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
Trial Snapshot
- Phase
- Phase 1
- Status
- Withdrawn
- Sponsor
- Primary Endpoint
- Mean residence time after single-dose use
Study Overview
Brief Summary
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
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.
Study Design
- Study Type
- Interventional
- Allocation
- Na
- Intervention Model
- Single Group
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to 80 Years (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
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).
Outcomes
Primary Outcomes
Mean residence time after single-dose use
Time Frame: up to 14 days
MRT - Mean residence time of T1h
Area under the plasma concentration versus time curve after Each Subsequent Introduction (multiple dose)
Time Frame: up to 24 weeks
Area under the plasma concentration versus time curve( AUC(0-t)) of T1Hh
volume of distribution after single - dose use
Time Frame: up to 14 days
Apparent VD - volume of distribution of T1h
Time to peak after single dose use
Time Frame: up to 14 days
Time to peak(Tmax) of T1h
AUC(0-∞) of T1h after Each Subsequent Introduction (multiple dose)
Time Frame: up to 24 weeks
Area under the plasma concentration versus time curve(AUC(0-∞))of T1h
Peak plasma concentration after single dose use
Time Frame: up to 14 days
Peak plasma concentration (Cmax) of T1h
Area under the plasma concentration after single - dose use
Time Frame: up to 14 days
Area under the plasma concentration versus time curve( AUC(0-t)) of T1Hh
Elimination rate constant after single - dose use
Time Frame: up to 14 days
Elimination rate constant of T1h
Area under the concentration-time curve after single dose use
Time Frame: up to 14 days
Area under the concentration-time curve from 0 to ∞ with extrapolation of the final phase of the drug distribution
Half time after single dose use
Time Frame: up to 14 days
Half time (t1/2) of T1h
Cmax of T1h after Each Subsequent Introduction (multiple dose)
Time Frame: up to 24 weeks
Peak plasma concentration (Cmax) of T1h
Time to peak after Each Subsequent Introduction (multiple dose)
Time Frame: up to 24 weeks
Time to peak(Tmax) of T1h
Total body clearance after single-dose use
Time Frame: up to 14 days
Total body clearance (CLs)of T1h
Elimination rate constant after Each Subsequent Introductions (multiple dose)
Time Frame: up to 24 weeks
Elimination rate constant of T1h
Secondary Outcomes
- Vss of T1h after Each Subsequent Introduction (multiple dose)(up to 24 weeks)
- CT or MRI or PET/CT Control(after 8 weeks)
- PGA after Each Subsequent Introduction (multiple dose)(every week up to 24 weeks)
- Blood Test / morphology after Each Subsequent Introduction (multiple dose)(every week (up to 24 weeks))
- Area under the plasma concentration after each subsequent introduction (multiple dose)(up to 24 weeks)
- Blood C-reactive protein level after Each Subsequent Introduction (multiple dose)(up to 24 weeks)
- TNF-α level after Each Subsequent Introduction (multiple dose)(up to 24 weeks)
- Average plasma concentration after Each Subsequent Introduction (multiple dose)(up to 24 weeks)