Dose escalation: solid tumors failing standard therapy. Dose-expansion: solid tumors A) with FGFR1 amplification and for breast cancer ? 1 prior endocrine therapy if ER+ or ? 1 chemotherapy otherwise
Conditions
Interventions
Product Name: S80881
Product Code: S80881, E-3810
Pharmaceutical Form: Capsule, hard
INN or Proposed INN: Lucitanib
CAS Number: 1058137-23-7
Current Sponsor code: S80881-2
Other descriptive name: LUCI
Sponsors
Institut de Recherches Internationales Servier
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Age ? 18 years 2. Histologically or citologically confirmed, locally advanced or metastatic solid tumour, relapsed or refractory to standard therapy. In addition, only for the dose-expansion phase: i) solid tumour bearing FGFR1 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 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 child bearing 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 Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 86 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 44
Exclusion criteria
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 fra-tion (LVEF) 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.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Phase I To determine the Maximum Tolerated Dose (MTD) of E-3810 when administered orally, once daily for 28 consecutive days Phase IIa: To evaluate the objective response and the rate of non-progressive disease at 24 weeks in patients with tumours bearing FGFR1 amplification;Secondary Objective: - To establish the safety profile and define the DLT of E-3810. - To select the RD and the optimal dosing schedule of E-3810 (after Amend.17Dec2012, in the expansion phase both continuous and 2 intermittent dosing schedules were explored). - To characterize the PK profile of E-3810 following single and multiple daily oral administrations - To evaluate the effect of E-3810 on tumour perfusion by DCE MRI and DCE-US - To evaluate the effects of E-3810 on circulating PD markers of angiogenesis, including soluble Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) and VEGFR1, VEGF, Collagen IV, bFGF, FGF23, PlGF, CEC, CEP and CTC - To identify genetic events that may be associated with response to E-3810 and with cancer disease (after Amend.04Nov2013) - To preliminarily evaluate the antitumour activity of E-3810 - To correlate the occurrence of hypertension with the PK of E-3810 and/or the antitumour activity;Primary end point(s): Phase I: Maximum Tolerated Dose (MTD) of E-3810 Phase IIa: Overall objective response (CR and PR according to RECIST); rate of non-progressive disease in patients with tumours bearing FGFR1 amplification;Timepoint(s) of evaluation of this end point: Phase I: end of cycle 1 Phase II: every two cycles throughout the study | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): safety profile, DLT, RD; PK profile; tumor perfusion; PD angiogenesis markers (VEGFR2, VEGFR1, VEGF, Collagen IV, bFGF, FGF23, PlGF, CEC, CEP, CTC; genetic events that may be associated with response to E-3810 and with cancer disease (after Amend.04Nov2013); preliminary antitumor activity; ipertension vs PK and/or vs antitumor activity;Timepoint(s) of evaluation of this end point: - | — |
Countries
Spain
Contacts
Public ContactClinical Studies Department
Institut de Recherches Internationales Servier
Outcome results
None listed