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

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to determine if CVX-241 (PF-05057459) is safe and tolerable when given as weekly infusions to adult patients with advanced solid tumors.

Detailed Description
-----------------
The study was prematurely discontinued on 14 September 2011 due to no significant pharmacological effects (safety/PD/efficacy) through 25 mg/kg cohort, the T1/2 based on VEGF binding was shorter than expected and the current and/or higher doses were not considered feasible for further development. There were no safety concerns associated with the decision to terminate the program/study.

Official Title
-----------------
A Phase 1, Multicenter, Open-label, Dose-escalation, Safety, Pharmacokinetic, And Pharmacodynamic Study Of Cvx-241, A Selective Angiopoietin-2 And Vascular Endothelial Growth Factor Binding, Anti-angiogenic Covx-body, In Patients With Advanced Solid Tumors

Conditions
-----------------
Advanced Solid Tumors

Intervention / Treatment
-----------------
* Drug: CVX-241
* Drug: CVX-241
* Drug: CVX-241
* Drug: CVX-241
* Drug: CVX-241
* Drug: CVX-241
* Drug: CVX-241
* Drug: CVX-241


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Confirmed solid tumors unresponsive to current therapy or for which there is no standard therapy. Stage 2 only: Histologically or cytologically documented EOC or PPC with < or equal to 3 previous anti-cancer therapies, but at least 1 prior platinum containing regimen. Adequate coagulation, liver, and renal function. Candidate for Dynamic Contrast-Enhanced Magnetic Resonance Imaging [DCE-MRI] evaluation Eastern Cooperative Oncology Group [ECOG] performance status of 0 or 1 Exclusion Criteria: History of clinically significant toxicity to Vascular Endothelial Growth Factor [VEGF] inhibition. Evidence of bleeding problems. Uncontrolled hypertension. Patients with primary brain cancer and/or non-small cell lung cancer of squamous cell histology

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Active Drug<br>Weekly infusions of CVX-241 at specified doses | Drug: CVX-241<br>* 0.3 mg/kg infusions of CVX-241 on Days 1, 8, 15, and 22 of each 28 day cycle. Weekly infusions administered until progression or unacceptable toxicity develops.<br>* Other names: PF-05057459;Drug: CVX-241<br>* 1 mg/kg infusions of CVX-241 on Days 1, 8, 15, and 22 of each 28 day cycle. Weekly infusions administered until progression or unacceptable toxicity develops.<br>* Other names: PF-05057459;Drug: CVX-241<br>* 3 mg/kg infusions of CVX-241 on Days 1, 8, 15, and 22 of each 28 day cycle. Weekly infusions administered until progression or unacceptable toxicity develops.<br>* Other names: PF-05057459;Drug: CVX-241<br>* 6 mg/kg infusions of CVX-241 on Days 1, 8, 15, and 22 of each 28 day cycle. Weekly infusions administered until progression or unacceptable toxicity develops.<br>* Other names: PF-05057459;Drug: CVX-241<br>* 12 mg/kg infusions of CVX-241 on Days 1, 8, 15, and 22 of each 28 day cycle. Weekly infusions administered until progression or unacceptable toxicity develops.<br>* Other names: PF-05057459;Drug: CVX-241<br>* 15 mg/kg infusions of CVX-241 on Days 1, 8, 15, and 22 of each 28 day cycle. Weekly infusions administered until progression or unacceptable toxicity develops.<br>* Other names: PF-05057459;Drug: CVX-241<br>* 18 mg/kg infusions of CVX-241 on Days 1, 8, 15, and 22 of each 28 day cycle. Weekly infusions administered until progression or unacceptable toxicity develops.<br>* Other names: PF-05057459;Drug: CVX-241<br>* 25 mg/kg infusions of CVX-241 on Days 1, 8, 15, and 22 of each 28 day cycle. Weekly infusions administered until progression or unacceptable toxicity develops.<br>* Other names: PF-05057459;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose (MTD) | MTD was defined as highest dose level for which no more than 1 participant in a dose cohort experienced dose limiting toxicity (DLT). 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). | Stage 1: Baseline up to Day 28 (end of cycle 1) | 
| Recommended Phase 2 Dose (RP2D) | RP2D was the highest dose where 0 of 3 or less than (<2) out of 6 participants experience a DLT. 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). | Stage 1: Baseline up to Day 28 (end of cycle 1) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Dose Limiting Toxicities (DLTs) | 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). | Stage 1: Baseline up to Week 4 | 
| Number of Participants With Treatment Emergent Adverse Events (TEAEs) or Serious Adverse Events (SAEs) | 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. | Baseline up to 28 days after last dose of study medication (last dose = up to Cycle 39) | 
| Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUCinf] | 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). | Pre-dose, 1, 2, 4, 6 hours post dose at Day 1 of cycle 1 | 
| Maximum Observed Plasma Concentration (Cmax) | Study drug was analysed using serum Angiopoietin-2 (Ang2) and plasma Vascular Endothelial Growth Factor (VEGF). | Pre-dose, 1, 2, 4, 6 hours post dose at Day 1, Day 22 of cycle 1 | 
| Minimum Observed Plasma Trough Concentration (Cmin) |  | Pre-dose, 1, 2, 4, 6 hours post dose at Day 1, Day 22 of cycle 1 | 
| Systemic Clearance (CL) | 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. | Pre-dose, 1, 2, 4, 6 hours post dose at Day 1, Day 22 of cycle 1 | 
| Plasma Decay Half-Life (t1/2) | 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). | Pre-dose, 1, 2, 4, 6 hours post dose at Day 1 of cycle 1 | 
| Change From Baseline in Plasma Vascular Endothelial Growth Factor (VEGF) Concentrations | 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. | Cycle 1/Day 1, Cycle 1/Day 5, Cycle 1/Day 8, Cycle 1/Day 15, Cycle 1/Day 22, Cycle 2/Day 1 | 
| Change From Baseline in Serum Angiopoietin-2 (Ang2) Concentrations | 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. | Cycle 1/Day 1, Cycle 1/Day 5, Cycle 1/Day 8, Cycle 1/Day 15, Cycle 1/Day 22, Cycle 2/Day 1 | 
| Number of Anti Drug Antibody Samples With Positive Anti-CVX-241 Antibodies | Results were summarized for overall study population as per planned analysis. | Day 1 pre-dose of each cycle up to last dose of study medication (last dose = up to Cycle 39) | 
| Objective Response Rate - Percentage of Participants With Objective Response | 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. | Every 8 weeks from start of treatment until last dose of study medication (last dose = up to Cycle 39) | 
| Participants WithTumor Response of CA-125 Epithelial Ovarian Cancer (EOC)/ Primary Peritoneal Cancer (PPC) | 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. | Stage 2 every cycle | 
| Participants With Reduction in Tumor Vascular Permeability: Blood Flow and Blood Volume as Measured by Dynamic Contrast-Enhanced Magnetic Resonance Imaging (DCE-MRI) | 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. | Stage 2 predose up to end of study | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Treatment Non-Randomized Single Group Assignment Safety Study Neoplasms Carcinoma Cancer Malignancy