Millie Das1,2, Sukhmani K Padda3, Adam Frymoyer4, Julian Molina5, Alex Adjei5, Janet L Lensing5, Dale Miles6, Branimir I Sikic3, Heather A Wakelee3. 1. Department of Medicine, Division of Medical Oncology, Stanford University, Stanford, CA, USA. mdas@stanford.edu. 2. VA Palo Alto Health Care System, 3801 Miranda Avenue, 111-ONC, Palo Alto, CA, 94304-1290, USA. mdas@stanford.edu. 3. Department of Medicine, Division of Medical Oncology, Stanford University, Stanford, CA, USA. 4. Department of Pediatrics, Stanford University, Stanford, CA, USA. 5. Mayo Clinic, Rochester, MN, USA. 6. Exelixis, Inc., South San Francisco, CA, USA.
Abstract
PURPOSE: To evaluate the safety, tolerability, and pharmacokinetics of XL647 and determine the maximum tolerated dose (MTD) of oral XL647 once-daily using intermittent or continuous dosing schedules. METHODS: Patients with advanced solid malignancies were enrolled in successive cohorts to receive escalating dose levels of oral once-daily XL647 using two different dosing schedules: 5 consecutive days of every 14-day cycle (study XL647-001) or continuously over 28-day cycles (study XL647-002). PK sampling was performed to determine Cmax, and AUC. Patients remained on study until progressive disease or unacceptable AEs. RESULTS: In XL647-001, 42 individuals were enrolled across 9 dose levels. The most frequently occurring drug-related AEs were diarrhea, nausea, rash, and fatigue. Expansion of the 4.68 mg/kg cohort to 6 patients occurred without further dose-limiting toxicities (DLTs) and this was considered the MTD. In XL647-002, 31 patients were enrolled across 5 dose levels. A DLT of grade 3 pneumonitis occurred in 1/6 patients at 300 mg, which was declared the MTD. The most common AEs included grade 1/2 rash, diarrhea, fatigue, dysgeusia, and QTc prolongation. Levels of pharmacodynamic plasma markers were not consistently changed after XL647 and no conclusions could be drawn with this limited data set. CONCLUSIONS: For oral XL647, the MTD was 4.68 mg/kg or 350 mg fixed dose when administered once-daily for 5 consecutive days of every 14-day cycle and was 300 mg when administered once-daily continuously. XL647 was well tolerated at doses up to the MTD.
PURPOSE: To evaluate the safety, tolerability, and pharmacokinetics of XL647 and determine the maximum tolerated dose (MTD) of oral XL647 once-daily using intermittent or continuous dosing schedules. METHODS:Patients with advanced solid malignancies were enrolled in successive cohorts to receive escalating dose levels of oral once-daily XL647 using two different dosing schedules: 5 consecutive days of every 14-day cycle (study XL647-001) or continuously over 28-day cycles (study XL647-002). PK sampling was performed to determine Cmax, and AUC. Patients remained on study until progressive disease or unacceptable AEs. RESULTS: In XL647-001, 42 individuals were enrolled across 9 dose levels. The most frequently occurring drug-related AEs were diarrhea, nausea, rash, and fatigue. Expansion of the 4.68 mg/kg cohort to 6 patients occurred without further dose-limiting toxicities (DLTs) and this was considered the MTD. In XL647-002, 31 patients were enrolled across 5 dose levels. A DLT of grade 3 pneumonitis occurred in 1/6 patients at 300 mg, which was declared the MTD. The most common AEs included grade 1/2 rash, diarrhea, fatigue, dysgeusia, and QTc prolongation. Levels of pharmacodynamic plasma markers were not consistently changed after XL647 and no conclusions could be drawn with this limited data set. CONCLUSIONS: For oral XL647, the MTD was 4.68 mg/kg or 350 mg fixed dose when administered once-daily for 5 consecutive days of every 14-day cycle and was 300 mg when administered once-daily continuously. XL647 was well tolerated at doses up to the MTD.
Authors: William F Elmquist; Jann N Sarkaria; Sani H Kizilbash; Shiv K Gupta; Karen E Parrish; Janice K Laramy; Minjee Kim; Gautham Gampa; Brett L Carlson; Katrina K Bakken; Ann C Mladek; Mark A Schroeder; Paul A Decker Journal: Mol Cancer Ther Date: 2021-03-30 Impact factor: 6.261
Authors: Julie Bolcaen; Shankari Nair; Cathryn H S Driver; Tebatso M G Boshomane; Thomas Ebenhan; Charlot Vandevoorde Journal: Pharmaceuticals (Basel) Date: 2021-06-29