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Abstract
Here we review the development of tivantinib, a selective oral inhibitor of c-MET. The initially identified dose and schedule for clinical use was 360 mg twice daily. Biological considerations and early results suggested its activity against hepatocellular carcinoma after progression on sorafenib. The results of randomized Phase II study in this setting have already been reported; while in the overall population, the risk of progression was reduced by 36% (HR: 0.64; 90% CI: 0.43–0.94; p = 0.04), in the pre-defined MET-high population median overall survival (7.2 vs 3.8 months; p = 0.01), median time to progression (2.7 vs 1.4 months; p = 0.03) as well as disease control rate (50 vs 20%), were increased by tivantinib. During study conduction, tivantinib dose was amended to 240 mg twice daily, due to a high incidence of neutropenia, without losing clinical efficacy. Presently, a global Phase III trial is being conducted.
Financial & competing interests disclosure
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties.
No writing assistance was utilized in the production of this manuscript.
The initial tivantinib dose used in the hepatocellular carcinoma Phase II trial was 360 mg b.i.d., a dose which during study conduction was reduced to 240 b.i.d., due to a higher-than-expected incidence of neutropenia.
The initial study dose of tivantinib in the ongoing Phase III trial was thus 240 mg b.i.d., employing a new tablet formulation, and not the capsule formulation used in Phase II.
Since in the first set of enrolled subjects the incidence of severe neutropenia was higher than that recorded overall in the Phase II study, tivantinib dose was reduced to 120 mg b.i.d. in all further patients.
A subsequent safety and pharmacokinetic analysis showed that the incidence of neutropenia at the new dose was comparable to the one observed in the Phase II study.
Plasma exposure with the 120 mg b.i.d. tablet dose was comparable to the exposure achieved with the 240 mg b.i.d. capsule dose employed in the Phase II trial, with similar medians and overlapping ranges.