The c-Met Tyrosine Kinase Inhibitor JNJ-38877605 Causes Renal Toxicity through Species-Specific Insoluble Metabolite Formation.
OBJECTIVE
The receptor tyrosine kinase c-Met plays an important role in tumorigenesis and is a novel target for anticancer treatment. This phase I, first-in-human trial, explored safety, pharmacokinetics, pharmacodynamics, and initial antitumor activity of JNJ-38877605, a potent and selective c-Met inhibitor.


METHODS
We performed a phase I dose-escalation study according to the standard 3+3 design.


RESULTS
Even at subtherapeutic doses, mild though recurrent renal toxicity was observed in virtually all patients. Renal toxicity had not been observed in preclinical studies in rats and dogs. Additional preclinical studies pointed toward the rabbit as a suitable toxicology model, as the formation of the M10 metabolite of JNJ-38877605 specifically occurred in rabbits and humans. Additional toxicology studies in rabbits clearly demonstrated that JNJ-38877605 induced species-specific renal toxicity. Histopathological evaluation in rabbits revealed renal crystal formation with degenerative and inflammatory changes. Identification of the components of these renal crystals revealed M1/3 and M5/6 metabolites. Accordingly, it was found that humans and rabbits showed significantly increased systemic exposure to these metabolites relative to other species. These main culprit insoluble metabolites were generated by aldehyde oxidase activity. Alternative dosing schedules of JNJ-3877605 and concomitant probenecid administration in rabbits failed to prevent renal toxicity at dose levels that could be pharmacologically active.


CONCLUSIONS
Combined clinical and correlative preclinical studies suggest that renal toxicity of JNJ-38877605 is caused by the formation of species-specific insoluble metabolites. These observations preclude further clinical development of JNJ-38877605.
Phase I Unit, Royal Marsden NHS Foundation Trust, Surrey & London, United Kingdom.|Dept. of medical Oncology, Erasmus MC Cancer Institute Rotterdam, The Netherlands.
Martijn P
MP
Lolkema
Janssen Research and Development, Beerse, Belgium.
Hilde H
HH
Bohets
Phase I Unit, Royal Marsden NHS Foundation Trust, Surrey & London, United Kingdom.
Hendrik-Tobias
HT
Arkenau
Janssen Research and Development, Beerse, Belgium.
Ann
A
Lampo
Janssen Research and Development, Beerse, Belgium.
Erio
E
Barale
Dept. of medical Oncology, Erasmus MC Cancer Institute Rotterdam, The Netherlands.
Maja J A
MJA
de Jonge
Dept. of medical Oncology, Erasmus MC Cancer Institute Rotterdam, The Netherlands.
Leni
L
van Doorn
Janssen Research and Development, Beerse, Belgium.
Peter
P
Hellemans
Phase I Unit, Royal Marsden NHS Foundation Trust, Surrey & London, United Kingdom.
Johann S
JS
de Bono
Dept. of medical Oncology, Erasmus MC Cancer Institute Rotterdam, The Netherlands.
Ferry A L M
FALM
Eskens
D000328:Adult; D000368:Aged; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000633:toxicity; D015179:Colorectal Neoplasms / Q000188:drug therapy*; D004285:Dogs; D005260:Female; D006801:Humans; D008658:Inactivation, Metabolic; D007668:Kidney / Q000187:drug effects / Q000473:pathology*; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D011720:Pyrazoles / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000633:toxicity; D011724:Pyridazines / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000633:toxicity; D011817:Rabbits; D051381:Rats; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D013045:Species Specificity
D000970:Antineoplastic Agents; C000599304:JNJ38877605; D011720:Pyrazoles; D011724:Pyridazines; C080835:RON protein; D020794:Receptor Protein-Tyrosine Kinases