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

Colorectal Cancer Clinical Trial

Official title:

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

Clinical Trial Details — Status: Withdrawn

Administrative data

• NCT number: NCT03644459
• Other study ID #: LY233-234V
• Status: Withdrawn
• Phase: Phase 1
• 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
• 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).

Related Conditions & MeSH terms

• Cervical Cancer
• Colorectal Cancer
• Ovarian Cancer
• Stomach Cancer
• Stomach Neoplasms

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