Phase 1 dose-escalation study of oral tyrosine kinase inhibitor masitinib in advanced and/or metastatic solid cancers.

Abstract

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.

• Authors: J C Soria, C Massard, N Magné, Th Bader, C D Mansfield, J Y Blay, B N Bui, A Moussy, O Hermine, J P Armand
• Journal: European journal of cancer (Oxford, England : 1990) (Eur J Cancer) Vol. 45 Issue 13 Pg. 2333-41 (Sep 2009) ISSN: 1879-0852 [Electronic] England
• PMID: 19541476 (Publication Type: Clinical Trial, Phase I, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Benzamides
• Piperidines
• Pyridines
• Thiazoles
• Receptor Protein-Tyrosine Kinases
• masitinib

Topics

• Administration, Oral
• Adult
• Aged
• Antineoplastic Agents (administration & dosage, adverse effects, pharmacokinetics)
• Benzamides
• Dose-Response Relationship, Drug
• Female
• Gastrointestinal Stromal Tumors (drug therapy, metabolism)
• Humans
• Male
• Maximum Tolerated Dose
• Middle Aged
• Piperidines
• Pyridines
• Receptor Protein-Tyrosine Kinases (antagonists & inhibitors)
• Thiazoles (administration & dosage, adverse effects, pharmacokinetics)
• Treatment Outcome