Recombinant human endostatin administered as a 28-day continuous intravenous infusion, followed by daily subcutaneous injections: A phase I and pharmacokinetic study in patients with advanced cancer

Background: Endostatin is an endogenous collagen XVIII-fragment with anti-angiogenic properties and remarkable antitumor activity in mice. Preclinical data suggest that continuous low dose administration of endostatin is much more potent than intermittent dosing. The feasibility of this approach is tested in a phase I study. Patients and methods: We determined the safety and pharmacokinetic profile of 4-week continuous intravenous infusion of recombinant human (rh)-endostatin, followed after an interval of 1 week by twice daily subcutaneous injections in patients with advanced cancer. Thirty-two patients received rh-endostatin in six dosing cohorts, ranging from 3.75 mg/m²/day to 120 mg/m²/day. Serum endostatin pharmacokinetics, toxicity and antitumor response were determined. Results: A total of 160 cycles were delivered without significant toxicities. Pharmacokinetic analysis showed a linear increase of steady-state serum endostatin concentrations with dose (i.v. r²= 0.96; s.c. r² = 0.99) reaching 300-1000 ng/ml for the two highest doses, with considerable interpatient variation. The main pharmacokinetic values for both routes of administration were similar. The apparent steady-state concentration and AUC reached at 60 = 120 mg/m²/day were within the range expected to induce anti-angiogenic and antitumor effects based on preclinical tumor models. Although no objective responses were observed, two patients had long-lasting stable disease (defined as a tumor increase <100%). Conclusion: rh-endostatin was safely administered both by continuous infusion and by twice daily subcutaneous injections up to 120 mg/m²/day. Predictable pK was seen in this dose range and the target endostatin levels were reached from 60 mg/m²/day and above.