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

• 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 ]

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.

Inclusion Criteria:

1. Age ≥ 18 years
2. Histologically or cytologically confirmed, locally advanced or metastatic solid tumour, relapsed or refractory to standard therapy. Only for the dose-expansion phase:(i) breast cancer, with FGFR1 amplification with at least one prior endocrine therapy in the metastatic setting if ER+, and at least one chemotherapy line otherwise or (ii) tumour progressing after at least one line of treatment with an antiangiogenic drug (e.g.: sorafenib, sunitinib, bevacizumab) as a single agent or in a chemotherapy combination
3. One or more lesion suitable for DCE-MRI and for DCE-US evaluation
4. Life expectancy ≥ 3 months
5. 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
6. 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)
7. ECOG performance status ≤ 1
8. Negative serum pregnancy test at screening
9. For men and women of child-bearing potential, use of a medically accepted method of contraception

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, ventricular and/or supra-ventricular arrhythmia, severe conduction disturbance (including QTc interval prolongation > 0.47 sec), history of severe arrhythmia, or history of familial arrhythmia, angina pectoris, LVEF < 50%, uncontrolled hypertension (systolic blood pressure ≥ 140 mm Hg and/or diastolic blood pressure ≥ 90 mm Hg with optimized antihypertensive therapy), myocardial infarction within 6 months prior to administration of the first dose, > Class I cardiovascular disease according to the NYHA Functional Criteria
6. Ongoing treatment with Warfarin
7. Unavoidable concomitant treatment with any drug known for potential risk of causing Torsades de Points
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