Solid Tumors Clinical Trial
Official title:
An Open-Label, Dose-escalation, Phase I/IIa Study to Determine the Maximum Tolerated Dose, Recommended Dose, Efficacy, Pharmacokinetics and Pharmacodynamics of the Dual VEGFR-FGFR Tyrosine Kinase Inhibitor, E-3810, Given Orally as Single Agent to Patients With Advanced Solid Tumours
Co-selective inhibition of VEGFRs and FGFR has the potential benefit of blocking the two most
relevant players in tumor angiogenesis and simultaneously targeting proliferation in
FGF-driven tumors. Lucitanib is a novel dual-targeted small molecule inhibitor of VEGFR1, 2,
3 and FGFR1 showing strong anti-angiogenic and anti-tumor activity in preclinical models at
well-tolerated oral doses, with a favorable pharmacokinetic profile. These properties make it
an attractive candidate for development in humans.
This is an open-label, uncontrolled, non-randomized, PhaseI/IIa study and its primary
objective is to determine the Maximum Tolerated Dose (MTD) of Lucitanib administered orally,
once daily, on a continuous schedule over the initial 28-day cycle.
Secondary objectives are to determine the safety profile, pharmacokinetics, pharmacodynamics
and antitumour activity of Lucitanib, given as a single agent to adult patients with advanced
solid tumours.
The study consists of two phases, a dose escalation phase followed by a dose-expansion phase
at the identified Recommended Dose (RD). Eligible patients have histologically or
cytologically confirmed locally advanced or metastatic solid tumours, relapsed or refractory
to standard therapy. For the dose expansion, patients should have tumours bearing FGFR1 or
11q 12-14 amplification, assessed by FISH or CGH array, or "sensitive" to antiangiogenic
treatment. These latter are defined as patients who have relapsed after having experienced
stable disease (lasting at least six months) or partial response with prior treatment with an
approved antiangiogenic regimen or patients with tumour types known to be potentially
responsive to antiangiogenic agents but without such pretreatment if no antiangiogenic agents
were approved and/or available for that specific condition (e.g thyroid cancer, thymic
carcinoma).
Serial safety assessments, including evaluation of symptoms, physical examination and blood
and urine laboratory analyses are performed throughout the study. Cardiac functions and blood
pressure are monitored in consultation with a cardiologist. PK parameters are determined on
plasma samples collected during the first 4-week cycle and analyzed using a validated
LC-MS/MS method. Correlative studies include: (i) quantitative assessment of the effects of
E-3810 on tumor vasculature by DCE-MRI and DCE-US imaging; (ii) assay of angiogenesis
biomarkers i.e. soluble VEGFR2, VEGFR1, VEGF, bFGF, Collagen IV, FGF23 and PIGF(by ELISA) and
circulating endothelial and progenitors cells (CEC and CEP). Tumor response is based on
imaging according to RECIST; circulating tumor cells (CTC) are measured by the immunomagnetic
CellSearch method.
In patients with tumours bearing FGFR1 amplifications the efficacy of Lucitanib will be
formally tested according to a phase IIa design (one-stage Flaming design, H0=0.05, H1=0,30,
power 0,80.
n/a
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