Study of Oral E-3810, a Dual VEGFR-FGFR Tyrosine Kinase Inhibitor, in Patients With Solid Tumors
Recruitment status was Recruiting
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. E-3810 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 a first-in-men open-label, uncontrolled, non-randomized, Phase I dose escalation study followed by dose-expansion at the identified Recommended Dose (RD) in patients with advanced solid tumours. The purpose of the study is to evaluate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of E-3810 given orally, once daily for a 4-week course; treatment can continue without interval until progression based on overall clinical benefit. The study follows a conventional 3+3 MTD design, with dose escalation according to a modified Fibonacci scheme. Escalation will proceed up to the Maximum Tolerated Dose (MTD) based on occurrence of Dose Limiting Toxicities (DLT) in the initial 4-week course. The MTD is the dose level where ≥ 2 out of 3-6 patients experience DLTs, the next lowest dose level being the RD. Once the RD has been identified, additional patients, who could benefit from E-3810 treatment, i.e. with tumours sensitive to anti-angiogenic therapy and failing a prior anti-angiogenic regimen, or breast cancer with FGFR1 amplification, will be enrolled to obtain a more robust evaluation of the safety, PK and PD profile of E-3810 and preliminary information on its anti-tumour activity.
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 (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.
|Study Design:||Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||An Open-Label, Dose-escalation, Phase I Study to Determine the Maximum Tolerated Dose, Recommended Dose, Pharmacokinetics, and Pharmacodynamics of the Dual VEGFR-FGFR Tyrosine Kinase Inhibitor, E-3810, Given Orally as Single Agent to Patients With Advanced Solid Tumours|
- Dose Limiting Toxicities (DLT) and Maximum Tolerated Dose (MTD) [ Time Frame: First 4-week treatment cycle ] [ Designated as safety issue: Yes ]
- 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 ]
|Study Start Date:||July 2010|
|Estimated Primary Completion Date:||February 2012 (Final data collection date for primary outcome measure)|
Oral administration, once daily (qd), on a continuous schedule, in fasting conditions. Starting daily dose 5 mg.
Dosage form: hard gelatin capsules for oral administration (5, 30 and 50 mg strengths)
|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||Recruiting|
|Milano, Italy, 20141|
|Vall d' Hebron University Hospital||Not yet recruiting|