A Phase I Trial of ProAgio, an Anti- Alpha-v-beta3 Integrin Cytotoxin, for Previously Treated Advanced Pancreatic Cancer and Other Solid Tumor Malignancies

Sponsor

National Cancer Institute (NCI) (NIH)

Overall Status

Not yet recruiting

CT.gov ID

NCT04937686

Collaborator

(none)

Enrollment

Location

Arms

59.9

Anticipated Duration (Months)

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Background:

Pancreatic cancer is the third leading cause of death from cancer in the United States.
The median overall survival for patients with metastatic disease and excellent performance status receiving the most effective combination chemotherapy regimens remains less than 1 year
Pancreatic ductal adenocarcinoma (PDAC), the most common pancreatic cancer histology, is surrounded by a dense desmoplastic stromal reaction generated by cross-talk between tumor cells and the cancer associated stellate cells (CASC) and fibroblasts (CAF) in the microenvironment.
This stroma physically inhibits delivery of therapeutic drugs to tumor cells, secretes growth factors and nutrients that promote therapy resistance and cancer cell survival and is also highly immunosuppressive
Activated CASCs, CAFs and angiogenic endothelial cells which form the abnormal vasculature around tumors, all express high levels of integrin vbeta3.
ProAgio is a rationally designed pegylated peptide drug that binds to integrin vbeta3 at a novel binding site that directly triggers cell apoptosis
ProAgio induces apoptosis of CASCs and angiogenic endothelial cells in pre-clinical models, inhibiting tumor growth and prolonging animal survival
Safety of ProAgio in rodent and non-human primate models has been established
ProAgio has never been tested in humans

Primary Objectives:

To determine the recommended phase 2 dose (RP2D) of ProAgio in participants with previously treated advanced solid tumors for which no curative therapy exists

Eligibility:

Adults >= 18 years of age
Histologically confirmed solid tumor malignancy for which no curative therapy exists as confirmed by the NCI Laboratory of Pathology
For the expansion cohort only: Histologically confirmed diagnosis of pancreatic cancer that is not neuroendocrine
Participants must have received at least one prior systemic treatment
Adequate end organ function is required
Participants in the Biopsy Arm of the expansion cohort must have disease amenable to safe biopsy and willingness to undergo the procedure

Design:

This is a Phase I study to assess the safety of ProAgio in Participants with advanced solid tumor malignancies including pancreatic cancer
All participants will receive ProAgio until disease progression, unacceptable toxicity, or withdrawal from study
For the dose escalation cohort, a modified 3+3 design with accelerated dose escalation in initial cohorts will be used
For the expansion cohort, all participants will receive ProAgio at the ideal dose identified during the dose escalation
The expansion cohort has two arms: standard arm and biopsy arm. Pre- and post-treatment tumor biopsy is optional for participants enrolled in the standard arm, but mandatory for participants enrolled in the biopsy arm....

Condition or Disease	Intervention/Treatment	Phase
Pancreatic Cancer Solid Tumors	Drug: ProAgio	Phase 1

Detailed Description

Background:

Pancreatic cancer is the third leading cause of death from cancer in the United States.
The median overall survival for patients with metastatic disease and excellent performance status receiving the most effective combination chemotherapy regimens remains less than 1 year
Pancreatic ductal adenocarcinoma (PDAC), the most common pancreatic cancer histology, is surrounded by a dense desmoplastic stromal reaction generated by cross-talk between tumor cells and the cancer associated stellate cells (CASC) and fibroblasts (CAF) in the microenvironment.
This stroma physically inhibits delivery of therapeutic drugs to tumor cells, secretes growth factors and nutrients that promote therapy resistance and cancer cell survival and is also highly immunosuppressive
Activated CASCs, CAFs and angiogenic endothelial cells which form the abnormal vasculature around tumors, all express high levels of integrin alpha-v-beta3.
ProAgio is a rationally designed pegylated peptide drug that binds to integrin alpha-v-beta3 at a novel binding site that directly triggers cell apoptosis
ProAgio induces apoptosis of CASCs and angiogenic endothelial cells in pre-clinical models, inhibiting tumor growth and prolonging animal survival
Safety of ProAgio in rodent and non-human primate models has been established
ProAgio has never been tested in humans

Primary Objectives:

To determine the recommended phase 2 dose (RP2D) of ProAgio in participants with previously treated advanced solid tumors for which no curative therapy exists

Eligibility:

Adults >= 18 years of age
Histologically confirmed solid tumor malignancy for which no curative therapy exists as confirmed by the NCI Laboratory of Pathology
For the expansion cohort only: Histologically confirmed diagnosis of pancreatic cancer that is not neuroendocrine
Participants must have received at least one prior systemic treatment
Adequate end organ function is required
Participants in the Biopsy Arm of the expansion cohort must have disease amenable to safe biopsy and willingness to undergo the procedure

Design:

This is a Phase I study to assess the safety of ProAgio in Participants with advanced solid tumor malignancies including pancreatic cancer
All participants will receive ProAgio until disease progression, unacceptable toxicity, or withdrawal from study
For the dose escalation cohort, a modified 3+3 design with accelerated dose escalation in initial cohorts will be used
For the expansion cohort, all participants will receive ProAgio at the ideal dose identified during the dose escalation
The expansion cohort has two arms: standard arm and biopsy arm. Pre- and post-treatment tumor biopsy is optional for participants enrolled in the standard arm, but mandatory for participants enrolled in the biopsy arm.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

58 participants

Allocation:

Non-Randomized

Intervention Model:

Sequential Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Phase I Trial of ProAgio, an Anti- Alpha-v-beta3 Integrin Cytotoxin, for Previously Treated Advanced Pancreatic Cancer and Other Solid Tumor Malignancies

Anticipated Study Start Date :

Jul 2, 2021

Anticipated Primary Completion Date :

Jan 31, 2025

Anticipated Study Completion Date :

Jun 30, 2026

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 1/Dose Escalation Treatment with ProAgio at escalating doses if necessary	Drug: ProAgio An initial dose of 3.2 mg/kg administered IV and at an MTD dose on day 1 of each 14-day cycle.
Experimental: 2A/Biopsy Arm Treatment with ProAgio at MTD fixed dose	Drug: ProAgio An initial dose of 3.2 mg/kg administered IV and at an MTD dose on day 1 of each 14-day cycle.
Experimental: 2B/Standard Arm Treatment with ProAgio at MTD fixed dose	Drug: ProAgio An initial dose of 3.2 mg/kg administered IV and at an MTD dose on day 1 of each 14-day cycle.

Arm

Intervention/Treatment

Experimental: 1/Dose Escalation

Treatment with ProAgio at escalating doses if necessary

Drug: ProAgio

An initial dose of 3.2 mg/kg administered IV and at an MTD dose on day 1 of each 14-day cycle.

Experimental: 2A/Biopsy Arm

Treatment with ProAgio at MTD fixed dose

Drug: ProAgio

An initial dose of 3.2 mg/kg administered IV and at an MTD dose on day 1 of each 14-day cycle.

Experimental: 2B/Standard Arm

Treatment with ProAgio at MTD fixed dose

Drug: ProAgio

An initial dose of 3.2 mg/kg administered IV and at an MTD dose on day 1 of each 14-day cycle.

Outcome Measures

Primary Outcome Measures

Determine the recommended phase 2 dose (RP2D) of ProAgio [until confirmed progression, unacceptable toxicity or trial withdrawal]
Identification of maximum tolerated dose

Secondary Outcome Measures

safety and tolerability of ProAgio [duration of treatment]
The fraction of patients with toxicity noted at each dose level will be reported by grade and type of toxicity identified.
pharmacokinetics of ProAgio [Cycle 1 and Cycle 3]
Calculate the concentration of circulating ProAgio
objective response rate (ORR) [every 45 days until completion of therapy, then until 1 year post-last dose of ProAgio]
Percentage of patients with the best overall response of CR or PR to therapy
disease control rate (DCR) [18 weeks]
Percentage of patients with CR, PR and SD to therapy
change in relevant serum tumor marker [every 15 days from start until completion of therapy, then 30 days post-last dose of ProAgio]
Calculate the concentration of serum tumor markers before, during and after therapy

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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 non- neuroendocrine 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

creatinine clearance >=60 mL/min/1.73 m^2 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 leptominengeal 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