Phase I Study of Trametinib in Combination with Whole-Brain Radiation Therapy for Brain Metastases

Abstract

Trametinib is an oral reversible, highly selective inhibitor of mitogen-activated extracellular signal regulated kinase 1 (MEK1) and 2, and preclinical data suggests that trametinib can radiosensitize tumor cells. We performed a phase I study to determine the maximum tolerable dose (MTD) and safety of trametinib in combination with whole brain radiation therapy (WBRT) in patients with brain metastases (BM). After confirmation of intracranial BM, patients were treated with trametinib and WBRT to a dose of 37.5 Gy in 15 fractions. Trametinib was given starting day -6 (7 total doses), followed by WBRT starting on day 1, and trametinib was given concurrently with radiation (7 days per week). The starting dose of trametinib was 1 mg and was escalated in a standard 3+3 fashion, to 1.5 mg and 2 mg. The primary endpoint was to determine the MTD of trametinib to be used in combination with WBRT. Secondary objectives included evaluation of tolerability and feasibility of WBRT + trametinib, objective response (RECIST criteria), neurologic progression-free survival (nPFS), and overall survival (OS). Characteristics of the 10 patients enrolled 2014-2016 were: mean age, 55 yrs; median BM, 5 (range 1 to >10); histologies were melanoma (n=5), breast (n=2), colorectal (n=1), esophageal adenocarcinoma (n=1) and eccrine carcinoma (n=1). Treatment involved WBRT 37.5 Gy in 10 fractions (n=9) and 30 Gy in 10 fractions (n=1). Dose level 1 was trametinib 1 mg (n=3), and level 2 was trametinib 1.5 mg (n=7). 1 patient withdrew consent in dose level 2. There were 39 Grade 1-2 toxicities and there were 13 Grade 3-4 toxicities. 1 patient experienced a grade 2 seizure during treatment, but no other reported neurotoxicities. 2 patients in dose level 2 experienced a DLT: grade 4 thrombocytopenia and grade 3 diarrhea. 1 patient experienced grade 4 elevation of hepatic enzymes, which was not a pre-defined DLT. 5 patients experienced ten grade 3 toxicities: lymphopenia, thrombocytopenia, diarrhea, fatigue, dehydration, nausea/vomiting, hyperglycemia, dyspnea, hyponatremia, and elevated troponin. The trial failed to accrue the 3 additional patients in dose level 1 and was closed early due to slow accrual. Median follow-up time from on treatment date to off-study date was 2.2 months. Median OS was 2.2 months. The median nPFS was 1.5 months. Objective response was measured in 6 patients as 4 did not live to complete follow up imaging. Of these 6, only 2 demonstrated a partial response to treatment. Trametinib failed to show a signal for response with concurrent WBRT, but survival in our cohort was worse than expected. The MTD is less than 1.5 mg. Concurrent use of WBRT with 1 mg of trametinib demonstrated safety in 3 patients; however, the trial was closed early due to slow accrual. Shifting patterns of practice contributed to slow accrual, particularly increased utilization of stereotactic radiosurgery (SRS). Future studies may attempt to ascertain the MTD in healthier individuals using SRS.