TY - JOUR
T1 - Phase I study of trametinib in combination with whole brain radiation therapy for brain metastases
AU - Palmer, Joshua D.
AU - Prasad, Rahul N.
AU - Fabian, Denise
AU - Wei, Lai
AU - Yildiz, Vedat O.
AU - Tan, Yubo
AU - Grecula, John
AU - Welliver, Meng
AU - Williams, Terence
AU - Elder, James B.
AU - Raval, Raju
AU - Blakaj, Dukagjin
AU - Haglund, Karl
AU - Bazan, Jose
AU - Kendra, Kari
AU - Arnett, Andrea
AU - Beyer, Sasha
AU - Liebner, David
AU - Giglio, Pierre
AU - Puduvalli, Vinay
AU - Chakravarti, Arnab
AU - Wuthrick, Evan
N1 - Funding Information:
This work was supported by funding from the National Cancer Institute. The funding source had no involvement in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the article for publication.
Publisher Copyright:
© 2022 Elsevier B.V.
PY - 2022/5
Y1 - 2022/5
N2 - Introduction: Trametinib is a MEK inhibitor with intracranial activity indicated for BRAF-mutant metastatic malignancies. Yet, the safety of trametinib concurrent with whole brain radiation therapy (WBRT) is unknown. We performed a single-institution, prospective, 3 + 3, phase I clinical trial to determine the maximum tolerated dose (MTD) of trametinib with WBRT. Methods and Materials: Patients with brain metastases (BM) received daily trametinib for 28 days, starting 7 days prior to and continuing through WBRT (37.5 Gy/15 fractions). Dose levels (DL)1–3 were 1.0, 1.5, and 2.0 mg. The MTD of trametinib plus WBRT, the max dose where ≤1 of 6 patients experienced a dose limiting toxicity (DLT), was the primary endpoint. Results: 10 patients were enrolled (median age-59 [47–64], BM-5 [1–10], 50% melanoma). Three and 7 patients were assigned to DL1 and 2. One DL2 patient withdrew. 89% of remaining patients completed therapy per protocol, but 1 DL2 patient with systemic progression discontinued therapy at 30 Gy. Thirteen grade (G)3–4 toxicities were observed, of which 12 occurred at DL2 (4/6 of patients). DLT was reached at DL2 (G4 thrombocytopenia and G3 diarrhea, 1 each). There were no G5 toxicities. Median overall survival was 2.2 months. During the study period, changing practice patterns favored utilization of stereotactic radiosurgery (SRS). Thus, the trial closed early prior to completion. Conclusions: In a patient population representative of modern candidates for WBRT, trametinib plus WBRT is highly toxic with a MTD <1.5 mg. The safety of trametinib with SRS remains an important question for future study.
AB - Introduction: Trametinib is a MEK inhibitor with intracranial activity indicated for BRAF-mutant metastatic malignancies. Yet, the safety of trametinib concurrent with whole brain radiation therapy (WBRT) is unknown. We performed a single-institution, prospective, 3 + 3, phase I clinical trial to determine the maximum tolerated dose (MTD) of trametinib with WBRT. Methods and Materials: Patients with brain metastases (BM) received daily trametinib for 28 days, starting 7 days prior to and continuing through WBRT (37.5 Gy/15 fractions). Dose levels (DL)1–3 were 1.0, 1.5, and 2.0 mg. The MTD of trametinib plus WBRT, the max dose where ≤1 of 6 patients experienced a dose limiting toxicity (DLT), was the primary endpoint. Results: 10 patients were enrolled (median age-59 [47–64], BM-5 [1–10], 50% melanoma). Three and 7 patients were assigned to DL1 and 2. One DL2 patient withdrew. 89% of remaining patients completed therapy per protocol, but 1 DL2 patient with systemic progression discontinued therapy at 30 Gy. Thirteen grade (G)3–4 toxicities were observed, of which 12 occurred at DL2 (4/6 of patients). DLT was reached at DL2 (G4 thrombocytopenia and G3 diarrhea, 1 each). There were no G5 toxicities. Median overall survival was 2.2 months. During the study period, changing practice patterns favored utilization of stereotactic radiosurgery (SRS). Thus, the trial closed early prior to completion. Conclusions: In a patient population representative of modern candidates for WBRT, trametinib plus WBRT is highly toxic with a MTD <1.5 mg. The safety of trametinib with SRS remains an important question for future study.
KW - Brain metastases
KW - Clinical trial
KW - Dose limiting toxicity
KW - MEK inhibitor
KW - Trametinib
KW - Whole brain radiation therapy
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U2 - 10.1016/j.radonc.2022.03.016
DO - 10.1016/j.radonc.2022.03.016
M3 - Article
C2 - 35367525
AN - SCOPUS:85128212906
SN - 0167-8140
VL - 170
SP - 21
EP - 26
JO - Radiotherapy and Oncology
JF - Radiotherapy and Oncology
ER -