GUA+IRI would overcome resistance in previously IRI-treated mCRC pts.
Methods: mCRC pts with prior IRI exposure were enrolled in a 3+3 Phase I, dose escalation study to define the maximum tolerated dose (MTD) and dose limiting toxicities of GUA+IRI. Pharmacodynamics studies were planned on pre- and post-treatment tumor biopsies (C1D8); serial blood was also taken. Pts were enrolled to 4 dose levels (DL) of GUA SQ qd D1-5 with IRI 125mg/m2 D8 and 15: GUA 45mg/m2 (DL 1), 30mg/m2 (DL -1), 30mg/m2 with growth factor support (GFS) (DL -1G), and 45mg/m2 with GFS (DL 1G) of a 28 day cycle.
Results: 22 heavily pre-treated pts were enrolled (DL 1 = 6, DL -1 = 3, DL -1G = 7, DL 1G = 6); the MTD was established at DL 1G. Grade (G) 3-5 toxicities attributed to therapy were hematologic [neutropenia (16), neutropenic fever (5), anemia (3), thrombocytopenia (2)]. Other G3-4 toxicities were diarrhea (3), fatigue (2), and dehydration (2). There was one death on study possibly due to study treatment (febrile neutropenia). There were some dose reductions of IRI (6) or GUA (3). Median cycles of therapy were 4 months (range 1-14). 15 pts had at least one restaging scan, 12:SD and 1:PR. LINE-1 methylation analysis on serial biopsies revealed mixed changes in global methylation on C1D8, but LINE-1 of circulating tumor DNA showed consistent, delayed, dose-dependent demethylation with peak demethylation at C2D15.
Conclusions: GUA+IRI is well tolerated and demonstrates potentially compelling activity in mCRC pts with prior IRI exposure. Further testing of the combination is ongoing in a randomized phase II trial (2:1 randomization to GUA+IRI or TAS-102/Regorafenib - provider choice). Clinical trial information: NCT01896856. Supported by Astex Pharma and VARI SU2C/AACR Epigenetics Dream Team. Toxicity attributable to therapy in ≤ 10% of patientsAny GG1/G2G3/G4/G5N (%)N (%)N (%)HematologicNeutropenia16 (73)0 (0)16 (73)Anemia13 (59)10 (45)3 (14)Thrombocytopenia9 (41)7 (32)2 (9)InfectionNon-neutropenic infection6 (27)6 (27)0 (0)Febrile Neutropenia5 (23)0 (0)5 (23) 1 death DL-1GFever9 (41)8 (36)1 (5)GastrointestinalNausea/Vomiting16 (73)16 (73)0 (0)Abdominal discomfort4 (18)4 (18)0 (0)Diarrhea11 (50)8 (36)3 (14)Constipation4 (18)4 (18)0 (0)Increased AST4 (18)3 (14)1 (5)Increased alkaline phosphatase9 (41)8 (36)1 (5)Injection Site Reactions15 (68)15 (68)0 (0)GeneralFatigue10 (45)8 (36)2 (9)Anorexia/Weight loss9 (41)8 (36)1 (5)Alopecia7 (32)7 (32)0 (0)Lower extremity edema5 (23)5 (23)0 (0)Dehydration5 (23)3 (14)2 (9)Headache3 (14)3 (14)0 (0)Taste changes4 (18)4 (18)0 (0)
Citation Format: Valerie Lee, Judy Wang, Anthony El Khoueiry, Henk Verheul, Elske Gootjes, Anup Sharma, Zachary Kerner, Peter Jones, Stephen Baylin, Ellen Lilly, Nita Ahuja, Thomas Brown, Nilofer Azad. A phase I study of guadecitabine (GUA) combined with irinotecan (IRI) in previously treated metastatic colorectal cancer (mCRC) patients. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT017.