Background: A novel immunological approach to colon cancer therapy is the antibody targeting of the fibroblast activation protein (FAP), which is highly expressed by stroma cells of this tumour. Unconjugated sibrotuzumab (BIBH 1), which is a humanised version of the murine anti-FAP mAb F19, was investigated for its anti-tumour activity, safety and pharmacokinetics. Patients and Methods: Patients with metastatic colorectal cancer received weekly intravenous infusions of unconjugated sibrotuzumab at a dose of 100 mg over 12 scheduled weeks. The study was implemented as an open-label, uncontrolled, multicentre trial. Results: 25 patients were enrolled. Patients had one or more measurable lesions, predominantly liver lesions, at baseline. At least 8 repeated weekly infusions of sibrotuzumab in 17 evaluable patients did not result in complete or partial remission. Rather, ongoing tumour progression was noted in all patients except for 2 patients with stable disease. However, progressive disease was also observed post-study in these 2 patients who received 1 and 6 additional infusions, respectively, of sibrotuzumab. Sibrotuzumab exhibited 2-compartment pharmacokinetics with a dominant terminal phase and t1/2 ? = 5.3 ± 2.3 days. Adverse drug reactions (rigors/chills, nausea, flushing and one incidence of bronchospasm) were observed in 5 patients. Of the 24 patients given 2 or more infusions of sibrotuzumab, antibodies against sibrotuzumab were found in 3 patients (12.5%) after 4–12 infusions. Conclusions: Sibrotuzumab was well tolerated and safe. The minimal requirement for the continuation of this exploratory trial, of at least one complete or partial remission, or equivalently, of 4 patients with stable disease, was not met.

To assess tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and clinical activity of the dual epidermal growth factor receptor (EGFR) 1 and 2 (HER2) tyrosine kinase inhibitor BIBW 2992. An escalating schedule of once-daily (OD) BIBW 2992 for 14 days followed by 14 days off medication was explored. Thirty-eight patients were enrolled. Dose levels were 10, 20, 30, 45, 70, 85, and 100 mg. At 100 mg dose-limiting toxicity (DLT) (common toxicity criteria grade 3 skin rash and grade 3 diarrhoea despite treatment with loperamide) occurred in two patients. In the next-lower dose of 70 mg, DLT (grade 3 fatigue and ALAT elevation) occurred in one of six patients. An intermediate dose level of 85 mg was studied. Here DLT occurred in two patients (grade 3 diarrhoea despite treatment and grade 2 diarrhoea lasting more than 7 days despite treatment). An additional 12 patients were treated at 70 mg. BIBW 2992 PK after single and multiple doses revealed moderately fast absorption, and no deviation from dose proportionality. Pharmacodynamics analysis in skin biopsies did not show significant changes in EGFR-associated biomarkers. However, a significant inhibitory effect on the proliferation index of epidermal keratinocytes was observed. No partial or complete responses were observed, stable disease lasting more than four cycles was seen in seven patients. The recommended dose for studies with BIBW 2992 for 14 days followed by 14 days off medication is 70 mg OD.

Population pharmacokinetics of sibrotuzumab, a humanized monoclonal antibody directed against fibroblast activation protein, were determined after multiple intravenous infusions of dosages ranging from 5 mg/m(2) to an absolute dose of 100 mg, in patients with advanced or metastatic carcinoma. In total, 1844 serum concentrations from 60 patients in three Phase I and II clinical studies were analyzed. The structural model incorporated two disposition compartments and two parallel elimination pathways from the central compartment, one linear and one nonlinear. Finally estimated pharmacokinetic parameters (%RSE) were: linear clearance CLL 22.1 ml/h (9.6), central distribution volume V1 4.13l (3.7), peripheral volume V2 3.19l (8.8), inter-compartmental clearance Q 37.6 ml/h (9.6); for the nonlinear clearance Vmax was 0.0338 mg/h (25) and Km 0.219 microg/ml (57). At serum concentrations between approximately 20 ng/ml and 7 microg/ml, the effect of the nonlinear clearance on pharmacokinetics was marked. Only at >7 microg/ml did CLL dominate overall clearance. Interindividual variability was 57% for CLL, 20% for V1 and V2, and 29% for Vmax and was larger than the inter-occasional variability of 13%. Of the many investigated patient covariates, only body weight was found to contribute to the population model. It significantly affected CLL, V1, V2 and Vmax resulting in marked differences in the model-predicted concentration-time profiles after multiple dosing in patients with low and high body weights. In conclusion, a robust population pharmacokinetic model was developed and evaluated for sibrotuzumab, which identified a possible need to consider body weight when designing dosage regimen for future clinical cancer trials.

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