Adenovirus Vector for Pancreatic Cancer

Overseen By Edward Greeno, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Masonic Cancer Center, University of Minnesota

Must not be taking: Immunosuppressants

Disqualifiers: HIV, Hepatitis B/C, Autoimmune, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 1

Duration: 1 day

18 Participants Needed

Trial Summary

What is the purpose of this trial?

This is a single center, Phase I dose finding study of a single direct tumor injection of an RGD modified conditionally replicative adenovirus (RGDCRAdcox2F) in persons with adenocarcinoma of the pancreas. The study is designed to determine the MTD of RGDCRAdCOX2F that corresponds to the maximum desired toxicity of ≤ 20%.

Will I have to stop taking my current medications?

The trial requires that at least 4 weeks have passed since your last dose of any prior therapy before receiving the study treatment. The protocol does not specify if you need to stop other current medications, so it's best to discuss this with the study team.

What data supports the effectiveness of the treatment RGDCRAdCOX2F for pancreatic cancer?

Research shows that using adenovirus-based treatments, similar to RGDCRAdCOX2F, can slow down the growth of pancreatic cancer in animal models and improve the effectiveness of other cancer drugs. This suggests that adenovirus vectors might be a promising approach for treating pancreatic cancer. ^{1 2 3 4 5}

Is the adenovirus vector treatment generally safe for humans?

Safety of oncolytic adenoviral mutants has been extensively assessed in clinical trials with only limited toxicity to normal healthy tissue being reported. ^{2 3 6 7 8}

What makes the treatment RGDCRAdCOX2F unique for pancreatic cancer?

The treatment RGDCRAdCOX2F is unique because it uses a genetically modified adenovirus to specifically target and destroy pancreatic cancer cells while sparing normal cells. This approach, known as oncolytic virotherapy, is different from traditional treatments as it leverages a virus to selectively infect and kill cancer cells, potentially offering a novel way to treat this aggressive cancer. ^{2 3 9 10 11}

Eligibility Criteria

This trial is for adults over 18 with pancreatic adenocarcinoma that hasn't spread beyond the pancreas and regional lymph nodes. Participants can have had one prior treatment but must wait 4 weeks before joining. They need to handle an EGD procedure, as the tumor has to be reachable by endoscopic ultrasound. Those who can get pregnant or have partners who can must use two forms of birth control.

Inclusion Criteria

Participants with partners of childbearing potential must be willing to use at least two forms of effective birth control (one form must be a barrier method) for at least 1 month after Day 1

I am 18 years old or older.

My heart and lungs are healthy based on recent exams.

Exclusion Criteria

My cancer is not a common type of pancreatic, ampulla, bile duct, or duodenum cancer.

My tumor is near vital areas and could cause blockage or press on major vessels if it swells.

I have had a gastrojejunostomy surgery.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Single direct tumor injection of RGD modified conditionally replicative adenovirus (RGDCRAdCOX2F) to determine the maximum tolerated dose (MTD)

1 day

1 visit (in-person)

Dose Limiting Toxicity (DLT) Observation

Observation period to monitor for dose limiting toxicity, with a minimum of 28 days between cohorts

28 days

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• RGDCRAdCOX2F

Trial Overview The study tests a single injection of RGDCRAdCOX2F, a modified virus designed to target pancreatic cancer cells. It's in Phase I to find the highest dose patients can take without serious side effects in more than 20% of cases.

Participant Groups

Group I: Level: 3 RGDCRAdcox2F (RGD) Experimental Treatment 1 Intervention

Patients given 3x10\^12 vp/d of RGD. Enrollment begins at DL 1 in cohorts of 2 patients. A minimum of 28 days (DLT period) must separate the last patient treated in the current cohort and the 1st patient in the next cohort of 2 patients. A minimum of 21 days must separate the 1st and 2nd patient within a cohort.

Group II: Level: 2 RGDCRAdcox2F (RGD) Experimental Treatment 1 Intervention

Patients given 9x10\^11 vp/d of RGD. Enrollment begins at DL 1 in cohorts of 2 patients. A minimum of 28 days (DLT period) must separate the last patient treated in the current cohort and the 1st patient in the next cohort of 2 patients. A minimum of 21 days must separate the 1st and 2nd patient within a cohort.

Group III: Level: 1 RGDCRAdcox2F (RGD) Experimental Treatment 1 Intervention

Patients given 3x10\^11 vp/d of RGD Enrollment begins at DL 1 in cohorts of 2 patients. A minimum of 28 days (DLT period) must separate the last patient treated in the current cohort and the 1st patient in the next cohort of 2 patients. A minimum of 21 days must separate the 1st and 2nd patient within a cohort.

Group IV: Level: -1 RGDCRAdcox2F (RGD) Experimental Treatment 1 Intervention

Patients given 3x10\^10 vp/d of RGD. Safety arm. Enrollment begins at DL 1 in cohorts of 2 patients. A minimum of 28 days (DLT period) must separate the last patient treated in the current cohort and the 1st patient in the next cohort of 2 patients. A minimum of 21 days must separate the 1st and 2nd patient within a cohort.

Who Is Running the Clinical Trial?

Masonic Cancer Center, University of Minnesota

Lead Sponsor

Trials

285

Recruited

15,700+

Findings from Research

The study developed a novel adenovirus (Ad5MK) that selectively targets pancreatic cancer cells expressing midkine, showing significant anti-tumor effects in both cell lines and mouse models, particularly in those with high midkine expression.

Ad5MK demonstrated greater cytotoxicity against midkine-expressing pancreatic cancer cells compared to midkine-negative cells, suggesting its potential as a targeted gene therapy for pancreatic cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Midkine promoter-based conditionally replicative adenovirus therapy for midkine-expressing human pancreatic cancer. Toyoda, E., Doi, R., Kami, K., et al.[2021]

The study successfully created an adenoviral vector that specifically targets the EphA2 receptor, which is highly expressed on pancreatic cancer cells, demonstrating improved targeting in laboratory tests with human pancreatic cancer cell lines.

Despite the promising in vitro results showing enhanced specificity and transduction of EphA2R-expressing cells, the vector did not show increased targeting effectiveness in live mouse models, indicating a gap between laboratory success and in vivo application.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ephrin A2 receptor targeting does not increase adenoviral pancreatic cancer transduction in vivo. van Geer, MA., Bakker, CT., Koizumi, N., et al.[2021]

The novel oncolytic adenovirus AV25CDC, driven by the CDC25B promoter, showed a strong ability to kill pancreatic cancer cells in vitro and significantly reduced tumor size by 70% to 80% in vivo when combined with gemcitabine in mouse models.

Treatment with AV25CDC not only effectively reduced tumor growth but also normalized liver toxicity markers and significantly lowered CA19.9 serum levels, indicating a potential for safe and effective chemovirotherapy in pancreatic cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Novel CDC25B Promoter-Based Oncolytic Adenovirus Inhibited Growth of Orthotopic Human Pancreatic Tumors in Different Preclinical Models. Weber, HL., Gidekel, M., Werbajh, S., et al.[2022]

In murine models of pancreatic adenocarcinoma, treatment with an adenovirus vector encoding soluble Flk1 (Flk1-Fc) resulted in significantly reduced tumor volumes, with 75% smaller tumors in murine models and 78% smaller tumors in human models compared to control treatments after 6 weeks.

Mice treated with Flk1-Fc showed longer survival rates and less liver tumor replacement, indicating that this antiangiogenic gene therapy could be a promising approach for improving outcomes in pancreatic cancer patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adenovirus-mediated delivery of a soluble form of the VEGF receptor Flk1 delays the growth of murine and human pancreatic adenocarcinoma in mice. Tseng, JF., Farnebo, FA., Kisker, O., et al.[2009]

A novel treatment strategy using oncolytic adenoviral mutants combined with gemcitabine significantly enhances the effectiveness of cancer therapy in pancreatic adenocarcinoma, a highly resistant cancer, as shown in both cultured cells and xenograft models.

The adenoviral mutants selectively induce apoptosis in pancreatic cancer cells while sparing normal cells, suggesting that this combination therapy could allow for lower doses of gemcitabine, reducing toxicity while maintaining efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oncolytic adenoviral mutants with E1B19K gene deletions enhance gemcitabine-induced apoptosis in pancreatic carcinoma cells and anti-tumor efficacy in vivo. Leitner, S., Sweeney, K., Oberg, D., et al.[2022]

Targeting pancreatic tumors through intraductal injection of adenoviruses significantly improves viral distribution and tumor targeting compared to intravenous delivery, as shown in two mouse models of pancreatic cancer.

The combination of intraductal adenovirus delivery with ganciclovir treatment resulted in substantial tumor regression and increased survival rates in mice with pancreatic xenografts, demonstrating a promising approach for localized pancreatic cancer therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intraductal delivery of adenoviruses targets pancreatic tumors in transgenic Ela-myc mice and orthotopic xenografts. José, A., Sobrevals, L., Miguel Camacho-Sánchez, J., et al.[2021]

The newly developed infectivity-enhanced COX-2 promoter-based conditionally replicative adenoviruses (CRAds) effectively target and kill pancreatic cancer cells, showing a strong antitumor effect in both in vitro and in vivo models.

Systemic administration of these CRAds demonstrated minimal toxicity, with no significant adverse effects on major organs and low levels of viral RNA detected in the liver, indicating a safe therapeutic profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Infectivity enhanced, cyclooxygenase-2 promoter-based conditionally replicative adenovirus for pancreatic cancer. Yamamoto, M., Davydova, J., Wang, M., et al.[2019]

Pancreatic ductal adenocarcinoma (PDAC) has a very low 5-year survival rate and is characterized by an aggressive nature and resistance to standard treatments like gemcitabine, highlighting the urgent need for new therapies.

Oncolytic adenoviruses show promise as a novel treatment option, demonstrating safety in clinical trials and potential efficacy when combined with existing chemotherapies, as they can activate anti-tumor immune responses and penetrate the tumor's protective stroma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Advances in oncolytic adenovirus therapy for pancreatic cancer. Nattress, CB., Halldén, G.[2022]

The modified oncolytic adenovirus Ad5/3-CXCR4-E1A was found to be more effective in infecting and destroying pancreatic cancer cells compared to an unmodified version, indicating its potential as a targeted therapy.

In a study involving 40 SCID mice with pancreatic tumor xenografts, treatment with Ad5/3-CXCR4-E1A resulted in significantly smaller tumors, improved body condition, and prolonged survival, suggesting its efficacy as a new therapeutic option for pancreatic cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Virotherapy using a novel chimeric oncolytic adenovirus prolongs survival in a human pancreatic cancer xenograft model. Chu, QD., Sun, G., Pope, M., et al.[2021]

The newly developed Ad-SGE-REIC vector significantly increased the expression of the REIC/Dkk-3 tumor suppressor gene in pancreatic cancer cells compared to the conventional Ad-CAG-REIC vector.

Ad-SGE-REIC not only reduced cell viability and induced apoptosis in pancreatic cancer cell lines but also demonstrated superior tumor growth inhibition in a mouse model, suggesting it could be a more effective treatment option for pancreatic cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Novel REIC/Dkk-3-encoding adenoviral vector as a promising therapeutic agent for pancreatic cancer. Sawahara, H., Shiraha, H., Uchida, D., et al.[2020]

The study evaluated adenoviral vectors for gene transfer in seven human pancreatic cancer cell lines, finding that the new Ad5/35GFP vector significantly improved transfection efficiency compared to the conventional Ad5GFP vector.

Transfection efficiency was not directly linked to the expression levels of the coxsackie and adenovirus receptor (CAR) or integrins, suggesting that the chimeric fiber proteins in Ad5/35GFP enhance gene delivery through mechanisms beyond just receptor binding.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adenovirus vectors with chimeric type 5 and 35 fiber proteins exhibit enhanced transfection of human pancreatic cancer cells. Toyoda, E., Doi, R., Kami, K., et al.[2012]

References

1. England pubmed.ncbi.nlm.nih.gov

Midkine promoter-based conditionally replicative adenovirus therapy for midkine-expressing human pancreatic cancer. [2021]

2. United States pubmed.ncbi.nlm.nih.gov

Ephrin A2 receptor targeting does not increase adenoviral pancreatic cancer transduction in vivo. [2021]

3. United States pubmed.ncbi.nlm.nih.gov

A Novel CDC25B Promoter-Based Oncolytic Adenovirus Inhibited Growth of Orthotopic Human Pancreatic Tumors in Different Preclinical Models. [2022]

4. United States pubmed.ncbi.nlm.nih.gov

Adenovirus-mediated delivery of a soluble form of the VEGF receptor Flk1 delays the growth of murine and human pancreatic adenocarcinoma in mice. [2009]

5. United States pubmed.ncbi.nlm.nih.gov

Oncolytic adenoviral mutants with E1B19K gene deletions enhance gemcitabine-induced apoptosis in pancreatic carcinoma cells and anti-tumor efficacy in vivo. [2022]

6. United States pubmed.ncbi.nlm.nih.gov

Intraductal delivery of adenoviruses targets pancreatic tumors in transgenic Ela-myc mice and orthotopic xenografts. [2021]

7. United States pubmed.ncbi.nlm.nih.gov

Infectivity enhanced, cyclooxygenase-2 promoter-based conditionally replicative adenovirus for pancreatic cancer. [2019]

8. Ireland pubmed.ncbi.nlm.nih.gov

Advances in oncolytic adenovirus therapy for pancreatic cancer. [2022]

9. United States pubmed.ncbi.nlm.nih.gov

Virotherapy using a novel chimeric oncolytic adenovirus prolongs survival in a human pancreatic cancer xenograft model. [2021]

10. England pubmed.ncbi.nlm.nih.gov

Novel REIC/Dkk-3-encoding adenoviral vector as a promising therapeutic agent for pancreatic cancer. [2020]

11. Greece pubmed.ncbi.nlm.nih.gov

Adenovirus vectors with chimeric type 5 and 35 fiber proteins exhibit enhanced transfection of human pancreatic cancer cells. [2012]