330 K.-H. Thierauch & A. Chlistalla

5.7. AMG 706

AMG 706 is an orally available inhibitor targeting the VEGF and PDGF receptor tyrosine kinases, as well as c-kit and Ret. The molecular structure has not been published. In a phase I study, a continuous oral dosing of 125 mg qd was established to be safe. Adverse event profile was characterized by hypertension, fatigue and headache.53 AMG 706 is currently explored in phase II studies in NSCLC, thyroid cancer and gastrointestinal cancer.

5.8. AZD 2171

AZD 2171 is an orally available kinase inhibitor of VEGFR-2, PDGFR, c-kit and FGFR, with an inhibitory activity for these kinases at a low nanomolar range. Preliminary results from phase I studies in different tumor types show that AZD 2171 is safe and generally well tolerated in a once daily dosing regimen. The terminal half-life is estimated to be in the range of 40 hours. Oral administration of doses below or equal to 45 mg qd seems to be safe and the adverse event profile consists of fatigue, nausea, diarrhea, vomiting and hypertension.54

5.9. BIBF 1120

BIBF 1120 is a potent orally available inhibitor of VEGF, PDGF and FGF receptor kinases. The molecular structure has not been published. In an ongoing phase I clinical trial, doses of 400 mg qd, or 250 mg bid have been established to be safe. Side-effect profile is characterized by nausea, vomiting, diarrhea, fatigue and reversible elevations of liver enzymes in serum.55,56

5.10. Chir-258

Chir-258 is a broader tyrosine kinase inhibitor of VEGFR, FLT-3, FGFR, PDGFR, c-kit and CSF-R. The molecular structure has not been published. Preliminary results of an ongoing phase I study in patients with advanced solid tumors demonstrate that doses up to 100 mg qd are tolerable. Major side-effects are hypertension, nausea,

vomiting, diarrhoea, fatigue, anemia, headache and transient pruritic rash. The latter points to EGFR-dependent side-effects.57

5.11. GW786034

GW786034 is a tyrosine kinase inhibitor of VEGFR-1, -2 and -3, PDGFR and c-kit. Preliminary results from an ongoing phase I clinical trial suggest that doses of 800 mg qd and 300 mg bid can be safely administered. Side-effect profile is characterized by hypertension, nausea, diarrhea, fatigue, anorexia, vomiting and hair depigmentation.58,59

5.12. SU5416 (Semaxinib)

SU5416 is a lipophilic, highly protein-bound non-selective tyrosine kinase inhibitor of VEGFR-2, c-Kit and FLT3. This compound was the first VEGF receptor tyrosine kinase inhibitor to be tested clinically. In several phase I/II trials in various patient populations, the compound showed signs of clinical activity with regards to complete remissions and partial responses in monotherapy treatment.60−63 SU5416 had to be dissolved in a cremophor plus ethanol vehicle for an i.v. administration route, with co-administration of steroids to prevent hypersensitivity reactions. Dosing schedule was 145 mg/m2 twice weekly for eight weeks by central catheter. In two large randomized trials, SU5416 was tested in combination with 5-FU/leucovorin and with irinotecan/5- FU/leucovorin in first line treatment of patients with metastatic colorectal cancer.64 The results of these completed trials have not been published. The development program has been stopped after the two negative phase III trials in metastatic colorectal cancer.

Toxicities as known from the phase I/II development include headache, nausea, vomiting, asthenia, pain at the infusion site, infections and phlebitis.

The formulation and administration mode may partly explain the high rate of infusion site pain and also a high rate of immuno- suppression-related infections. A prolonged binding of the compound to VEGFR kinase had been postulated65 for an explanation of the efficacy even though the t1/2 in humans is below 40 minutes.66