486P - Individualized pharmacokinetically-guided dosing of pazopanib: A feasibility study in cancer patients

Date 27 September 2014
Event ESMO 2014
Session Poster Display session
Topics Anti-Cancer Agents & Biologic Therapy
Pharmacology
Presenter Remy Verheijen
Citation Annals of Oncology (2014) 25 (suppl_4): iv146-iv164. 10.1093/annonc/mdu331
Authors R. Verheijen1, S. Bins2, C. Gadellaa-van Hooijdonk3, R. Mathijssen2, M.P. Lolkema3, L. van Doorn2, K. Rotteveel-Buchholtz4, J. Schellens4, J. Beijnen1, A.D.R. Huitema1, N. Steeghs4
  • 1Department Of Pharmacy & Pharmacology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek, 1066EC - Amsterdam/NL
  • 2Department Of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam/NL
  • 3Department Of Medical Oncology, University Medical Center Utrecht, Utrecht/NL
  • 4Department Of Medical Oncology & Clinical Pharmacology, Netherlands Cancer Institute - Antoni van Leeuwenhoek, Amsterdam/NL

Abstract

Aim

Retrospective analyses of clinical studies of pazopanib showed an increased median PFS in patients with plasma trough levels (TLs) ≥ 20.6 mg/L compared to patients with lower TLs (49.4 wks vs. 20.3 wks). This is in line with preclinical data showing optimal efficacy at concentrations above 17.5 mg/L. Due to inter-individual variability in plasma exposure, target TLs are not reached in ∼30% of patients with the current dosing schedule of 800 mg daily. Therefore, a Phase I study was performed to determine the safety and feasibility of pharmacokinetically (PK)-guided dosing of pazopanib.

Methods

30 patients with solid tumors with a potential benefit from pazopanib treatment were included. Weekly TLs were measured by LC-MS/MS. At week 3, 5 and 7 the dose could be increased when the measured TL was <20 mg/L. If the TL was <15 mg/L or between 15 and 20 mg/L and the patient did not show any non-tolerable toxicity (≥ grade 3 toxicity (CTCAE 4.02)), the daily pazopanib dose was increased by 400mg or 200 mg, respectively. If the patient experienced ≥grade 3 toxicity, the pazopanib dose was interrupted and lowered by steps of 200 mg.

Results

At data cut-off (April 2014) the planned total of 30 patients was included of which 26 patients had completed the PK evaluation period of 8 weeks or had stopped treatment due to toxicity (n = 4). 14 out of 26 patients had at least one TL below the target during this period. Of these, 8 patients had successful dose increases of 25% to 125% (1,000 to 1,800 mg), without non-tolerable toxicity. The mean TL (CV%, range) increased from 12.3(41.9, 7.80 – 22.5) to 22.4 (44.0, 8.77 – 43.1) mg/L. In the remaining 6 patients dose escalation was not possible due to toxicity. 12 out of 26 patients had all TLs above target. Of these 12 patients, 8 patients needed a dose reduction due to grade 3 and 4 toxicity and, therefore, the mean TL in this group decreased from 49.1 (39.9, 30.2 – 79.5) to 26.3 (27.5, 17.8 – 36.0) mg/L.

Conclusions

Individualized pharmacokinetically guided dosing of pazopanib is feasible and safe and leads to a higher proportion of patient reaching the desired target exposure. Additional (randomized) clinical trials on outcome parameters such as response rate and progression free survival are needed.

Disclosure

All authors have declared no conflicts of interest.