A Phase I Trial of MEK Inhibitor Trametinib in Combination With Neoadjuvant 5-Fluorouracil Chemoradiation in the Treatment of KRAS, BRAF, and NRAS-MUTANT Rectal Cancers
I. To identify the maximally tolerated dose and recommended phase II dose of trametinib to
be used in combination with 5FU (fluorouracil) and radiation in patients with rectal
II. To determine a recommended phase II dose of trametinib to be used with 5FU
chemoradiation in patients with locally advanced rectal cancer.
I. Evaluation of the tolerability and safety of the combination of trametinib and 5-FU
chemoradiation in locally advanced rectal cancer.
II. Evaluation of post-therapy pathologic response. III. Evaluation of the rate of local
control, disease-free survival and overall survival.
IV. Analysis of biomarkers - total mutations in v-Ki-ras2 Kirsten rat sarcoma viral oncogene
homolog (KRAS), v-raf murine sarcoma viral oncogene homolog B1(BRAF), and neuroblastoma RAS
viral (v-ras) oncogene homolog (NRAS), as well as RAS/mitogen-activated protein kinase
(MAPK) and phosphatidylinositol-4,5-bisphosphate 3-kinas (PI3K)/v-akt murine thymoma viral
oncogene homolog 1 (AKT) pathway signaling pathways to potentially correlate with clinical
OUTLINE: This is a dose-escalation study of trametinib.
Patients receive trametinib orally (PO) once daily (QD) on days -14 to -10 and 1-38 and
fluorouracil intravenously (IV) continuously 5 days a week from days 1-38. Patients also
undergo radiation therapy 5 days a week on days 1-33. Patients then undergo surgery 6-10
Patients achieving negative surgical margins after complete resection of tumor receive
postoperative chemotherapy comprising leucovorin calcium IV over 2 hours and fluorouracil IV
continuously over 46 hours on days 1 and 15 OR oxaliplatin IV over 2 hours, leucovorin
calcium IV over 2 hours and fluorouracil IV continuously over 46 hours on days 1 and 15.
Treatment repeats every 28 days for up to 4 courses in the absence of disease progression or
After completion of study treatment, patients are followed up every 3 months for 2 years,
and then annually for 3 years.
Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Identify the maximally tolerated dose of Trametinib to be used in combination with 5FU and radiation in patients with rectal cancers.
up to 9 weeks
Ohio State University Comprehensive Cancer Center
United States: Food and Drug Administration
|Arthur G. James Cancer Hospital and Solove Research Institute at Ohio State University Medical Center||Columbus, Ohio 43210-1240|