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 C_max 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.

Patient characteristics

A total of 39 Caucasian CRC patients (adenocarcinoma) were included into a noncontinuous (n = 11; telatinib administration 14 days on / 7 days off in repeating cycles of 28 days) and a continuous treatment group (n = 28; daily telatinib administration) at dose levels of 600 mg bid (overall n = 6; continuous n = 1), 900 mg bid (overall n = 6; continuous n = 3), 1200 mg bid (only continuous dosing n = 2), 1500 mg bid (overall n = 4; continuous n = 1), and 900 mg bid continuous dosing for the patients enrolled in the phase II-like extension cohort of the study (n = 21). Patient demographics are summarized in Table 1. The patients were heavily pretreated, 98% had received any prior systemic therapy: oxaliplatin (87%), fluorouracil (87%), irinotecan (77%), cetuximab (56%), capecitabine (28%), bevacizumab (15%), and mitomycin (15%).

Safety

The most frequent adverse event assessed by the investigators as study drug related was hypertension (all grades: 36%, grade 3: 28%). In 1 patient at 1500 mg bid noncontinuous dosing group, hypertension resulted in dose reduction and dose interruption. Other study drug related adverse events occurring in ≥15% of patients were diarrhoea (26%, grade 3: 15%), anorexia (26%, only grades 1 - 2), nausea (18%, only grades 1 - 2) and fatigue (15%, grade 3: 3%). Gastrointestinal toxicities occurred more often in the continuous dosing group (Table 2). There were no study drug-related adverse events of CTC grades 4 or 5 reported. Study drug-related adverse events leading to a dose reduction or study drug discontinuation followed by a restart were diarrhoea (n = 4), hypertension (n = 1) and nausea with vomiting (n = 1). Serious study drug-related adverse events occurred in 3 patients: diarrhoea, hypertension, hand-foot skin reaction and dehydration.

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 post-dose. 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).

Figure 1   ( Jump back to reading ◀ )

Pharmacodynamics

The analysis of telatinib AUC_(0-12) on day 14 of cycle 1 versus the ratio of the DCE-MRI contrast agent gadolinium iAUC60 on day 14 of cycle 1 to iAUC60 at baseline is shown in Figure 2a. The gadolinium iAUC60 ratio decreased with increasing telatinib AUC_(0-12) (regression r² = 0.2637; Pearson correlation coefficient ρ = -0.514; test for no correlation, H₀: ρ = 0, p = 0.0026).

Figure 2   ( Jump back to reading ◀ )

The analysis of telatinib AUC_(0-12) on day 14 of cycle 1 versus the ratio of sVEGFR-2 in plasma on day 14 of cycle 1 to sVEGFR-2 at baseline is shown in Figure 2b. The ratio of sVEGFR-2 decreased with increasing telatinib AUC_(0-12), i. e. essentially in an exposure-dependent manner (r² = 0.2241; ρ = -0.473; H₀: ρ = 0, p = 0.0035).

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 (r² = 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 and baseline of sVEGFR-2 to the tumour shrinkage showed a tendency for correlation (r² = 0.2068, ρ = 0.455, p = 0.0102; Figure 2c). A decrease in tumour blood flow as measured by DCE-MRI was shown in the majority of patients (Figure 2e).

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 617 days) and 13 out of 39 patients. (33%) had a progression free survival of > 100 days (Figure 3b).

Figure 3   ( Jump back to reading ◀ )