Phase I/IIa study evaluating the safety, efficacy, pharmacokinetics, and pharmacodynamics of lucitanib in advanced solid tumors
Mené sur 64 patients atteints d'une tumeur solide de stade avancé, cet essai de phase I/IIa évalue la toxicité et l'activité clinique du lucitanib
Background : Lucitanib is a potent, oral inhibitor FGFR1/2, VEGFR1-3 and PDGFRA/B, which are essential kinases for tumor growth, survival, migration, and angiogenesis. Several tumor types, including breast carcinoma, demonstrate amplification of FGF-related genes. There are no approved drugs for molecularly defined FGF-aberrant (FGFR1 or FGF3/4/19 amplified) tumors. Methods : This open-label phase I/IIa study involved a dose-escalation phase to determine maximum tolerated dose (MTD), recommended dose (RD), and pharmacokinetics of lucitanib in patients with advanced solid tumors, followed by a dose-expansion phase to obtain preliminary evidence of efficacy in patients who could potentially benefit from treatment (i.e. with tumors harboring FGF-aberrant pathway or considered angiogenesis-sensitive). Results : Doses from 5 to 30 mg were evaluated with dose-limiting toxicities (DLTs) dominated by VEGF-inhibition-related toxicity at the 30 mg dose level (one case of grade 4 depressed level of consciousness and two cases of grade 3 thrombotic microangiopathy). The most common adverse events (all grades, all cohorts) were hypertension (91%), asthenia (42%), and proteinuria (57%). Exposure increased with dose and t1/2 was 31-40 hours, suitable for once daily administration. Seventy-six patients were included. All but one had stage IV; 42% had >3 lines of previous chemotherapy. Sixty-four patients were evaluable for response; 58 had measurable disease. Clinical activity was observed at all doses tested with durable RECIST partial responses in a variety of tumor types. In the angiogenesis-sensitive group, objective RECIST response rate (complete response+partial response) was 26% (7 of 27) and PFS was 25 weeks. In evaluable FGF-aberrant breast cancer patients, 50% (6 of 12) achieved RECIST partial response with a median PFS of 40.4 weeks for all treated patients. Conclusion : Lucitanib has promising efficacy and a manageable side-effect profile. The spectrum of activity observed demonstrates clinical benefit in both FGF-aberrant and angiogenesis-sensitive populations. A comprehensive phase II program is planned.