This is an open-label Phase I/Ib dose-escalation, dose-expansion clinical trial of the safety, pharmacokinetics and clinical activity of ProAgio combined with gemcitabine, nab-paclitaxel (G-nP) or gemcitabine, nab-paclitaxel (G-nP) and atezolizumab in previously untreated subjects with metastatic pancreatic ductal adenocarcinoma (PDAC)
This is an open-label Phase I/Ib dose-escalation, dose-expansion clinical trial of the safety, pharmacokinetics and clinical activity of ProAgio combined with gemcitabine, nab-paclitaxel (G-nP) or gemcitabine, nab-paclitaxel (G-nP) and atezolizumab in previously untreated subjects with metastatic PDAC. The study will use an EWOC design in Phase I to determine the recommended RP2D of ProAgio with gemcitabine, nab paclitaxel (G-nP) and atezolizumab. After the estimation of RP2D of ProAgio alone, the trial will continue to estimate the RP2D of ProAgio when combined with G-nP, starting from 2 dose levels lower than the estimated RP2D of ProAgio alone. EWOC design will enroll 2 subjects per cohort with 4 combination dose levels. Subjects will be selected based on following criteria: previously untreated advanced PDAC, ECOG performance status (0-1), and adequate organ functions. Subjects with recent surgeries, history of recent thromboembolic events or significant cardiovascular disease will be excluded. Once the MTD and RP2D of ProAgio with G-nP RP2D have been identified, an expansion cohort of 12 subjects with metastatic PDAC (n=6 receiving ProAgio and n=6 receiving ProAgio + GnP) will begin. The purpose of the expansion cohort is to confirm the safety of the regimen and provide preliminary data on the activity of both ProAgio monotherapy and ProAgio + GnP. An additional expansion cohort with ProAgio, GnP and atezolizumab will enroll patients with metastatic PDAC (n=18 including 6 patients safety run-in). The purpose of the expansion cohort is to confirm the safety of the regimen and provide preliminary data on the activity of and ProAgio, GnP and atezolizumab combination. Data regarding adverse events will be collected, attributed and graded according to NCI CTCAE version 5.0 criteria. Pharmacokinetic and pharmacodynamic data will be collected per the study flow chart. Response will be evaluated every 2 months using RECIST criteria. Planned secondary analyses will include ORR, duration of response, PFS and OS.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
46
ProAgio combined with gemcitabine and nab paclitaxel (G-nP) in previously untreated subjects with metastatic PDAC.
ProAgio combined with gemcitabine and nab paclitaxel (G-nP) in previously untreated subjects with metastatic PDAC.
O'Neal Comprehensive Cancer Center, University of Alabama
Birmingham, Alabama, United States
RECRUITINGDetermine the safety of ProAgio combined with gemcitabine and nab paclitaxel.
Physical examination, vital signs, clinical laboratory evaluations (CBC, serum chemistry, coagulation studies, LFTs, and assessment of subject reported AEs (via CTCAE v5.0) and SAEs will be used to evaluate safety.
Time frame: 2 Years
Determine the patient's height.
Height measured in Centimeters (cm)
Time frame: 2 Years
Determine the patient's weight.
Weight measured in Kilograms (kg)
Time frame: 2 Years
Determine the patient's body temperature.
Body Temperature measured in Celsius
Time frame: 2 Years
Determine the patient's Respiration Rate.
Respiration Rate measured in times/min
Time frame: 2 Years
Determine the patient's Heart Rate.
Heart Rate measured in beats/min
Time frame: 2 Years
Determine the patient's Systolic Blood Pressure
Systolic Blood Pressure measured in mmHg
Time frame: 2 Years
Determine the patient's Diastolic Blood Pressure.
Diastolic Blood Pressure measured in mmHg
Time frame: 2 Years
Determine the patient's Pulse Oximetry.
Perform Pulse Oximetry measured in (SpO2)
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Time frame: 2 Years
Determine a single ideal dose which will be selected for further investigation in the dose escalation cohort.
Following completion of the dose escalation cohort, all available data relating to the pharmacokinetics, pharmacodynamics, efficacy and safety of ProAgio combined with gemcitabine and nab paclitaxel will be reviewed by the study team including the Principle Investigator, clinical pharmacology collaborators and the sponsor. A single ideal dose will then be selected for further investigation in the dose escalation cohort. This ideal dose may or may not be the same as the MTD.
Time frame: 2 Years
Determine the total integrated area under the plasma drug concentration-time curve (AUC).
Analyze pharmacokinetics to determine the total integrated area under the plasma drug concentration-time curve (AUC).
Time frame: 2 Years
Determine the Peak Plasma Concentration (Cmax).
Pharmacokinetics will be analyzed by determining Peak Plasma Concentration (Cmax).
Time frame: 2 Years
Determine how well the patient eliminates the study drug (CL).
Pharmacokinetics will be analyzed by determining how well the patient eliminates the drug (CL).
Time frame: 2 Years
Determine Volume of distribution (Vd).
Pharmacokinetics will be analyzed by determining Volume of distribution (Vd).
Time frame: 2 Years
Determine the study drug half-life (t1/2).
Pharmacokinetics will be analyzed by determining the study drug half-life (t1/2).
Time frame: 2 Years
An attempt will be made to determine dose proportionality of ProAgio.
Pharmacokinetics will be analyzed by determining the amount of drug reaching the systemic circulation.
Time frame: 2 Years
Evaluate Objective response rate (ORR).
Objective response rate (ORR), defined as complete response (CR) or partial response (PR) through cycle 6 per RECIST 1.1 as a proportion of n=6 of the Phase1b cohorts.
Time frame: 2 Years
Evaluate Duration of response (DOR).
Duration of response (DOR), determined from date of best response to progression or death.
Time frame: 2 Years
Evaluate Progression-free Survival (PFS).
Progression-free Survival (PFS), determined from date of 1st dose of study drug to progression or death.
Time frame: 2 Years
Evaluate Overall Survival (OS).
Overall Survival (OS) determined from date of 1st dose of study drug to death from any cause. CA19-9 will be assessed by descriptive statistics.
Time frame: 2 Years
Evaluate patient tumor response.
MR imaging assessment of patient tumor response using a unique MRI photon to monitor tumor changes and tumor blood perfusion changes.
Time frame: 2 Years