Phase 1 dose-escalation study of oral tyrosine kinase inhibitor masitinib in advanced and/or metastatic solid cancers.
BACKGROUND
Masitinib is a tyrosine kinase inhibitor with a pre-clinical profile suggesting greater affinity and selectivity in vitro for the wild-type c-Kit receptor and its juxtamembrane mutation than imatinib.


METHODS
This dose-escalation study was conducted in patients with advanced and/or metastatic cancer to determine the maximum tolerated dose (MTD) for orally administered masitinib over a 12-week period. Secondary objectives were a clinical assessment of masitinib's activity in cancer patients and establishment of a pharmacokinetic profile.


RESULTS
Forty patients with various solid tumours (predominantly GIST, 19 patients) were treated with masitinib at doses ranging between 0.7 and 17.2mg/kg/day. Although the MTD was not formally reached, an acceptable dose for chronic use was identified at 12 mg/kg/day. Treatment-related AEs were frequent (38/40 patients), however, the majority were grade 1 or 2 and demonstrated dose dependency at higher concentrations. Pharmacokinetic results showed a linear, dose-dependent increase of C(max) and AUC. One of two GIST patients with imatinib intolerance had a partial response at 11.1mg/kg/day. About 29% of the imatinib-resistant GIST population and 38% of the overall population had stable disease.


CONCLUSIONS
The safety profile of masitinib at 12 mg/kg/day b.i.d. for the treatment of solid cancers appears favourable and compatible with a long-term regimen. Tumour control rate in imatinib-resistant patients was encouraging, hence, the activity of masitinib in c-Kit expressing tumours, such as GIST, warrants further exploration as first-line anticancer therapy as well as for imatinib-resistant patients.
Soria
J C
JC
Département de Médecine, Institut Gustave Roussy, Université Paris XI, Service des Innovations Thérapeutiques Précoces, 94805 Villejuif, France. soria@igr.fr
Massard
C
C
Magné
N
N
Bader
Th
T
Mansfield
C D
CD
Blay
J Y
JY
Bui
B N
BN
Moussy
A
A
Hermine
O
O
Armand
J P
JP
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D001549:Benzamides; D004305:Dose-Response Relationship, Drug; D005260:Female; D046152:Gastrointestinal Stromal Tumors / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D010880:Piperidines; D011725:Pyridines; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D013844:Thiazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D001549:Benzamides; D010880:Piperidines; D011725:Pyridines; D013844:Thiazoles; D020794:Receptor Protein-Tyrosine Kinases; C526575:masitinib