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Westin SN , Sill MW , Coleman RL , Waggoner S , Moore KN , Mathews CA , Martin LP , Modesitt SC , Lee S , Ju Z , Mills GB , Schilder RJ , Fracasso PM , Birrer MJ , Aghajanian C
Safety lead-in of the MEK inhibitor trametinib in combination with GSK2141795, an AKT inhibitor, in patients with recurrent endometrial cancer: An NRG Oncology/GOG study
Gynecol Oncol. 2019 Oct 15;155(3) :420-428
PMID: 31623857    PMCID: PMC6922584    URL: https://www.ncbi.nlm.nih.gov/pubmed/31623857
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Abstract
OBJECTIVE: We sought to determine safety and efficacy of the AKT inhibitor, GSK2141795, combined with the MEK inhibitor, trametinib, in endometrial cancer. METHODS: Patients with measurable recurrent endometrial cancer were eligible. One to two prior cytotoxic regimens were allowed; prior use of a MEK or PI3K pathway inhibitor was excluded. Initial trial design consisted of a KRAS mutation stratified randomized phase II with a safety lead-in evaluating the combination. For the safety lead in, the previously recommended phase 2 dose (RP2D; trametinib 1.5 mg, GSK2141795 50 mg) was chosen for Dose Level 1 (DL1). RESULTS: Of 26 enrolled patients, 14 were treated on DL1 and 12 were treated on DL-1 (trametinib 1.5 mg, GSK2141795 25 mg). Most common histologies were endometrioid (58%) and serous (27%). Four of 25 (16%) patients were KRAS mutant. Dose limiting toxicities (DLTs) were assessed during cycle 1. DL1 had 8 DLTs (hypertension (n = 2), mucositis (2), rash (2), dehydration, stroke/acute kidney injury). DL1 was deemed non-tolerable so DL-1 was explored. DL-1 had no DLTs. Sixty-five percent of patients had >/= grade 3 toxicity. There were no responses in DL1 (0%, 90%CI 0-15%) and 1 response in DL-1 (8.3%, 90%CI 0.4-33.9%). Proportion PFS at 6 months for DL1 is 14%, and 25% for DL-1. CONCLUSION: The combination of trametinib and GSK2141795 had high levels of toxicity in endometrial cancer at the previously RP2D but was tolerable at a reduced dose. Due to insufficient preliminary efficacy at a tolerable dose, the Phase II study was not initiated.
Notes
1095-6859 Westin, Shannon N Sill, Michael W Coleman, Robert L Waggoner, Steven Moore, Kathleen N Mathews, Cara A Martin, Lainie P Modesitt, Susan C Lee, Sanghoon Ju, Zhenlin Mills, Gordon B Schilder, Russell J Fracasso, Paula M Birrer, Michael J Aghajanian, Carol Journal Article United States Gynecol Oncol. 2019 Oct 15. pii: S0090-8258(19)31548-3. doi: 10.1016/j.ygyno.2019.09.024.