Study of Oral Lucitanib (E-3810), a Dual VEGFR-FGFR Tyrosine Kinase Inhibitor, in Patients With Solid Tumors
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.
|Study Design:||Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|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|
- Maximum Tolerated Dose (MTD) [ Time Frame: First 4-week treatment cycle ] [ Designated as safety issue: Yes ]
- Objective response rate (CR and PR according to RECIST) and rate of non-progressive disease at 24 weeks [ Time Frame: Throughout the treatment period (tumor evaluation every 8 weeks) ] [ Designated as safety issue: No ]To be assessed only in patients with tumours bearing FGFR1 amplification.
- Pharmacokinetics following single and multiple dose administration [ Time Frame: first 4-week treatment cycle ] [ Designated as safety issue: No ]
- Tumor perfusion measured by DCE MRI and DCE-US [ Time Frame: First 4-week treatment cycle ] [ Designated as safety issue: No ]
- Circulating markers of angiogenesis: VEGFR2, VEGFR1, VEGF, Collagen IV, bFGF, CEC and CEP [ Time Frame: First 4-week treatment cycle ] [ Designated as safety issue: No ]
- Tumor response according to RECIST; CTC [ Time Frame: Throughout the treatment period ] [ Designated as safety issue: No ]
- Safety profile and dose limiting toxicities (DLT) [ Time Frame: Troughout the treatment period ] [ Designated as safety issue: Yes ]
|Study Start Date:||July 2010|
|Estimated Primary Completion Date:||February 2014 (Final data collection date for primary outcome measure)|
Oral administration, once daily (qd), in fasting conditions.
Dose escalation - continuous schedule
Dose expansion - continuous or intermittent dosing schedules (i.e. 5 days on/2days off or 21 days on/7 days off)
Dosage form: hard gelatin capsules for oral administration (5, 10, 30 and 50 mg strengths)
Other Name: E-3810
|Contact: Roberta Cereda, PhD||+39 02 firstname.lastname@example.org|
|Contact: Maria Gabriella Camboni, MD||+39 02 email@example.com|
|Institute Gustave Roussy||Recruiting|
|Villejuif, Paris, France, 94805|
|European Institute of Oncology||Active, not recruiting|
|Milano, Italy, 20141|
|Vall d' Hebron University Hospital||Recruiting|