TY - JOUR
T1 - Phase I trial of trametinib with neoadjuvant chemoradiation in patients with locally advanced rectal cancer
AU - Wu, Christina
AU - Williams, Terence M.
AU - Robb, Ryan
AU - Webb, Amy
AU - Wei, Lai
AU - Chen, Wei
AU - Mikhail, Sameh
AU - Ciombor, Kristen K.
AU - Cardin, Dana B.
AU - Timmers, Cynthia
AU - Krishna, Somashekar G.
AU - Arnold, Mark
AU - Harzman, Alan
AU - Abdel-Misih, Sherif
AU - Roychowdhury, Sameek
AU - Bekaii-Saab, Tanios
AU - Wuthrick, Evan
N1 - Funding Information:
This study was approved and funded in part by the National Comprehensive Cancer Network (NCCN) Oncology Research Program from general research support provided by Novartis Pharmaceutical Corporation. We thank Dr. Tanios Bekaii-Saab for mentorship on this project. We also thank Hamida Umar and Barbara Kleiber for support in the Clinical Trials Office.
Funding Information:
C. Wu is a paid consultant/advisory board member for Array Biopharma and Signatera, and reports receiving other commercial research support from Vacci-nex, Boston Biomedical Inc., Lycera, Seattle Genetics, Symphogen, and Rapt Therapeutics. K.K. Ciombor is an employee/paid consultant for Natera and Research to Practice, and reports receiving commercial research grants from Incyte, Array, Nucana, and Daiichi-Sankyo. No potential conflicts of interest were disclosed by the other authors.
Publisher Copyright:
© 2020 American Association for Cancer Research.
PY - 2020/7
Y1 - 2020/7
N2 - Purpose: The RAS/RAF/MEK/ERK signaling pathway is critical to the development of colorectal cancers, and KRAS, NRAS, and BRAF mutations foster resistance to radiation. We performed a phase I trial to determine the safety of trametinib, a potent MEK1/2 inhibitor, with 5-fluorouracil (5-FU) chemoradiation therapy (CRT) in patients with locally advanced rectal cancer (LARC). Patients and Methods: Patients with stage II/III rectal cancer were enrolled on a phase I study with 3þ3 study design, with an expansion cohort of 9 patients at the MTD. Following a 5-day trametinib lead-in, with pre- and posttreatment tumor biopsies, patients received trametinib and CRT, surgery, and adjuvant chemotherapy. Trametinib was given orally daily at 3 dose levels: 0.5 mg, 1 mg, and 2 mg. CRT consisted of infusional 5-FU 225 mg/m2/day and radiation dose of 28 daily fractions of 1.8 Gy (total 50.4 Gy). The primary endpoint was to identify the MTD and recommended phase II dose. IHC staining for phosphorylated ERK (pERK) and genomic profiling was performed on the tumor samples. Results: Patients were enrolled to all dose levels, and 18 patients were evaluable for toxicities and responses. Treatment was well tolerated, and there was one dose-limiting toxicity of diarrhea, which was attributed to CRT rather than trametinib. At the 2 mg dose level, 25% had pathologic complete response. IHC staining confirmed dose-dependent decrease in pERK with increasing trametinib doses. Conclusions: The combination of trametinib with 5-FU CRT is safe and well tolerated, and may warrant additional study in a phase II trial, perhaps in a RAS/RAF-mutant selected population.
AB - Purpose: The RAS/RAF/MEK/ERK signaling pathway is critical to the development of colorectal cancers, and KRAS, NRAS, and BRAF mutations foster resistance to radiation. We performed a phase I trial to determine the safety of trametinib, a potent MEK1/2 inhibitor, with 5-fluorouracil (5-FU) chemoradiation therapy (CRT) in patients with locally advanced rectal cancer (LARC). Patients and Methods: Patients with stage II/III rectal cancer were enrolled on a phase I study with 3þ3 study design, with an expansion cohort of 9 patients at the MTD. Following a 5-day trametinib lead-in, with pre- and posttreatment tumor biopsies, patients received trametinib and CRT, surgery, and adjuvant chemotherapy. Trametinib was given orally daily at 3 dose levels: 0.5 mg, 1 mg, and 2 mg. CRT consisted of infusional 5-FU 225 mg/m2/day and radiation dose of 28 daily fractions of 1.8 Gy (total 50.4 Gy). The primary endpoint was to identify the MTD and recommended phase II dose. IHC staining for phosphorylated ERK (pERK) and genomic profiling was performed on the tumor samples. Results: Patients were enrolled to all dose levels, and 18 patients were evaluable for toxicities and responses. Treatment was well tolerated, and there was one dose-limiting toxicity of diarrhea, which was attributed to CRT rather than trametinib. At the 2 mg dose level, 25% had pathologic complete response. IHC staining confirmed dose-dependent decrease in pERK with increasing trametinib doses. Conclusions: The combination of trametinib with 5-FU CRT is safe and well tolerated, and may warrant additional study in a phase II trial, perhaps in a RAS/RAF-mutant selected population.
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U2 - 10.1158/1078-0432.CCR-19-4193
DO - 10.1158/1078-0432.CCR-19-4193
M3 - Article
C2 - 32253228
AN - SCOPUS:85087470195
SN - 1078-0432
VL - 26
SP - 3117
EP - 3125
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 13
ER -