Highlights of the NCCN Oncology Research Program

The NCCN Oncology Research Program (ORP) strives to improve the quality of life for patients and reduce cancer-related deaths by advancing cancer therapies through research. Since the program’s establishment in 1999, the NCCN ORP has brought millions of dollars in research grants to investigators at NCCN Member Institutions. Research grants are provided to NCCN through collaborations with pharmaceutical and biotechnology companies; these grants are in turn used to support scientifically meritorious cancer research efforts.

NCCN ORP studies typically explore new avenues of clinical investigation and seek answers to important cancer-related questions. All studies are approved and funded through a scientific peer-review process and are overseen by the ORP.

NCCN studies funded through the grant mechanism are highlighted below.

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

Principal Investigator: Evan Wuthrick, MD

Condition: Rectal cancer

Institution: The Ohio State University Comprehensive Cancer Center – James Cancer Hospital and Solove Research Institute and Washington University, St. Louis

This phase I trial studies the side effects and best dose of trametinib when given together with fluorouracil and radiation therapy before surgery in patients with stage II–III rectal cancer. Many rectal cancers harbor mutations in key cancer proliferation proteins in the MAPK pathway. Trametinib is an MEK inhibitor that has robust preclinical activity in malignancies with MAPK pathway overexpression and may arrest tumor cell growth by blocking key proteins needed for cell growth and proliferation. Preclinically, MEK inhibitors are exciting candidates for radiosensitization. Trametinib will be used in combination with standard-of-care chemoradiation for locally advanced rectal cancer in this trial. The underlying hypothesis of the trial is that trametinib together with fluorouracil and radiation therapy before surgery will make the tumor smaller, reduce the amount of normal tissue that needs to be removed, and improve pathologic response rates.

Patients receive trametinib orally alone once daily for a week and then concurrently with fluorouracil intravenously (IV) continuously 5 days a week from days 1-38 of radiation therapy. The total radiation therapy dose is 50.4 Gy in 1.8-Gy daily fractions given in 5 fractions per week. Patients then undergo surgery 6 to 10 weeks later.

Patients achieving negative surgical margins after complete tumor resection 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.

Primary Objective:

• To identify the maximally tolerated dose of trametinib to be used in combination with fluorouracil and radiation in patients with rectal cancers, to be used in a phase II trial

Secondary Objectives:

• Evaluation of tolerability and safety of the combination

• Evaluation of posttherapy pathologic response

• Evaluation of disease-free and overall survivals

• Analysis of biomarkers: total mutations in KRAS, BRAF, and NRAS

Contacts: Ohio State University Medical Center • 800-293-5066 • Jamesline@osumc.edu

Evan Wuthrick, MD • 614-293-3422 • Evan.Wuthrick@osumc.edu

ClinicalTrials.gov Identifier: NCT01713972