ProAgio in Previously Treated Advanced Pancreatic Cancer and Other Solid Tumor Malignancies

Study Overview
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Brief Summary
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The study is a first-in-human, Phase I study to assess the safety of ProAgio in participants with advanced solid tumor malignancies including pancreatic cancer.

Detailed Description
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Pancreatic cancer is the third leading cause of death from cancer in the United States. The median overall survival for patients with metastatic disease who are receiving the most effective combination of chemotherapy regimens remains less than 1 year. ProAgio has been evaluated in nonclinical pharmacology, safety pharmacology, pharmacokinetic (PK), and toxicity studies. It has demonstrated efficacy at treating pancreatic cancer and prolonging survival in mice. ProAgio is being developed for intravenous (IV) administration. All participants will receive ProAgio until disease progression, unacceptable toxicity, or withdrawal from study. Subjects in the dose escalation cohorts who will be administered ProAgio at doses ranging from 3.2 to 36.8 mg/kg. Following the dose escalation phase, an expansion cohort of patients with advanced nonendocrine pancreatic adenocarcinoma will be administered ProAgio at the maximum tolerated dose (MTD) from the dose escalation phase. The expansion cohort will comprise 16 subjects, divided into two blocks (n=8 each) of patients who agree to have optional pre and post-treatment biopsies, and those who decline the optional biopsies.

Official Title
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A Phase I Trial of ProAgio, an Anti- αvβ3 Integrin Cytotoxin, for Previously Treated Advanced Pancreatic Cancer and Other Solid Tumor Malignancies

Conditions
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Advanced Pancreatic Cancer, Solid Tumor Malignancies

Intervention / Treatment
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* Drug: ProAgio Dose Levels (DL) 1,2,3
* Drug: ProAgio Dose Levels (DL) 4,5,6
* Drug: ProAgio Dose Levels 4a,5a,6a


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically confirmed diagnosis of a solid tumor malignancy for which no curative therapy exists as confirmed by the NCI Laboratory of Pathology. For expansion cohort: histologically or cytologically confirmed diagnosis of nonneuroendocrine pancreatic cancer. Participants with mixed acinar- neuroendocrine histology are permitted. Participants in the Biopsy Arm of the expansion cohort must have disease amenable to safe biopsy and willingness to undergo the procedure. Participants must have received at least one prior systemic treatment for advanced disease. Participants must be more than 14 days removed from most recent standard of care or experimental drug treatment for their tumor Participants in the dose escalation cohort must have evaluable disease, either by clinical exam, biochemical markers (including but not limited to CA 19-9 serum tumor marker for pancreatobiliary cancer participants, or other appropriate tumor marker in other tumor types), and/or radiographic studies. Participants in the expansion cohort must have measurable disease, per RECIST 1.1. Age >18 years. Because no dosing or adverse event data are currently available on the use of ProAgio in participants <18 years of age, children are excluded from this study. ECOG performance status <2 (Karnofsky >60%. Participants must have adequate organ and marrow function as defined below: absolute neutrophil count >1,000 mcl hemoglobin >9 g/dl platelets >75,000/mcl AST(SGOT)/ALT(SGPT) < 2.5 x ULN. AST and ALT (up to 5x ULN is permitted for participants with liver metastases) Total bilirubin <1.5 X institutional ULN creatinine within normal institutional limits OR creatinine clearance >60 mL/min/1.73 m2 for participants with creatinine levels above institutional normal Serum albumin > 2.5 mg/dl without intravenous supplementation Participants must have: Resting systolic blood pressure < 145 and diastolic blood pressure < 90. Baseline QTcF interval of = 470 ms Baseline resting heart rate > 45 beats per minute and <100 beats per minute The effects of ProAgio on the developing human fetus are unknown. For this reason, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation and for the 3 months following the last dosing of study drug. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Ability of subject to understand and the willingness to sign a written informed consent document. Exclusion Criteria: Diagnosis of primary malignant CNS tumor. Participants who are receiving any other investigational agents. Evidence of significant, uncontrolled concomitant diseases which could affect compliance with the protocol or interpretation of results, including but not limited to significant pulmonary disease other than that related to the primary cancer, uncontrolled diabetes mellitus, unstable angina, significant cardiovascular disease (such as New York Heart Association Class III or IV cardiac disease) and/or psychiatric illness/social situations within 12 weeks that would limit compliance with study requirements. Participants with known diagnosis of a chronic neurologic disorders (such as multiple sclerosis, Huntington's disease, Parkinson's disease, or uncontrolled epilepsy) which causes motor disturbance, visual disturbance or seizure and could confound assessment of neurologic toxicity caused by the study drug. Pregnant or nursing women are excluded from this study because ProAgio is an agent with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with ProAgio, breastfeeding should be discontinued if the mother is treated with ProAgio. Participants with leptomeningeal disease or with CNS metastases that are untreated, have required steroid treatment within the last 4 weeks, or anti-convulsant therapy in the last 14 days. For dose escalation cohort only: Participants with any known CNS metastases are excluded. Those with symptoms suggestive of possible CNS metastases (such as new headaches) must undergo brain MRI as part of screening. Participants who have undergone a recent minor surgical procedure (within <14 days) such as biliary stenting or major surgical procedure (within < 28 days) are excluded. Participants who have undergone recent (within <14 days) radiation therapy are excluded. Participants with uncontrolled bleeding episodes <28 days prior to enrollment are excluded. Participants with active or uncontrolled infections are excluded. Participants with HIV and detectable viral load are excluded. Patents on appropriate highly active anti-retroviral therapy with undetectable viral load are eligible. Participants with a history of Hepatitis B or C are excluded unless there is documented evidence of effective treatment and/or cure with undetectable viral load. Participants with recent (within < 28 days) thromboembolic disease including but not limited to acute coronary syndrome, stroke, or transient ischemic attack, recent deep vein thrombosis or pulmonary embolism are excluded. Participants with thromboembolic disease including but not limited to acute coronary syndrome, stroke, or transient ischemic attack, recent deep vein thrombosis or pulmonary embolism who have continued symptoms, or who are not on stable doses of appropriate antiplatelet / anticoagulant regimens are excluded.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: This study includes a dose escalation arm, followed by an expansion arm at the ideal dose for participants with non-neuroendocrine pancreatic cancer.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose Escalation<br>Participants will receive ProAgio in escalating doses. | Drug: ProAgio Dose Levels (DL) 1,2,3<br>* ProAgio is administered to study participants by intravenous injections once every 14 days.<br>* Other names: ACT50;Drug: ProAgio Dose Levels (DL) 4,5,6<br>* ProAgio is administered to study participants by intravenous injections once every 7 days.<br>* Other names: ACT50;Drug: ProAgio Dose Levels 4a,5a,6a<br>* ProAgio is administered to study participants by intravenous injections once every 7 days with a drug holiday after every 5 administrations.<br>* Other names: ACT50;|
| Experimental: Biopsy Arm<br>Participants will receive ProAgio at the RP2D and undergo tumor biopsy. | Drug: ProAgio Dose Levels (DL) 1,2,3<br>* ProAgio is administered to study participants by intravenous injections once every 14 days.<br>* Other names: ACT50;Drug: ProAgio Dose Levels (DL) 4,5,6<br>* ProAgio is administered to study participants by intravenous injections once every 7 days.<br>* Other names: ACT50;Drug: ProAgio Dose Levels 4a,5a,6a<br>* ProAgio is administered to study participants by intravenous injections once every 7 days with a drug holiday after every 5 administrations.<br>* Other names: ACT50;|
| Experimental: Standard Arm<br>Participants will receive ProAgio at the RP2D. | Drug: ProAgio Dose Levels (DL) 4,5,6<br>* ProAgio is administered to study participants by intravenous injections once every 7 days.<br>* Other names: ACT50;Drug: ProAgio Dose Levels 4a,5a,6a<br>* ProAgio is administered to study participants by intravenous injections once every 7 days with a drug holiday after every 5 administrations.<br>* Other names: ACT50;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Determine Recommended Phase 2 Dose (RP2D) | Following completion of the dose escalation cohort, all available data relating to the pharmacokinetics, pharmacodynamics, efficacy and safety of ProAgio 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. | 3 Years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and Tolerability of ProAgio | Toxicities will be tabulated and reported per dose level according to grade and type of toxicity experienced. This will take place during the dose escalation phase as well as during the expansion phase. | 3 Years | 
| Evaluate the Maximum Plasma Concentration of ProAgio | ProAgio concentrations will be measured by a validated ELISA assay modified from the assay used in non-clinical studies. This PK data will be used to mathematically describe the kinetic disposition of ProAgio in humans following the current dosing schedule. | 3 Years | 
| Evaluate the area under the curve of ProAgio | Statistical analysis of study data will calculate the area under the plasma concentration curve for each study subject that received ProAgio. | 3 Years | 
| Evaluate the Serum half-life of ProAgio | ProAgio Serum half-life will be determined using standard statistical calculations. . | 3 Years | 
| Evaluate the volume of distribution of ProAgio | If there are sufficient participant data available, a population PK analyses will be conducted to identify covariates that may be significantly associated with the inter-individual variability for a particular PK parameter (e.g. clearance of volume of distribution).The NCI CPP may also conduct dose-response and/or exposure-response analyses that will assess PK/PD relationships with relevant biomarkers, clinical response, and adverse event data. | 3 Years | 
| Rate of study drug elimination in research participants | 58 study participants will have study drug concentration levels analyzed with regard to drug elimination. Results will be expressed in units of inverse time, i.e. 1/hr or 1/day. | 3 Years | 
| Objective Response Rate (ORR) | Make a preliminary assessment of anti-tumor activity by measuring objective response rate (ORR), | 3 Years | 
| Disease control rate (DCR). | Make a preliminary assessment of anti-tumor activity by measuring disease control rate at 18 weeks (DCR). | At 18 Weeks | 
| Assess serum tumor marker CA19-9 or appropriate tumor specific marker. | Make a preliminary assessment of anti-tumor activity by measuring change in relevant serum tumor marker CA19-9 appropriate tumor specific marker. | Day 1 of each treatment cycle and 30 days after the last dose of study therapy. |