A W Tolcher1, J C Bendell2, K P Papadopoulos3, H A Burris2, A Patnaik3, S F Jones2, D Rasco3, D S Cox4, M Durante4, K M Bellew5, J Park4, N T Le6, J R Infante2. 1. South Texas Accelerated Research Therapeutics LLC, San Antonio. Electronic address: atolcher@start.stoh.com. 2. Sarah Cannon Research Institute/Tennessee Oncology, PLLC, Nashville. 3. South Texas Accelerated Research Therapeutics LLC, San Antonio. 4. GlaxoSmithKline, Collegeville. 5. Pharmaceutical Companies of Johnson and Johnson, Greater Philadelphia Area. 6. Novartis, East Hanover, USA.
Abstract
BACKGROUND: This phase Ib trial investigated the safety, tolerability, and recommended phase II dose and schedule of the MEK inhibitor trametinib in combination with the mammalian target of rapamycin (mTOR) inhibitor everolimus. Secondary objectives included pharmacokinetic (PK) characterization and evaluation of clinical activity. PATIENTS AND METHODS: A total of 67 patients with advanced solid tumors were enrolled in this open-label, single-arm, dose-escalation study. Dose escalation followed a 3 + 3 design. Patients were assigned to one of 10 different cohorts, involving either daily dosing with both agents or daily dosing with trametinib and intermittent everolimus dosing. This included an expansion cohort comprising patients with pancreatic tumors. PKs samples were collected predose, as well as 1, 2, 4, and 6 h post-dose on day 15 of the first treatment cycle. RESULTS: Concurrent treatment with trametinib and everolimus resulted in frequent treatment-related adverse events, including mucosal inflammation (40%), stomatitis (25%), fatigue (54%), and diarrhea (42%). PK assessment did not suggest drug-drug interactions between these two agents. Of the 67 enrolled patients, 5 (7%) achieved partial response (PR) to treatment and 21 (31%) displayed stable disease (SD). Among the 21 patients with pancreatic cancer, PR was observed in 1 patient (5%) and SD in 6 patients (29%). CONCLUSIONS: This study was unable to identify a recommended phase II dose and schedule of trametinib in combination with everolimus that provided an acceptable tolerability and adequate drug exposure.
BACKGROUND: This phase Ib trial investigated the safety, tolerability, and recommended phase II dose and schedule of the MEK inhibitor trametinib in combination with the mammalian target of rapamycin (mTOR) inhibitor everolimus. Secondary objectives included pharmacokinetic (PK) characterization and evaluation of clinical activity. PATIENTS AND METHODS: A total of 67 patients with advanced solid tumors were enrolled in this open-label, single-arm, dose-escalation study. Dose escalation followed a 3 + 3 design. Patients were assigned to one of 10 different cohorts, involving either daily dosing with both agents or daily dosing with trametinib and intermittent everolimus dosing. This included an expansion cohort comprising patients with pancreatic tumors. PKs samples were collected predose, as well as 1, 2, 4, and 6 h post-dose on day 15 of the first treatment cycle. RESULTS: Concurrent treatment with trametinib and everolimus resulted in frequent treatment-related adverse events, including mucosal inflammation (40%), stomatitis (25%), fatigue (54%), and diarrhea (42%). PK assessment did not suggest drug-drug interactions between these two agents. Of the 67 enrolled patients, 5 (7%) achieved partial response (PR) to treatment and 21 (31%) displayed stable disease (SD). Among the 21 patients with pancreatic cancer, PR was observed in 1 patient (5%) and SD in 6 patients (29%). CONCLUSIONS: This study was unable to identify a recommended phase II dose and schedule of trametinib in combination with everolimus that provided an acceptable tolerability and adequate drug exposure.
Authors: Dan R Laks; Juan A Oses-Prieto; Alvaro G Alvarado; Jonathan Nakashima; Shreya Chand; Daniel B Azzam; Ankur A Gholkar; Jantzen Sperry; Kirsten Ludwig; Michael C Condro; Serli Nazarian; Anjelica Cardenas; Michelle Y S Shih; Robert Damoiseaux; Bryan France; Nicholas Orozco; Koppany Visnyei; Thomas J Crisman; Fuying Gao; Jorge Z Torres; Giovanni Coppola; Alma L Burlingame; Harley I Kornblum Journal: Neuro Oncol Date: 2018-05-18 Impact factor: 12.300