A safety, tolerability, and pharmacokinetic analysis of two phase I studies of multitargeted small molecule tyrosine kinase inhibitor XL647 with an intermittent and continuous dosing schedule in patients with advanced solid malignancies

Cancer Chemother Pharmacol. 2018 Sep;82(3):541-550. doi: 10.1007/s00280-018-3646-0. Epub 2018 Jul 20.


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.

Keywords: Angiogenesis; EGFR; Kinase inhibitor; Tesevatinib; VEGFR; XL647.

Publication types

  • Clinical Trial, Phase I
  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Adult
  • Aged
  • Azabicyclo Compounds / administration & dosage*
  • Azabicyclo Compounds / adverse effects
  • Azabicyclo Compounds / pharmacokinetics*
  • Cohort Studies
  • Dose-Response Relationship, Drug
  • Drug Administration Schedule
  • Female
  • Humans
  • Male
  • Middle Aged
  • Neoplasms / drug therapy*
  • Neoplasms / enzymology
  • Neoplasms / metabolism*
  • Protein Kinase Inhibitors / adverse effects
  • Protein Kinase Inhibitors / pharmacokinetics
  • Quinazolines / administration & dosage*
  • Quinazolines / adverse effects
  • Quinazolines / pharmacokinetics*


  • Azabicyclo Compounds
  • Protein Kinase Inhibitors
  • Quinazolines
  • XL647