A Safety, Tolerability, And Pharmacokinetic Trial With CVX-241 In Patients With Advanced Solid Tumors

DLT was defined as any of the following events occurring during the first 28 days of study medication and considered at least possibly-related to study medication: any grade 3 or 4 clinically-relevant non-hematologic toxicity, any clinically-significant grade 2 non-hematologic toxicity that requires 14 days to resolve (to grade 1).

Adverse event (AE) was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent are events between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pretreatment state. AEs included SAEs and non-SAEs that occurred during the study.

AUCinf = Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0 - ∞)u for unbound drug. It is obtained from AUC (0 - t)u plus AUC (t - ∞)u for unbound drug. Study drug was analysed using serum Angiopoietin-2 (Ang2) and plasma Vascular Endothelial Growth Factor (VEGF).

Study drug was analysed using serum Angiopoietin-2 (Ang2) and plasma Vascular Endothelial Growth Factor (VEGF).

CL is a quantitative measure of the rate at which a drug substance is removed from the body. Due to premature termination of the study, only certain exposure-related noncompartmental PK parameters were calculated.

Plasma decay half-life is the time measured for the plasma concentration to decrease by one half. Study drug was analysed using serum Angiopoietin-2 (Ang2) and plasma Vascular Endothelial Growth Factor (VEGF).

VEGF family consists of five glycoproteins known as VEGF-A, -B, -C, and -D, and placental growth factor (PlGF), which bind to three structurally similar receptor tyrosine kinases VEGFR1, VEGFR2, and VEGFR3. The different ligands have distinctive binding specificities for each of the receptors. In response to ligand binding, the VEGFRs activate distinct downstream signalling pathways. VEGFR2 is expressed in the vasculature and is the key mediator of VEGF-induced angiogenesis.

Angiopoietin-2 (Ang2) and a related protein, angiopoietin-1 (Ang1) are ligands of the endothelial cell receptor Tie-2, a receptor tyrosine kinase, and are known to mediate the angiogenesis process together with VEGF and other angiogenic regulators. Ang1 stimulates the phosporylation of Tie-2, recruits pericytes to newly formed blood vessels, and promotes their maturation. Ang2 competes with Ang1 for binding of Tie-2, promotes the dissociation of pericytes, and results in unstable blood vessels. In the presence of VEGF and other angiogenic factors, endothelial cells in these unstable vessels proliferate and migrate to form new blood vessels.

Results were summarized for overall study population as per planned analysis.

Percentage of participants with objective response based assessment of complete response (CR) or partial response (PR) according to Response Evaluation Criteria in Solid Tumors (RECIST 1.1). CR was defined as complete disappearance of all target lesions and non-target disease, with the exception of nodal disease. All nodes, both target and non-target, must decrease to normal (short axis <10 mm). No new lesions. PR was defined as >=30% decrease under baseline of the sum of diameters of all target lesions. The short aixs was used in the sum for target nodes, while the longest diameter was used in the sum for all other target lesions. No unequivocal progression of non-target disease. No new lesions. Stable disease was defined as not qualifying for CR, PR, and Progressive Disease.

Participants with epithelial ovarian cancer or primary peritoneal cancer having CA-125 levels greater than 2x the upper limit of normal, 2 weeks prior to starting therapy were evaluated for CA-125 response and response is defined as a 50% decrease in CA-125 from a pre-treatment sample. The response was confirmed and maintained for at least 28 days. CA-125 response was calculated as intervening samples and the 28-day confirmatory sample must be less than or equal to (within assay variability of 10%) the previous sample Progression or recurrence based on serum CA-125 is defined according to the participants baseline levels.

DCE-MRI is a non-invasive method that provides a functional assessment of microvasculature. The technique can measure changes in vascular permeability, extracellular, and extravascular and vascular volumes. Based on its ability to detect vascular changes, DCE-MRI has recently been evaluated as a biomarker of drug efficacy in clinical trials of angiogenesis inhibitors. Assessment of DCE-MRI started at the 3.0 mg/kg dose cohort.