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Phase I study of telatinib (BAY 57-9352): analysis of safety, pharmacokinetics, tumor efficacy, and biomarkers in patients with colorectal cancer

Background Telatinib (BAY 57-9352) is an orally available, small-molecule inhibitor of vascular endothelial growth factor receptors 2 and 3 (VEGFR-2/-3) and platelet-derived growth factor receptor β tyrosine kinases. Methods In this multicenter phase I dose-escalation study including a phase II like expansion part, 39 patients with refractory colorectal cancer (CRC) were enrolled into 14 days on / 7 days off in repeating cycles of 28 days (n = 11) or continuous dosing groups (n = 28) to receive ≥ 600 mg telatinib twice-daily (bid). Results Hypertension (28%) and diarrhoea (15%) were the most frequent study drug-related adverse events of CTC grade 3. In this population, no clear relationship between telatinib dose and individual Cmax and AUC was apparent in the 600 mg bid to 1500 mg bid dose range. No partial remission according to RECIST was reached, but 41% of the patients reached some tumour shrinkage during treatment. Tumour blood flow measured by dynamic contrast-enhanced magnetic resonance imaging and sVEGFR-2 plasma levels decreased with increasing telatinib AUC(0-12). Conclusion Telatinib treatment was well tolerated. The observed single agent antitumor activity in heavily pretreated CRC patients was limited. Pharmacodynamic results are suggestive for the biological activity of telatinib justifying a further evaluation of telatinib bid in combination with standard chemotherapy regimens in CRC patients.


Background
Telatinib (BAY 57-9352) is an orally available, potent, small-molecule inhibitor of vascular endothelial growth factor (VEGF) receptors 2 and 3 (VEGFR-2/-3) and platelet-derived growth factor (PDGF) receptor β (PDGFR-β) tyrosine kinases. The data presented in this paper describe the results of colorectal cancer (CRC) patients from the dose escalation part and the phase II-like expansion part of a phase I dose escalation study in which patients received telatinib at doses of ≥ 600 mg bid (n = 39). Data from 19 of these 39 CRC patients were presented earlier [1].

Methods
The study methods, treatment plan, patient evaluation, pharmacokinetic sampling, and pharmacodynamic measurements from the phase I dose escalation part of this study have been previously described [1] and the study assessments were not changed for the expansion part.

Pharmacokinetics
Steady-state pharmacokinetic parameters for telatinib and its metabolite BAY 60-8246 on day 14 of cycle 1 are summarized in Table 3. Maximum telatinib concentrations were typically observed less than 3 hours postdose. No clear relationship between telatinib dose and C max and AUC was apparent in the 600 mg bid to 1500 mg bid dose range ( Figure 1). Furthermore, average metabolite BAY 60-8246 C max and AUC values were also comparable in the 600 mg bid to 1500 mg bid dose range (Table 3).
In order to correlate biomarker changes to the clinical outcome, the relative changes between cycle 1, day 14 and baseline for VEGF, bFGF, tumour blood flow and tumour vessel permeability as measured by DCE-MRI (r 2 = 0.0025, ρ = 0.050, p = 0.7769; Figure 2d), and diastolic blood pressure were correlated to the best tumour shrinkage reached during therapy. The measured biomarkers were not predictive for the clinical outcome. However, the relative change between cycle 1, day 14

Efficacy
Tumour shrinkage at any point in time during treatment was observed in 41% of the patients (Figure 3a) and more than half had stable disease as best response ( Table 4). The median progression free survival was 77 days (2 to

Discussion
This analysis of 39 CRC patients enrolled in a phase I dose escalation study with a phase II like expansion cohort showed that telatinib administered at clinically relevant doses of ≥ 600 mg bid was well tolerated in this patient population. The recommended phase II dose for the single agent therapy with telatinib of 900 mg bid continuous dosing, as defined in the all comer dose escalation part of the study, was confirmed of being well tolerated in these heavily pretreated CRC patients. Hypertension was clinically manageable in most of the patients with a standard antihypertensive treatment. Study drug-related diarrhoea led to dose reduction or study drug discontinuation followed by a restart in 4 patients. The occurrence of gastrointestinal toxicities is known for other VEGF-inhibiting compounds [2,3]. The variability in pharmacokinetic parameters was considerable and individual patient telatinib exposure values were generally comparable in the dose range reported herein. Detailed pharmacokinetic analysis results in 71 patients covering a wider dose range of 75 mg bid to 1500 mg bid was reported earlier [1].
The biomarkers assessed in this study demonstrated the biological activity of telatinib. Most of the patients, 29 out of 36, showed a decrease of iAUC60 in the DCE-MRI measurements indicating an anti-angiogenic effect in tumour tissue. The angiogenic factors VEGF and sVEGFR-2 showed effects known from other VEGFinhibiting compounds. Changes in the DCE-MRI and decreases in sVEGFR-2 were correlated to telatinib exposure. There was no correlation between the clinical outcome and the biomarker activity, only the correlation of sVEGFR-2 changes to the tumour shrinkage showed some dependency.
The treatment with single-agent telatinib showed no objective remission in patients with CRC refractory to standard chemotherapy. This is in line with phase II study results of single-agent sunitinib treatment in CRC patients [4]. However, one third of the CRC patients had a PFS of > 100 days, suggesting some clinical activity in this heavily pretreated patient population.
The profiles of all competitors are summarized in a review [5]. Telatinib is currently in the clinical development for Gastric carcinoma and showed promising results in a phase II study (ref.

Conclusions
The observed single agent antitumor activity of telatinib in heavily pretreated CRC patients was limited. Pharmacodynamic results are suggestive for the biological activity of telatinib. Further evaluation of telatinib bid in combination with standard chemotherapy regimens in CRC patients should be considered. -PD -progressive disease -SD -stable disease.