jueves, 14 de noviembre de 2019

Safety lead-in of the MEK inhibitor trametinib in combination with GSK2141795, an AKT inhibitor, in patients with recurrent endometrial cancer: An ... - PubMed - NCBI

2019 Oct 15. pii: S0090-8258(19)31548-3. doi: 10.1016/j.ygyno.2019.09.024. [Epub ahead of print]

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.

Westin SN1, Sill MW2, Coleman RL3, Waggoner S4, Moore KN5, Mathews CA6, Martin LP7, Modesitt SC8, Lee S9, Ju Z10, Mills GB11, Schilder RJ12, Fracasso PM13, Birrer MJ14, Aghajanian C15.

Author information

1: Department of Gynecologic Oncology, University of Texas M. D Anderson Cancer Center, USA. Electronic address: swestin@mdanderson.org.
2: NRG Oncology Statistics and Data Management Center Buffalo Office, Roswell Park Cancer Institute, USA. Electronic address: SillM@NRGOncology.org.
3: Department of Gynecologic Oncology, University of Texas M. D Anderson Cancer Center, USA. Electronic address: rcoleman@mdanderson.org.
4: Department of Gynecologic Oncology, Case Western Reserve University, USA. Electronic address: Steven.Waggoner@UHhospitals.org.
5: Department of Gynecologic Oncology, University of Oklahoma Health Sciences Center, Stephenson Cancer Center, USA. Electronic address: Kathleen-moore@ouhsc.edu.
6: Department of Gynecologic Oncology, Women & Infants Hospital, USA. Electronic address: cmathews@wihri.org.
7: Department of Hematology/Oncology, Fox Chase Cancer Center, USA. Electronic address: lainie.martin@uphs.upenn.edu.
8: Director of Gynecologic Oncology Division, University of Virginia, USA. Electronic address: scm6h@virginia.edu.
9: Department of Medicine and the UVA Cancer Center, University of Virginia, USA. Electronic address: SLee29@mdanderson.org.
10: Department of Bioinformatics and Computational Biology, University of Texas M. D Anderson Cancer Center, USA. Electronic address: zju@mdanderson.org.
11: Department of Medicine and the UVA Cancer Center, University of Virginia, USA. Electronic address: millsg@ohsu.edu.
12: Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University Hospital, USA. Electronic address: russell.schilder@jefferson.edu.
13: Department of Systems Biology, University of Texas M.D Anderson Cancer Center, USA. Electronic address: fracasso@virginia.edu.
14: OB/GYN and Pathology, University of Alabama at Birmingham, USA. Electronic address: mbirrer@uab.edu.
15: Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, USA. Electronic address: aghajanc@mskcc.org.

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.