Study of Oral Lucitanib (E-3810), a Dual VEGFR-FGFR Tyrosine Kinase Inhibitor, in Patients With Solid Tumors

This study is currently recruiting participants.
Verified July 2013 by Ethical Oncology Science
Sponsor:
Information provided by (Responsible Party):
Ethical Oncology Science
ClinicalTrials.gov Identifier:
NCT01283945
First received: January 25, 2011
Last updated: July 12, 2013
Last verified: July 2013
  Purpose

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.


Condition Intervention Phase
Solid Tumors
Drug: Lucitanib
Phase 1
Phase 2

Study Type: Interventional
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

Resource links provided by NLM:


Further study details as provided by Ethical Oncology Science:

Primary Outcome Measures:
  • 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.


Secondary Outcome Measures:
  • 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 ]

Estimated Enrollment: 110
Study Start Date: July 2010
Estimated Primary Completion Date: February 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Lucitanib Drug: Lucitanib

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

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Age ≥ 18 years
  2. Histologically or cytologically confirmed, locally advanced or metastatic solid tumour, relapsed or refractory to standard therapy.

    In addition, only for the dose-expansion phase:

    i) solid tumour bearingFGFR1 amplification and, if breast cancer, with at least one prior endocrine therapy in the metastatic setting if ER+, and at least one chemotherapy line otherwise or ii) solid tumour progressing after having experienced SD (lasting for at least six month) or PR as best response to prior treatment with an approved or investigational antiangiogenic drug (e.g.: sorafenib, sunitinib, bevacizumab) as a single agent or in a chemotherapy combination or iii) solid tumour potentially sensitive to antiangiogenic treatments provided no antiangiogenic agents are approved and\or available for that specific condition.

  3. Life expectancy ≥ 3 months
  4. Full recovery (to Grade ≤ 1) from any prior surgical procedure(s) and from reversible side effects of prior therapy for cancer including radiation therapy, chemotherapy, and immunotherapy
  5. Adequate haematologic function (haemoglobin ≥ 9 g/dL, absolute neutrophil count [ANC] ≥ 1500/mL, platelets ≥ 100,000/mL), adequate renal function (serum creatinine< 1.5 mg/dL or creatinine clearance > 40 mL/min), and adequate hepatic function (serum bilirubin ≤ 1.5 x upper limit of normal (ULN) mg/dL, aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≤ 3 x ULN)
  6. Eastern Co-operative Oncology Group (ECOG) performance status ≤ 1
  7. Negative serum pregnancy test at screening in women of childbearing potential
  8. For men and women of child-bearing potential, use of a medically accepted method of contraception (abstinence, barrier method with spermicide, intrauterine device, or steroidal contraceptive for women and barrier method for men) for the duration of the study and for 60 days after participation in the study
  9. Willingness and ability to give written informed consent and to comply with study procedures

Exclusion Criteria:

  1. Active central nervous system (CNS) metastases not controlled by prior surgery or radiotherapy and/or low dose steroids
  2. Haematologic malignancies (including leukaemia of any form, lymphoma, and multiple myeloma)
  3. Active second malignancy or history of another malignancy within 2 years, with the exception of non-melanoma skin cancers or carcinoma in situ (CIS) of the breast or cervix or controlled, superficial carcinoma of the bladder
  4. Treatment with any anticancer agent within 3 weeks, including investigational agents, chemotherapy, immunotherapy, biologic or hormonal therapy, surgery or radiation therapy (6 weeks for nitrosoureas, mitomycin or bevacizumab); luteinizing hormone releasing hormone (LHRH) agonist for prostate and mitotane for adrenal carcinoma are allowed.
  5. Significant cardiovascular disease or condition, including:

    • Congestive heart failure requiring therapy
    • Ventricular and/or supra-ventricular arrhythmia requiring therapy
    • Severe conduction disturbance (including QTc interval prolongation > 0.47 sec [corrected], history of severe arrhythmia, or history of familial arrhythmia [e.g., Wolff-Parkinson-White syndrome])
    • Angina pectoris requiring therapy
    • Left ventricular ejection fraction (LVEF) < 50% evaluated by cardiac ultrasound (ECHO) or Multi Gated Acquisition Scan (MUGA)
    • Uncontrolled hypertension (defined as systolic blood pressure ≥ 140 mm Hg and/or diastolic blood pressure ≥ 90 mm Hg with optimized antihypertensive therapy)
    • Myocardial infarction (MI) within 6 months prior to administration of the first dose
    • > Class I cardiovascular disease according to the New York Heart Association's (NYHA) Functional Criteria
  6. Ongoing treatment with Warfarin
  7. Unavoidable concomitant treatment with any drug known for potential risk of causing Torsades de Pointes (see list in Appendix 4)
  8. Significant gastrointestinal abnormalities, including ulcerative colitis, chronic diarrhoea associated with intestinal malabsorption, Crohn's disease, and/or prior surgical procedures affecting absorption or requirement for intravenous (IV) alimentation
  9. Known pre-existing clinically significant disorder of the hypothalamic-pituitary axis, thyroid and adrenal gland
  10. Serious/active bacterial, viral or fungal infection (including known active human immunodeficiency virus [HIV] infection) requiring systemic treatment
  11. Concurrent severe or uncontrolled medical disease or organ system dysfunction which, in the opinion of the Investigators, would limit life expectancy to < 3 months, compromise the patient's safety, or interfere with evaluation of the safety of the investigational product
  12. Psychiatric disorder or altered mental status that would preclude understanding of the informed consent process and/or completion of the necessary study procedures
  13. Known hypersensitivity to gelatin or lactose monohydrate
  14. Difficulty with swallowing
  15. Pregnant or lactating women.
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01283945

Contacts
Contact: Roberta Cereda, PhD +39 02 87391608 roberta.cereda@eosmilano.com
Contact: Maria Gabriella Camboni, MD +39 02 87391608 gabriella.camboni@eosmilano.com

Locations
France
Institute Gustave Roussy Recruiting
Villejuif, Paris, France, 94805
Italy
European Institute of Oncology Active, not recruiting
Milano, Italy, 20141
Spain
Vall d' Hebron University Hospital Recruiting
Barcellona, Spain
Sponsors and Collaborators
Ethical Oncology Science
  More Information

No publications provided

Responsible Party: Ethical Oncology Science
ClinicalTrials.gov Identifier: NCT01283945     History of Changes
Other Study ID Numbers: E-3810-I-01
Study First Received: January 25, 2011
Last Updated: July 12, 2013
Health Authority: France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)
Italy: National Institute of Health
Spain: Agencia Española de Medicamentos y Productos Sanitarios

Keywords provided by Ethical Oncology Science:
VEGFRs
FGFR1
angiogenesis

Additional relevant MeSH terms:
Neoplasms

ClinicalTrials.gov processed this record on April 17, 2014