Study of Nab-Paclitaxel and Gemcitabine and Plus/Minus VCN-01 in Patients With Metastatic Pancreatic Cancer

Pancreatic Adenocarcinoma Clinical Trial

— VIRAGE  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05673811
• Other study ID #: P-VCNA-003
• Status: Recruiting
• Phase: Phase 2
• Start date: January 10, 2023
• Est. completion date: April 28, 2025

Study information

• Verified date: February 2024
• Source: Theriva Biologics SL
• Contact: Manuel Cascallo, PhD
• Phone: +34 93 571 2359
• Email: MCascallo[@]therivabio.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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

Description:

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 96
• Est. completion date: April 28, 2025
• Est. primary completion date: April 28, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Adenocarcinoma
• Metastatic
• Pancreatic Adenocarcinoma

Intervention

Drug:
• Nab-paclitaxel
Nab-paclitaxel administered as an IV infusion at a rate of 125 mg/m2. Nab-paclitaxel is administered on Day 1, Day 8 and Day 15 of each 28-day cycles.
• Gemcitabine
Gemcitabine administered as an IV infusion at a dose of 1,000 mg/m2 immediately after the completion of nab-paclitaxel administration as part of SoC. Gemcitabine is administered on Day 1, Day 8 and Day 15 of each 28-day cycles.

Genetic:
• VCN-01
VCN-01 administrated as a single IV infusion at dose 1xE13 viral particles (vp) on Day 1 of the 1st cycle and then again on Day 1 of the 4th cycle (Day 92). On cycle 1 and cycle 4, nab-paclitaxel and gemcitabine administered on Day 8, Day 15 and Day 22.

Locations

Country	Name	City	State
Spain	Hospital Universitari Vall d'Hebron	Barcelona
Spain	Hospital Duran i Reynals (ICO)	Hospitalet de Llobregat	Barcelona
Spain	Hospital Gregorio Marañon	Madrid
Spain	Hospital Universitario 12 de Octubre	Madrid
Spain	Hospital Universitario Ramon y Cajal	Madrid
Spain	Hospital Universitario Virgen de la Victoria	Málaga
Spain	Hospital Universitario Marqués de Valdecilla	Santander	Cantabria
Spain	Hospital Universitario Virgen del Rocío	Sevilla	Andalucia
Spain	Hospital General Univesitario de Valencia	Valencia
Spain	Hospital Miguel Servet	Zaragoza
United States	Martha Morehouse Tower	Columbus	Ohio
United States	Virginia Cancer Specialists	Fairfax	Virginia
United States	University of Louisville - Brown Cancer Center	Louisville	Kentucky
United States	Weill Cornell Medical Center	New York	New York
United States	Hoag Memorial Hospital Presbyterian	Newport Beach	California
United States	University of California - Davis Cancer Center	Sacramento	California
United States	Huntsman Cancer Institute, University of Utah	Salt Lake City	Utah

Sponsors (1)

Lead Sponsor	Collaborator
Theriva Biologics SL

Countries where clinical trial is conducted

United States,  Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Neutralizing anti-VCN-01 antibodies (Anti-Ad-Nabs)	Determination of neutralizing anti-VCN-01 antibodies (Anti-Ad-Nabs) in serum of Arm 2 patients at different time-points during the study.; Cycle 1 (VCN-01+SoC dosing): Pre-dose on day 1, day 8, and day 15; Cycle 2 (SoC dosing): Day 1; Cycle 3 (SoC dosing): Day 1; Cycle 4 (VCN-01+SoC dosing): Pre-dose on day 1, day 8, and day 15; On Day 1 of any subsequent SoC cycle.	From pre-dose up to 3 years
Other	PH20 levels in serum	Determination of PH20 levels in serum of Arm 2 (VCN-01 + SoC) patients at the following time-points: Cycle 1 (VCN-01+SoC dosing): Pre-dose on day 1, 48h post-dose and on day 8; Cycle 2 (SoC dosing): Day 1; Cycle 3 (SoC dosing): Day 1; Cycle 4 (VCN-01+SoC dosing): Pre-dose on day, 48h post-dose and on day 8; On Day 1 of any subsequent SoC cycle.	From pre-dose to end of treatment defined as 1 month after the last dose of nab-paclitaxel/gemcitabine.
Other	VCN-01 genomes levels in blood	Determination of VCN-01 genomes in whole blood of Arm 2 (VCN-01 + SoC) patients at the following time-points: Cycle 1 (VCN-01+SoC dosing): Pre-dose and 4h post-dose on day 1, 48h post-dose, on day 8 and day 15; Cycle 2 (SoC dosing): Day 1; Cycle 3 (SoC dosing): Day 1; Cycle 4 (VCN-01+SoC dosing): Pre-dose and 4h post dose on day 1, 48h post-dose, on day 8 and day 15; On Day 1 of any subsequent SoC cycle.	From pre-dose to end of treatment defined as 1 month after the last dose of nab-paclitaxel/gemcitabine.
Other	Immune markers	Determination of immune markers in serum of Arm 1 (SoC) or Arm 2 (VCN-01 + SoC) patients at the following time-points: Arm 1: Cycle 1 (SoC): Pre-dose on day 1, day 8 and day 15. On Day 1 of any subsequent SoC cycle.; Arm 2: Cycle 1 (VCN-01+SoC dosing): Pre-dose, 4h and 48h post-dose and on day 8; Cycle 2 (SoC dosing): Day 1; Cycle 3 (SoC dosing): Day 1; Cycle 4 (VCN-01+SoC dosing): Pre-dose, 4h and 48h post-dose, on day 8 and day 15; On Day 1 of any subsequent SoC cycle.	From pre-dose to end of treatment defined as 1 month after the last dose of nab-paclitaxel/gemcitabine.
Other	Radiomics	Change in radiomics assessed from the images of CT scans or MRI.	Changes from baseline to every 8 week or every 4 weeks if there is a suspicion of Progressive Disease (PD) not radiologically confirmed during treatment and until disease progression up to 3 years.
Other	Tumor growth	Change in tumor growth assessed from the images of CT scans or MRI.	Changes from baseline to every 8 week or every 4 weeks if there is a suspicion of Progressive Disease (PD) not radiologically confirmed during treatment and until disease progression up to 3 years.
Other	Changes in Quality of Life (QoL) via the validated Quality of Life Questionnaire of the European Organization for Research and Treatment of Cancer (EORTC QLQ-C30) version 3.	Changes in QoL assessed as the difference between QoL in day 1 of 1st treatment cycle (35 d) to QoL in day 1 of Cycle 2 (28d), to QoL in day 1 of Cycle 3 (28d), to QoL in day 1 of Cycle 4 (35d) and to QoL in day 1 of any subsequent SoC cycle (28d).; Changes in QoL in EoT visit (1 month after last SoC treatment).; Changes in QoL until disease progression in each monthly follow-up visit.; After disease progression, changes in QoL in each monthly follow up visit during the first 6 months; changes in bimonthly follow-up visits up to to 2 years from progression and changes in each follow-up visit every 6 months onwards.; The QoL scale ranges in score from 0 to 100, a high score represents a higher response level.	From Day 1 in first treatment cycle (35-days) to last follow-up visit up to 3 years.
Other	Disease Control Rate (DCR) to subsequent therapies	Disease Control Rate (DCR) defined as: stable disease (SD) + partial response (PR) + complete response (CR)	From disease progression to exitus for any cause up to 3 years
Primary	Overall Survival	Time from randomization until death in both arms	From randomization until death for any cause up to 3 years
Primary	Incidence of Adverse Events after VCN-01 IV administration	Safety and tolerability of VCN-01, IV administered at Week 1 and Week 14 in Arm 2 measured as incidence of Adverse Events as assessed by CTCAE v5.0	From randomization until disease progression assessed up to 3 years
Secondary	Time to progression (TTP) or Progression Free Survival (PFS)		TTP: From randomization until disease progression assessed up to 3 years or death due to progression.PFS: From randomization to either progression or death from any cause.
Secondary	Overall Response Rate (ORR)	Objective response rate (ORR) defined as the sum of patients who achieved partial response (PR) plus patients who achieved complete response (CR) using RECIST version 1.1 criteria.	From randomization until death for any cause up to 3 years
Secondary	Disease Control Rate (DCR)	Disease Control Rate (DCR) defined as: stable disease (SD) + partial response (PR) + complete response (CR)	From randomization until death for any cause up to 3 years
Secondary	Landmark 1-year survival		From randomization to 1-year landmark
Secondary	Progression Free Survival (PFS) at the 1-year landmark	Time from randomization to either progression or death from any cause.	From randomization to1-year landmark
Secondary	Duration of Response (DoR)	Time from the date of first documented response until date of documented disease progression or death in the absence of disease progression.	From randomization to disease progression assessed up to 3 years
Secondary	Changes in tumor marker Ca 19.9	Tumor marker Ca 19.9 measured every 4 weeks while on study	From randomization until disease progression assessed up to 3 years