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Clinical Trial Details — Status: Withdrawn

Administrative data

NCT number NCT03644459
Other study ID # LY233-234V
Secondary ID
Status Withdrawn
Phase Phase 1
First received
Last updated
Start date April 3, 2019
Est. completion date August 2020

Study information

Verified date March 2020
Source Lynkcell Inc.
Contact n/a
Is FDA regulated No
Health authority
Study type Interventional

Clinical Trial 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


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.

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.


Recruitment information / eligibility

Status Withdrawn
Enrollment 0
Est. completion date August 2020
Est. primary completion date June 2020
Accepts healthy volunteers No
Gender All
Age group 18 Years to 80 Years
Eligibility 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).

Study Design


Intervention

Biological:
LYN00101
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.

Locations

Country Name City State
n/a

Sponsors (1)

Lead Sponsor Collaborator
Lynkcell Inc.

Outcome

Type Measure Description Time frame Safety issue
Other CLs after Each Subsequent Introduction (multiple dose) Total body clearance CLs (T1h) up to 24 weeks
Other Apparent VD - volume of distribution of T1h after Each Subsequent Introduction (multiple dose) Apparent VD - volume of distribution of T1h up to 24 weeks
Other Half time (t1/2) of T1h after Each Subsequent Introduction (multiple dose) Half time (t1/2) of T1h up to 24 weeks
Primary Area under the concentration-time curve after single dose use Area under the concentration-time curve from 0 to 8 with extrapolation of the final phase of the drug distribution up to 14 days
Primary Peak plasma concentration after single dose use Peak plasma concentration (Cmax) of T1h up to 14 days
Primary 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
Primary Elimination rate constant after single - dose use Elimination rate constant of T1h up to 14 days
Primary Time to peak after single dose use Time to peak(Tmax) of T1h up to 14 days
Primary Half time after single dose use Half time (t1/2) of T1h up to 14 days
Primary volume of distribution after single - dose use Apparent VD - volume of distribution of T1h up to 14 days
Primary Total body clearance after single-dose use Total body clearance (CLs)of T1h up to 14 days
Primary Mean residence time after single-dose use MRT - Mean residence time of T1h up to 14 days
Primary Time to peak after Each Subsequent Introduction (multiple dose) Time to peak(Tmax) of T1h up to 24 weeks
Primary Elimination rate constant after Each Subsequent Introductions (multiple dose) Elimination rate constant of T1h up to 24 weeks
Primary 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
Primary Cmax of T1h after Each Subsequent Introduction (multiple dose) Peak plasma concentration (Cmax) of T1h up to 24 weeks
Primary AUC(0-8) of T1h after Each Subsequent Introduction (multiple dose) Area under the plasma concentration versus time curve(AUC(0-8))of T1h up to 24 weeks
Secondary Average plasma concentration after Each Subsequent Introduction (multiple dose) Average plasma concentration in steady state/Css_avg/ of T1h up to 24 weeks
Secondary Vss of T1h after Each Subsequent Introduction (multiple dose) Apparent volume of distribution in steady state /Vss/ of T1h up to 24 weeks
Secondary CT or MRI or PET/CT Control Tumor Necrosis and Dynamic of the Treatment ( by CT or MRI or PET/CT) after 8 weeks
Secondary 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
Secondary Blood C-reactive protein level after Each Subsequent Introduction (multiple dose) C-reactive protein/CARP/ up to 24 weeks
Secondary Blood Test / morphology after Each Subsequent Introduction (multiple dose) Blood Test / morphology every week (up to 24 weeks)
Secondary TNF-a level after Each Subsequent Introduction (multiple dose) Tumor Necrosis Factor -alpha (TNF-a) up to 24 weeks
Secondary PGA after Each Subsequent Introduction (multiple dose) Physician's Global Assessment /PGA/ every week up to 24 weeks
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