A phase IIb, open-label, randomized study of Nab-Paclitaxel and Gemcitabine and plus/minus VCN-01 in Patients with Metastatic Pancreatic Cancer

Multi-center, open label, randomized, 2-parallel arm, phase IIb study of nab-paclitaxel and gemcitabine as Standard of Care (SoC) plus/minus VCN-01 in patients with metastatic pancreatic cancer. Gemcitabine and nab-paclitaxel are chemotherapy drugs approved by the FDA to treat pancreatic cancer. VCN-01 is a genetically modified adenovirus characterized by the presence of four independent genetic modifications in the backbone of the wild-type human adenovirus serotype 5 (HAd5) genome that confer tumor selective replication and antitumor activity. Approximately 92 patients in sites in North America and European Union (EU) will be recruited and randomized in a 1:1 ratio to one of two treatment arms (i.e., approximately 46 patients per treatment arm):

• Arm 1- (SoC): Nab-paclitaxel and gemcitabine as SoC (28-day cycles). Patients in this arm will not receive the investigational medicinal product (IMP) VCN-01.
• Arm 2- (VCN-01+ SoC): A maximum of two (2) doses of VCN-01 administrated in combination with nab-paclitaxel and gemcitabine as SoC (28-day cycles with exception of the IMP dose cycles, which will be 35-day cycles).

A Data Monitoring Committee (DMC) will be convened at regular intervals to assess safety and to look at OS to determine if the trial can continue.

Inclusion Criteria:

1. Written informed consent obtained prior to any study-specific procedures or assessments.

2. Male/female patients aged 18 years or over.

3. 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.

4. Patients willing to comply with the study treatment.

5. Patients with a minimum life expectancy of 5 months.

6. ECOG performance status of 0 or 1.

7. 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.

8. Adequate baseline organ function (hematologic, liver, renal and nutritional)verified by laboratory analyses performed within 72 hours prior to dosing*:

   Hematology:

   • Absolute neutrophil count ≥1.5xE9 /L

   • Hemoglobin ≥9 g/dL

   • Platelets ≥100xE9/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

   • Note: Adequate organ function specified in this criterion must also be met prior to VCN-01 dosing on Cycle 4 Day 1 for ARM II.

   Exclusion Criteria:

1. Patients not willing to complete the study procedures for geographic, psychiatric, or social reasons.

2. 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 Virus (HBV; positive HBV surface antigen [HBsAg] result), Hepatitis C Virus (HCV; positive HCV Ribonucleic acid [RNA]), or human immunodeficiency virus (positive HIV 1/2 antibodies). HBV carriers (patients positive for 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:

   o Patients with past or resolved TB are eligible;

   o 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;

   o Patients positive for HCV antibody are eligible only if polymerase chain reaction is negative for HCV RNA.

3. 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.

4. Known chronic liver disease (liver cirrhosis, chronic hepatitis). If there is a suspicion 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.

5. Treatment with another investigational agent within five of that treatment's half-lives prior to infusion of study treatment.

6. Viral syndrome diagnosed during the 2 weeks before start of study treatment administration.

7. Chronic immunosuppressive therapy 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).

8. Concurrent malignant hematologic or solid disease. Patients with a prior history of cancer can be allowed if complete remission for at least 3 years.

9. 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).

10. Patients with Li Fraumeni syndrome or with previously known retinoblastoma protein pathway germline deficiency.

11. A female patient, who is pregnant or lactating.

12. 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.

13. Untreated brain metastases and/or leptomeningeal carcinomatosis with progressive symptoms despite corticosteroid coverage. Patients with brain metastases with stable symptoms can be included.

14. 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.

15. Patients with previous pneumonitis or interstitial lung disease.

16. Patients with pre-existing sensory neuropathy >G1.

17. Patients with known risk factors for bowel perforation.

18. 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.

19. Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients.

20. Subjects, for whom first line treatment options other than the combination Gemcitabine/Nab-Paclitaxel are recommended by the investigator.