Clinical trial NCT03644459: Safety and Efficacy of the Fully Humanized Anti - VEGF Monoclonal Antibody LYN00101
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
Study type: INTERVENTIONAL
Overall status: WITHDRAWN
Phase: PHASE1
Conditions: Ovarian Cancer
Cervical Cancer
Colorectal Cancer
Stomach Cancer
Keywords: Tolerability
Safety
Humanized Anti-VEGF Monoclonal Antibody
autocrine loops
LYN00101
Lead sponsor: Lynkcell Inc.
Sponsor class: OTHER
First posted: 2018-08-23
Enrollment: 0
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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.

Eligibility criteria: 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).

Primary outcomes:
measure: Area under the concentration-time curve after single dose use
timeFrame: up to 14 days
measure: Peak plasma concentration after single dose use
timeFrame: up to 14 days
measure: Area under the plasma concentration after single - dose use
timeFrame: up to 14 days
measure: Elimination rate constant after single - dose use
timeFrame: up to 14 days
measure: Time to peak after single dose use
timeFrame: up to 14 days
measure: Half time after single dose use
timeFrame: up to 14 days
measure: volume of distribution after single - dose use
timeFrame: up to 14 days
measure: Total body clearance after single-dose use
timeFrame: up to 14 days
measure: Mean residence time after single-dose use
timeFrame: up to 14 days
measure: Time to peak after Each Subsequent Introduction (multiple dose)
timeFrame: up to 24 weeks
measure: Elimination rate constant after Each Subsequent Introductions (multiple dose)
timeFrame: up to 24 weeks
measure: Area under the plasma concentration versus time curve after Each Subsequent Introduction (multiple dose)
timeFrame: up to 24 weeks
measure: Cmax of T1h after Each Subsequent Introduction (multiple dose)
timeFrame: up to 24 weeks
measure: AUC(0-∞) of T1h after Each Subsequent Introduction (multiple dose)
timeFrame: up to 24 weeks
Secondary outcomes:
measure: Average plasma concentration after Each Subsequent Introduction (multiple dose)
timeFrame: up to 24 weeks
measure: Vss of T1h after Each Subsequent Introduction (multiple dose)
timeFrame: up to 24 weeks
measure: CT or MRI or PET/CT Control
timeFrame: after 8 weeks
measure: Area under the plasma concentration after each subsequent introduction (multiple dose)
timeFrame: up to 24 weeks
measure: Blood C-reactive protein level after Each Subsequent Introduction (multiple dose)
timeFrame: up to 24 weeks
measure: Blood Test / morphology after Each Subsequent Introduction (multiple dose)
timeFrame: every week (up to 24 weeks)
measure: TNF-α level after Each Subsequent Introduction (multiple dose)
timeFrame: up to 24 weeks
measure: PGA after Each Subsequent Introduction (multiple dose)
timeFrame: every week up to 24 weeks
Other outcomes:
measure: CLs after Each Subsequent Introduction (multiple dose)
timeFrame: up to 24 weeks
measure: Apparent VD - volume of distribution of T1h after Each Subsequent Introduction (multiple dose)
timeFrame: up to 24 weeks
measure: Half time (t1/2) of T1h after Each Subsequent Introduction (multiple dose)
timeFrame: up to 24 weeks
Locations:
Study officials:
References: