Phase IIb Open-label Randomized Study of Nab-Paclitaxel, Gemcitabine, and VCN-01 in Metastatic Pancreatic Cancer Patients

Trial ID: 2024-511290-30-00
Protocol: P-VCNA-003
Sponsor: Theriva Biologics S.L.

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Diseases & Conditions

Pancreatic carcinoma metastatic

Objectives

The primary objective of this study is to evaluate the **overall survival** (OS) in patients with metastatic pancreatic cancer, comparing the time from randomization until death in both treatment arms. Additionally, the study aims to assess the safety and tolerability of VCN-01, administered intravenously at Week 1 and Week 14 in Arm II. This is clinically relevant as it seeks to determine the potential benefit of VCN-01 in extending survival and its safety profile in combination with standard therapy.

Secondary objectives include:

Evaluating the time to progression (TTP) or progression-free survival (PFS).
Determining the objective response rate (ORR).
Assessing the disease control rate (DCR), which includes stable disease (SD), partial response (PR), and complete response (CR).
Determining the landmark 1-year survival and PFS at the 1-year landmark.
Evaluating the duration of response (DoR).
Assessing changes in tumor marker Ca 19.9 measured every 4 weeks while on study.

Participants

The clinical trial involves a total of **30 participants** diagnosed with **Metastatic Pancreatic Cancer**. The study population includes both male and female subjects aged 18 years and older, with a confirmed diagnosis of first-line metastatic pancreatic adenocarcinoma stage IV de novo. Participants have not received any previous systemic treatment for their pancreatic cancer, and the established therapy is nab-paclitaxel/gemcitabine. All participants must have at least one measurable tumor lesion for imaging assessments. The trial population was selected based on their willingness to comply with the study treatment and a minimum life expectancy of 5 months. Participants are required to have an **ECOG performance status** of 0 or 1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. Adequate baseline organ function, including hematologic, liver, renal, and nutritional parameters, is verified by laboratory analyses. The study does not include a vulnerable population, and participants are expected to use reliable contraception methods if they are of childbearing potential. The selection criteria ensure that participants are in a general health status that allows them to undergo the study procedures safely.

Plans and Procedures

The clinical trial is designed as a **randomized**, open-label study to evaluate the efficacy and safety of VCN-01 in combination with nab-paclitaxel and gemcitabine in patients with **metastatic pancreatic cancer**. The trial aims to assess the overall survival (OS) and the safety and tolerability of VCN-01 when administered intravenously at Week 1 and Week 14 in one of the study arms. The trial is expected to run from November 15, 2022, to March 28, 2025, with recruitment having started on January 13, 2023, and anticipated to end by September 18, 2024.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, diagnosis, and baseline organ function. Following randomization, participants will attend regular follow-up visits to monitor treatment response and safety, with assessments including imaging of tumor lesions as per RECIST 1.1 guidelines. The end-of-study visit will occur after the final treatment cycle or upon early termination, which may be due to adverse events, disease progression, or withdrawal of consent.

The expected duration of participant involvement is approximately 36 weeks, corresponding to the maximum treatment period. Conditions that may lead to early termination from the study include significant adverse reactions, non-compliance with study protocols, or any other medical reasons deemed necessary by the investigator. The primary endpoints of the study are overall survival and safety, while secondary endpoints include progression-free survival (PFS), overall response rate (ORR), and changes in tumor marker Ca 19.9.

Treatment

The clinical trial involves the administration of **VCN-01**, an experimental medication formulated as a **concentrate for solution for infusion**. The active substance in VCN-01 is a **genetically modified human adenovirus encoding human PH20 hyaluronidase**. This investigational product is administered intravenously. The dosing schedule for VCN-01 includes administration at Week 1 and Week 14. The maximum daily dose is set at 10 trillion AgU antigen units, with a total maximum dose of 100 septillion AgU antigen units over the treatment period. The maximum treatment duration is 36 weeks. Participant compliance with the dosing regimen is monitored throughout the study to ensure adherence to the protocol.

In addition to VCN-01, the study includes a standard-of-care therapy consisting of nab-paclitaxel and gemcitabine. This combination serves as a comparator treatment in the trial. The administration of nab-paclitaxel and gemcitabine follows established dosing guidelines for patients with metastatic pancreatic cancer. The frequency and route of administration for these non-experimental treatments are consistent with current clinical practice standards. Monitoring of participant compliance with the standard-of-care therapy is conducted to maintain the integrity of the study data.

Efficacy

The efficacy of the clinical trial will be assessed using several primary and secondary endpoints. The primary endpoints include overall survival (OS) and the safety and tolerability of the investigational product, VCN-01, which is administered intravenously at Week 1 and Week 14 in Arm II. Secondary endpoints encompass progression-free survival (PFS) or time to progression (TTP), objective response rate (ORR), disease control rate (DCR) which includes stable disease (SD), partial response (PR), and complete response (CR), as well as landmark 1-year survival and PFS at the 1-year mark. Additionally, duration of response (DoR) and changes in the tumor marker **Ca 19.9** will be evaluated.

The trial is designed as a Phase IIb, open-label, randomized study involving patients with metastatic pancreatic cancer. Efficacy parameters will be measured and collected at specified timepoints throughout the trial, with assessments determined by RECIST 1.1 criteria for tumor lesions. The trial aims to provide comprehensive data on the efficacy of VCN-01 in combination with nab-paclitaxel and gemcitabine, compared to the standard of care. The study will continue until the estimated end date of October 1, 2025, with recruitment having started on October 1, 2022.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Written informed consent obtained prior to any study-specific procedures or assessments.
Male/female patients aged 18 years or over.
Patients with histologically or cytologically confirmed, first line metastatic pancreatic adenocarcinoma stage IV de novo, who never received previous systemic treatment for their pancreatic cancer for which the established therapy is nab-paclitaxel/gemcitabine (clinical SoC). All patients must have at least one measurable tumor lesion that can be imaged for assessments determined by RECIST 1.1.
Patients willing to comply with the study treatment.
Patients with a minimum life expectancy of 5 months.
ECOG performance status of 0 or 1
Use of a reliable method of contraception in fertile men and women. Female patients of childbearing potential (i.e., female patients who are not postmenopausal or surgically sterile) must agree to use effective contraception. Male patients must agree to use effective contraception or be surgically sterile. All male patients must use a male condom.
Adequate baseline organ function (hematologic, liver, renal and nutritional) verified by laboratory analyses performed within 72 hours prior to dosing*: Hematology: Absolute neutrophil count #1.5x109 /L, Hemoglobin #9 g/dL, Platelets #100x109/L, Coagulation (*except in patients on anticoagulants), Prothrombin time or international normalized ratio #1x upper limit of normal (ULN), Activated partial thromboplastin time #1.2xULN Hepatic:Total bilirubin #1.5xULN, ALT and AST #2.5xULN (if there are no liver metastases), ALT and AST <5xULN, and bilirubin <1.5xULN (if there are liver metastases) Renal: Serum creatinine #1.5xULN, and if >1.5xULN: Estimated creatinine, clearance >50 mL/min using Cockcroft and Gault formula Nutritional: Serum Albumin #30 g/L

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Exclusion Criteria

Patients not willing to complete the study procedures for geographic, psychiatric, or social reasons.
Active infection or other serious illness or autoimmune disease at the moment of randomization. Active infection includes tuberculosis (TB; clinical evaluation that includes clinical history, physical examination and radiographic findings, and TB testing in line with local practice), hepatitis B (HBV; positive HBV surface antigen [HBsAg] result), hepatitis C (HCV; positive HCV Ribonucleic acid [RNA]), or human immunodeficiency virus (positive HIV 1/2 antibodies). HBV carriers (patients positive or HBsAg) or those patients requiring antiviral therapy treatment for HBV virus or HCV are not eligible to participate. However, the following patients are eligible to participate in the study: - Patients with past or resolved TB are eligible; - Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody [HBcAb] and absence of HBsAg) are eligible. Blood HBV DNA must be obtained and must be negative in these patients prior to treatment; - Patients positive for HCV antibody are eligible only if polymerase chain reaction is negative for HCV RNA.
Treatment with live attenuated vaccines in the last 3 weeks and with the adenovirus type-5 (Ad5)-based COVID-vaccine in the last 12 weeks before the administration of study treatment.
Known chronic liver disease (liver cirrhosis, chronic hepatitis). If there is a suspect of hepatic fibrosis, a fibroscan must be performed; patients with a value #9.5 kPa will be excluded. Note: Transient elastography (Fibroscan) is a non-invasive method for the assessment of hepatic fibrosis.
Treatment with another investigational agent within five of that treatment’s half-lives prior to infusion of study treatment.
Viral syndrome diagnosed during the 2 weeks before start of study treatment administration.
Chronic immunosuppressive and/or disease modifying therapy, except inhaled corticosteroids, and oral or IV corticosteroids with a dose lower than 10 mg prednisone or equivalent/day (exception: dexamethasone 1 mg/day as maximum).
Concurrent malignant hematologic or solid disease. Patients with a prior history of cancer can be allowed if complete remission for at least 3 years.
Patients in close contact (e.g., living in same house) with immunosuppressed patients (i.e., patients with chronic immunosuppressive therapy including high dose of corticosteroids, patients with acquired immunodeficiency syndrome (AIDS), and other chronic immune system diseases).
Patients with Li Fraumeni syndrome or with previously known retinoblastoma protein pathway germline deficiency.
A female patient, who is pregnant or lactating.
Patients receiving full-dose anticoagulant therapy or in whom these therapies cannot be withdrawn 2 days prior and 2 days after VCN-01 administration. Patients with uncontrolled coagulopathy should be excluded.
Untreated brain metastases and/or leptomeningeal carcinomatosis with progressive symptoms despite corticosteroid coverage. Patients with brain metastases with stable symptoms can be included.
Any other condition, disease, metabolic dysfunction (e.g., uncontrolled diabetes mellitus), active or uncontrolled infection/inflammation, physical examination finding, mental state or clinical laboratory finding that would contraindicate participation in the clinical study due to safety concerns or compliance with clinical study procedures.
Patients with previous pneumonitis or interstitial lung disease.
Patients with pre-existing sensory neuropathy >G1.
Patients with risk factors for bowel perforation.
Patients with QT interval corrected by Fridericia (QTcF) assessment >450 ms for men or >470 ms for women and left ventricular ejection fraction (LVEF) evaluation less than 50% measured by ECHO or multigated acquisition scan.
Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients.
Subjects, for whom first line treatment options other than the combination Gemcitabine/Nab-Paclitaxel are recommended by the investigator.