Safety and Efficacy of the Fully Humanized Anti - VEGF Monoclonal Antibody LYN00101

Study Overview
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Brief Summary
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The purpose of this study is evaluate the pharmacokinetics, pharmacodynamics, immunogenicity and anti-tumor effect of of fully human anti - VEGF monoclonal antibody LY00101 and explore the potential prognostic and predictive biomarkers. This study will not take into account the results of molecular-genetic tests of patients enrolled in the study

Detailed Description
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Tumors can be inactive for years, until transformation of cells into an angiogenic phenotype occurs. This phenomenon is known as angiogenic switch. It is based on balance between inhibitors and activators of angiogenesis. Multiple genetic changes and processes leading to malignancies, such as activation of oncogenes, can trigger angiogenic switch. Simple diffusion of nutrients and oxygen normally occurs within not more than 1-2 mm of tumor tissue. For further growth, blood supply and development of the vasculature are necessary. Angiogenesis level in a tumor and it's metastasis activity has correlation with density of microvessels in a primary tumor and significantly affects disease prognosis. Angiogenesis in a body is regulated through Vascular endothelial growth factor (VEGF) and its receptors. There is a unique binding pattern of corresponding receptors typical for all members of the VEGF family: VEGF-A binds with VEGFR1 and VEGFR2 VEGF-B and PlGF bind and activate receptor VEGFR1 only VEGF-C and VEGF-D communicate with receptor VEGFR3 (Flt4), triggering lymphangiogenesis, and demonstrate activity correlated with VEGFR2. According to studies, VEGFR1 binds to the ligand with the highest affinity, binding VEGF and inhibiting VEGF-mediated signaling. The VEGF-VEGFR2 binder induces autophosphorylation (and partial dimerization) of the catalytic domain of the PI3K / v-akt signaling pathway receptor (Phosphoinositide 3-kinase / murine thymoma viral oncogene homolog - Akt or serine / threonine protein kinase B, PKB), as well as Raf and MAP2K, which further phosphorylate MAPK (Erk). Monoclonal antibody LYN00101 is not only a potent inhibitor of VEGF, also blocks autocrine growth factor loops by inhibiting VEGF and VEGFR 1/2/3 receptors and effectively blocking neoangiogenesis. The purpose of this study is evaluate the pharmacokinetics, pharmacodynamics, immunogenicity and anti-tumor effect of of fully human anti - VEGF monoclonal antibody LY00101 and explore the potential prognostic and predictive biomarkers. This study will not take into account the results of molecular-genetic tests of patients enrolled in the study.

Official Title
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Phase I Study of the Safety, Tolerability,Pharmacokinetics and Pharmacodynamics of the Fully Humanized Anti - VEGF Monoclonal Antibody LYN00101 With Blocking of Autocrine Loops VEGFR1/2/3

Conditions
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Ovarian Cancer, Cervical Cancer, Colorectal Cancer, Stomach Cancer

Intervention / Treatment
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* Biological: LYN00101


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: patients with histopathologically-documented, measurable or non measurable {evaluable}, advanced solid tumors refractory a life expectancy of >3 months ECOG performance status score of ≤ 2 at study entry able to provide written informed consent. use of effective contraceptive measures if procreative potential exists. an absolute neutrophil count ≥1500/mm3 a hemoglobin level ≥ 9gm/dL a platelet count ≥100,000/mm3 a total bilirubin level ≤1.5 x the ULN aspartate transaminase (AST) and alanine transaminase (ALT) levels ≤2.5 x the ULN or ≤5 x the ULN if known liver metastases adequate renal function, as defined by a serum creatinine level ≤1.5 x the ULN. Exclusion Criteria: patients with any active infection (nail bed induced fungal infections were excluded), chronic infections, and tuberculosis history. the females were pregnant, or lactating or showed positive urine pregnancy reaction during screening. patients with severe heart disease, heart failure, asthma, chronic obstructive pulmonary disease or neuropsychiatric diseases. uncontrolled diabetes or poor compliance with hypoglycemics; the presence of chronically unhealed wound or ulcers other chronic diseases, which, in the opinion of the investigator, could compromise safety of the patient or the integrity of study. newly-diagnosed or symptomatic brain metastases (patients with a history of brain metastases must have received definitive surgery or radiotherapy, be clinically stable, and not taking steroids for brain edema). Anticonvulsants are allowed. peritoneal carcinomatosis pregnancy (confirmed by serum beta human chorionic gonadotropin [ßHCG]) or breast-feeding (for female patients only). a known history or clinical evidence of a deep vein or arterial thrombosis, or pulmonary embolism less than six weeks from last infusion of any anti-VEGF monoclonal antibody therapy known history of human immunodeficiency virus infection (HIV).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: LYN00101<br>Intravenous Infusion at the rate of 8 mg/kg of the patient's weight every 14 days. | Biological: LYN00101<br>* Concentrate for intravenous infusions (10 mg / ml) with Molecular Weight 150 - 151 kDa. Each cycle of treatment consists of 24 weeks. Patients who enroll into this study will receive an infusion of assigned dose of LYN00101 biweekly. No intra-patient dose escalation is allowed. The proposed dose escalation sequence is 10mg/kg, starting from 8 mg/kg.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area under the concentration-time curve after single dose use | Area under the concentration-time curve from 0 to ∞ with extrapolation of the final phase of the drug distribution | up to 14 days | 
| Peak plasma concentration after single dose use | Peak plasma concentration (Cmax) of T1h | up to 14 days | 
| Area under the plasma concentration after single - dose use | Area under the plasma concentration versus time curve( AUC(0-t)) of T1Hh | up to 14 days | 
| Elimination rate constant after single - dose use | Elimination rate constant of T1h | up to 14 days | 
| Time to peak after single dose use | Time to peak(Tmax) of T1h | up to 14 days | 
| Half time after single dose use | Half time (t1/2) of T1h | up to 14 days | 
| volume of distribution after single - dose use | Apparent VD - volume of distribution of T1h | up to 14 days | 
| Total body clearance after single-dose use | Total body clearance (CLs)of T1h | up to 14 days | 
| Mean residence time after single-dose use | MRT - Mean residence time of T1h | up to 14 days | 
| Time to peak after Each Subsequent Introduction (multiple dose) | Time to peak(Tmax) of T1h | up to 24 weeks | 
| Elimination rate constant after Each Subsequent Introductions (multiple dose) | Elimination rate constant of T1h | up to 24 weeks | 
| Area under the plasma concentration versus time curve after Each Subsequent Introduction (multiple dose) | Area under the plasma concentration versus time curve( AUC(0-t)) of T1Hh | up to 24 weeks | 
| Cmax of T1h after Each Subsequent Introduction (multiple dose) | Peak plasma concentration (Cmax) of T1h | up to 24 weeks | 
| AUC(0-∞) of T1h after Each Subsequent Introduction (multiple dose) | Area under the plasma concentration versus time curve(AUC(0-∞))of T1h | up to 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Average plasma concentration after Each Subsequent Introduction (multiple dose) | Average plasma concentration in steady state/Css_avg/ of T1h | up to 24 weeks | 
| Vss of T1h after Each Subsequent Introduction (multiple dose) | Apparent volume of distribution in steady state /Vss/ of T1h | up to 24 weeks | 
| CT or MRI or PET/CT Control | Tumor Necrosis and Dynamic of the Treatment ( by CT or MRI or PET/CT) | after 8 weeks | 
| Area under the plasma concentration after each subsequent introduction (multiple dose) | Area under the plasma concentration versus time curve in steady state (AUCss) of T1h | up to 24 weeks | 
| Blood C-reactive protein level after Each Subsequent Introduction (multiple dose) | C-reactive protein/CARP/ | up to 24 weeks | 
| Blood Test / morphology after Each Subsequent Introduction (multiple dose) | Blood Test / morphology | every week (up to 24 weeks) | 
| TNF-α level after Each Subsequent Introduction (multiple dose) | Tumor Necrosis Factor -alpha (TNF-α) | up to 24 weeks | 
| PGA after Each Subsequent Introduction (multiple dose) | Physician's Global Assessment /PGA/ | every week up to 24 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Tolerability, Safety, Humanized Anti-VEGF Monoclonal Antibody, autocrine loops, LYN00101