Journal
GYNECOLOGIC ONCOLOGY
Volume 155, Issue 3, Pages 420-428Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.ygyno.2019.09.024
Keywords
Endometrial cancer; MEK inhibition; AKT inhibition; PI3K; KRAS mutation; NRG oncology
Categories
Funding
- NIH SPORE in Uterine Cancer [NIH 2P50 CA098258-06]
- NCI [U10CA180822]
- NRG Operations Grant [U10CA180868]
- Andrew Sabin Family Fellowship
- NCI Cancer Center Support Grants [P30CA016672, P30 CA008748, P30 CA056036]
- Ann Rife Cox Chair in Gynecology
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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%Cl 0-15%) and 1 response in DL-1 (8.3%, 90%Cl 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. (C) 2019 Elsevier Inc. All rights reserved.
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