NCT01740648

Trametinib, Fluorouracil, and Radiation Therapy Before Surgery in Treating Patients With Stage II-III Rectal Cancer

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

• Status: Completed
• Phase: Phase 1
• Study type: Interventional
• Enrollment: 19 (actual)
• Sponsor: Ohio State University Comprehensive Cancer Center · Academic / Other
• Sex: All
• Age: 18 Years
• Healthy volunteers: Not accepted

Summary

This phase I trial studies the side effects and best dose of trametinib when given together with fluorouracil and radiation therapy before surgery in treating patients with stage II-III rectal cancer. Trametinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as fluorouracil, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Radiation therapy uses high-energy x-rays to kill tumor cells. Giving trametinib together with fluorouracil and radiation therapy before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed

Detailed description

PRIMARY OBJECTIVES: 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 cancers. II. To determine a recommended phase II dose of trametinib to be used with 5FU chemoradiation in patients with locally advanced rectal cancer. SECONDARY OBJECTIVES: 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-kinase (PI3K)/v-akt murine thymoma viral oncogene homolog 1 (AKT) pathway signaling pathways to potentially correlate with clinical benefit. 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 weeks later. 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 unacceptable toxicity. After completion of study treatment, patients are followed up every 3 months for 2 years, and then annually for 3 years.

Conditions

• Recurrent Rectal Cancer
• Stage IIA Rectal Cancer
• Stage IIB Rectal Cancer
• Stage IIC Rectal Cancer
• Stage IIIA Rectal Cancer
• Stage IIIB Rectal Cancer
• Stage IIIC Rectal Cancer

Interventions

Type	Name	Description
DRUG	trametinib	Trametinib will be given for 5-day lead-in period by mouth daily Monday-Friday starting at day -14 through -10 and concurrently for the duration of radiation therapy (approximately days 1-38).The dose of Trametinib will be escalated: 0.5 mg, 1.0 mg, 2mg. If the 2 mg dose level causes DLT (dose-limiting toxicity)in 2 out of 6 patients and the 1mg dose level was acceptable, then a 1.5 mg dose cohort will be used.
DRUG	fluorouracil	Will be administered as a continuous infusion over 120 hours at a dose of 225 mg/m2/day on Monday to Friday of every week starting day 1-38.
RADIATION	radiation therapy	Radiation therapy will be delivered to the pelvis during (approximately) days 1-33 (five days a week, Mondays through Fridays for 25 fractions) using a 3-field or 4-field 3-D conformal plan to the primary tumor, surrounding soft tissues, and at risk lymph node stations (peri-rectal, presacral, internal iliac, with or without external iliac) to a total dose of 45 Gy in 1.8 Gy daily fractions. A boost radiation field will be delivered during (approximately) days 36-38. The boost will encompass the primary rectal tumor and involved lymph nodes with a 2-2.5 cm margin, which should include the presacral space. The boost dose will be 5.4 Gy in 1.8 Gy fractions for a total dose of 50.4 Gy.

Timeline

• Start date: 2012-11-26
• Primary completion: 2021-09-29
• Completion: 2021-09-29
• First posted: 2012-12-04
• Last updated: 2023-09-18

Locations

4 sites across 1 country: United States

Regulatory

• FDA-regulated drug study