Immunotherapy for Pancreatic Cancer

Overseen By Chris Lefeber

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Vaccinex Inc.

Must be taking: 5FU, Gemcitabine

Must not be taking: Steroids, Immunosuppressants

Disqualifiers: Autoimmune disease, Organ transplant, others

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

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: Unknown

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a combination of two drugs, Pepinemab and Avelumab (an immunotherapy), to determine their safety and effectiveness for individuals with pancreatic cancer that has spread and worsened after initial chemotherapy. It targets those who have already tried treatments like 5FU or Gemcitabine but still have detectable cancer on scans. Participants should have metastatic pancreatic cancer and should not have responded to their first treatment. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new combination therapy.

Do I need to stop my current medications to join the trial?

The trial information does not specify if you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that using Pepinemab with Avelumab is generally safe for patients. In past studies, this combination was well-tolerated, with most side effects being mild to moderate and manageable. Such side effects are common with treatments that enhance the immune system's ability to fight cancer. Serious side effects were rare.

Avelumab, one of the drugs in this combination, has been used in other cancer treatments and is known for its safety. It aids the immune system in attacking cancer cells. Researchers are testing Pepinemab with Avelumab to determine if it can enhance treatment effectiveness.

Overall, this combination demonstrated a good safety record in earlier trials. However, as with any treatment, monitoring for possible side effects remains important. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about Avelumab and Pepinemab for pancreatic cancer because they represent a novel approach compared to traditional treatments like chemotherapy and radiation. Avelumab is an immunotherapy drug that works by blocking the PD-L1 pathway, helping the immune system recognize and attack cancer cells more effectively. Pepinemab is an antibody that targets the semaphorin 4D protein, which plays a role in suppressing the immune response; by inhibiting this protein, Pepinemab can potentially enhance immune activity against cancer. Together, these drugs aim to boost the body's natural defenses to fight the cancer more effectively than existing options.

What evidence suggests that this trial's treatments could be effective for pancreatic cancer?

Research shows that using Pepinemab with Avelumab might help treat pancreatic cancer. In this trial, all participants will receive both Avelumab and Pepinemab. Studies suggest that Pepinemab can make cancer cells more responsive to treatments like Avelumab, enabling the immune system to attack the cancer more effectively. Additionally, Pepinemab blocks a protein called SEMA4D, which aids immune cells in entering and fighting the tumor. Early results are promising, indicating that this combination could improve treatment outcomes for pancreatic cancer. ^{1 2 3 4 6}

Who Is on the Research Team?

Daniel Mulkerin, MD

Principal Investigator

[e-mail]

Are You a Good Fit for This Trial?

Adults with metastatic pancreatic adenocarcinoma that worsened after first-line chemo can join. They need measurable disease, have had specific prior treatments, and a life expectancy of at least 3 months. Good organ function and performance status are required. Participants must agree to use contraception and consent to biopsies.

Inclusion Criteria

I have a biliary stent for obstruction.

My bone marrow and organs are functioning normally.

- Absolute neutrophil count >1,500/mcl

Exclusion Criteria

I can follow the study's schedule and requirements.

I still have side effects from previous cancer treatments.

I have had an organ or bone marrow transplant.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase 1b Treatment

Participants receive escalating doses of Avelumab and Pepinemab to determine the maximum tolerated dose (MTD)

16-24 weeks

Phase 2 Treatment

Participants receive treatment at the MTD to assess efficacy and objective response rates

24 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

10 years

What Are the Treatments Tested in This Trial?

Interventions

• Avelumab
• Pepinemab

Trial Overview The trial is testing the safety of Pepinemab combined with Avelumab in patients whose cancer progressed post-chemo. Phase 2 will check how effective this combo is against metastatic pancreatic adenocarcinoma.

How Is the Trial Designed?

Group I: Experimental Experimental Treatment 1 Intervention

Single arm, all patients serially enrolled to combination doses of Avelumab and Pepinemab

Who Is Running the Clinical Trial?

Vaccinex Inc.

Lead Sponsor

Trials

12

Recruited

740+

University of Rochester

Collaborator

Trials

883

Recruited

555,000+

Published Research Related to This Trial

In a study using mice with pancreatic tumors, the combination of anti-PD-1 and anti-OX40 antibodies significantly improved survival rates, with almost 100% of treated mice surviving for 225 days and showing no detectable tumors, compared to control groups that had poor survival.

The combination therapy not only enhanced survival but also altered the immune cell landscape in tumors, reducing suppressive T cells and increasing memory T cells, suggesting a potential mechanism for overcoming immune resistance in pancreatic ductal adenocarcinoma (PDAC).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combination of PD-1 Inhibitor and OX40 Agonist Induces Tumor Rejection and Immune Memory in Mouse Models of Pancreatic Cancer. Ma, Y., Li, J., Wang, H., et al.[2022]

In pancreatic ductal adenocarcinoma (PDAC), a significant portion of tumor-infiltrating T cells exhibit an exhausted phenotype characterized by high levels of PD-1 and TIGIT, indicating a challenging immune environment for effective therapy.

Combining anti-PD-1 and TIGIT blockade has been shown to enhance T cell activity, suggesting that this dual approach could improve immunotherapy outcomes in PDAC patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tissue-Resident Memory T Cells in Pancreatic Ductal Adenocarcinoma Coexpress PD-1 and TIGIT and Functional Inhibition Is Reversible by Dual Antibody Blockade. Pearce, H., Croft, W., Nicol, SM., et al.[2023]

Pancreatic ductal adenocarcinoma (PDAC) shows resistance to traditional immune checkpoint therapies (ICTs), but combining agonist 41BB and antagonist LAG3 ICTs can enhance survival and boost antitumor immunity by improving T cell activity and reducing immunosuppressive cells.

The most effective treatment strategy involved a triple therapy combining T cell-activating ICTs with a CXCR1/2 inhibitor, which led to durable complete responses in PDAC, suggesting a promising new approach for this challenging cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeting T cell checkpoints 41BB and LAG3 and myeloid cell CXCR1/CXCR2 results in antitumor immunity and durable response in pancreatic cancer. Gulhati, P., Schalck, A., Jiang, S., et al.[2023]

The combination of GVAX vaccine with nivolumab and urelumab significantly increased the number of activated CD8+ CD137+ T cells in tumors, indicating a robust immune response, and was well-tolerated by patients.

While the median disease-free and overall survival rates were numerically improved with the combination therapy compared to other treatment arms, the results were not statistically significant, suggesting that further studies are needed to confirm these promising findings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A platform trial of neoadjuvant and adjuvant antitumor vaccination alone or in combination with PD-1 antagonist and CD137 agonist antibodies in patients with resectable pancreatic adenocarcinoma. Heumann, T., Judkins, C., Li, K., et al.[2023]

Pancreatic adenocarcinomas (PDAC) are highly aggressive cancers with poor treatment responses, particularly to immunotherapies, due to a uniquely inflammatory and dysfunctional tumor microenvironment.

Research indicates that the significant heterogeneity in tumor and stromal biology of PDAC necessitates personalized and combinatorial treatment approaches to improve patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pancreatic Cancer Immuno-oncology in the Era of Precision Medicine. Hegde, S.[2022]

In a systematic review of 59 randomized controlled trials involving 41,757 patients, immune checkpoint inhibitors (ICIs) were found to be associated with a 0.93% incidence of all-grade pancreatitis and higher rates of pancreatic enzyme elevations, indicating a notable risk of pancreatic adverse events (AEs) during treatment.

The study revealed that PD-1 inhibitors carry a greater risk of pancreatic AEs compared to PD-L1 inhibitors, and patients receiving dual ICI therapy face an even higher risk than those on single ICI therapy, highlighting the need for clinician awareness regarding these potential complications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pancreatic adverse events of immune checkpoint inhibitors therapy for solid cancer patients: a systematic review and meta-analysis. Zhao, Z., Zhang, W., Pang, L., et al.[2023]

A study analyzing 70,330 adverse events reported to the FDA found that immune checkpoint inhibitors (ICIs) significantly increase the risk of gastrointestinal (GI) toxicities, particularly colitis, hepatobiliary disorders, and pancreatitis, with colitis showing the highest reporting odds ratio of 17.2.

The risk of these GI adverse events was notably higher with anti-CTLA-4 treatments compared to anti-PD-1 and anti-PD-L1 therapies, and factors such as female gender and polytherapy were identified as strong risk factors for these complications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Common Immune-Related Adverse Events of Immune Checkpoint Inhibitors in the Gastrointestinal System: A Study Based on the US Food and Drug Administration Adverse Event Reporting System. Bai, X., Jiang, S., Zhou, Y., et al.[2021]

Pancreatic ductal adenocarcinoma (PDAC) tissues showed significantly higher levels of VISTA expression compared to non-tumorous pancreatic tissues, and high VISTA levels in tumors were associated with reduced overall survival in patients.

Blocking VISTA in an orthotopic PDAC mouse model led to reduced tumor weights, suggesting that targeting VISTA could be a promising immunotherapy strategy for improving treatment outcomes in PDAC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

VISTA Ligation Reduces Antitumor T-Cell Activity in Pancreatic Cancer. Digomann, D., Strack, J., Heiduk, M., et al.[2023]

The novel immune checkpoint molecule VSIG4 is found to be overexpressed in pancreatic ductal adenocarcinoma (PDAC) and correlates with larger tumor size, liver metastasis, and poorer patient prognosis, suggesting its role as a potential biomarker for disease severity.

Knocking down VSIG4 in pancreatic cancer cells reduced their proliferation and migration, while also enhancing the recruitment of immune cells like CD8+ T cells, indicating that targeting VSIG4 could improve the effectiveness of immunotherapy in PDAC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Identification of a novel immune checkpoint molecule V-set immunoglobulin domain-containing 4 that leads to impaired immunity infiltration in pancreatic ductal adenocarcinoma. Jiang, Y., Han, L., Yang, J., et al.[2023]

Recent research indicates that human pancreatic cancer is not an immune-privileged site, as previously thought, showing significant infiltration of CD8+ T cells that express PD-1.

The presence of these immune cells suggests that targeting immune checkpoints could be a promising therapeutic approach for treating pancreatic cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The pancreatic cancer microenvironment: an immunologic battleground. Pillarisetty, VG.[2021]

In a phase I trial involving 50 patients with advanced pancreatic cancer, the combination of nivolumab, nab-paclitaxel, and gemcitabine showed a manageable safety profile, with 48 patients experiencing grade 3/4 treatment-emergent adverse events, but only one dose-limiting toxicity reported.

The treatment resulted in a median overall survival of 9.9 months and an overall response rate of 18%, indicating limited efficacy, which led to the conclusion that further investigation of this combination is not supported.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Open-label, Phase I Study of Nivolumab Combined with nab-Paclitaxel Plus Gemcitabine in Advanced Pancreatic Cancer. Wainberg, ZA., Hochster, HS., Kim, EJ., et al.[2022]

The combination of galunisertib and durvalumab was found to be tolerable with no dose-limiting toxicities, and the recommended dose for further studies was established at 150 mg of galunisertib taken twice daily alongside durvalumab.

While the treatment showed a disease control rate of 25% among 32 patients, clinical activity was limited, suggesting that this combination may be more effective if used earlier in treatment or in patients selected based on specific biomarkers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and activity of the TGFβ receptor I kinase inhibitor galunisertib plus the anti-PD-L1 antibody durvalumab in metastatic pancreatic cancer. Melisi, D., Oh, DY., Hollebecque, A., et al.[2021]

A study analyzing 2,364 cases of pancreatic adverse events (AEs) linked to immune checkpoint inhibitors (ICIs) found significant associations, particularly with ICI-associated pancreatitis and diabetes mellitus, indicating a notable risk for patients undergoing ICI treatment.

Combination therapy with ICIs showed a higher frequency of pancreatic AEs compared to monotherapy, suggesting that while the risk of these adverse events increases, the fatality rate remains lower, highlighting the importance of patient awareness regarding these potential side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pancreatic Adverse Events Associated With Immune Checkpoint Inhibitors: A Large-Scale Pharmacovigilance Analysis. Zhang, Y., Fang, Y., Wu, J., et al.[2022]

Citations

1. ascopubs.org ascopubs.org/doi/10.1200/JCO.2024.42.3_suppl.TPS712

A phase 1b/2 trial of pepinemab and avelumab as second ... Thus, we hypothesized that pepinemab may improve clinical outcomes in PDAC by sensitizing tumors to ICB. Methods: We designed a phase Ib/II ...

2. ir.vaccinex.com ir.vaccinex.com/static-files/24efca32-8eaf-40da-9fe4-7abb73550b02

Phase 1b/2 trial of pepinemab plus avelumab as second ... Preclinical and clinical studies demonstrated that antibody blockade of semaphorin 4D (SEMA4D) promotes tumoral infiltration, organization, and activation of ...

3. gatewaycr.org gatewaycr.org/for-researchers/clinical-trials/a-phase-1b-2-trial-of-immunotherapy-with-avelumab-and-pepinemab-as-second-line-treatment-for-patients-with-metastatic-pancreatic-adenocarcinoma/

A Phase 1b/2 Trial of Immunotherapy with Avelumab and ... Treatment outcomes remain dismal with a 5-year survival of 9%. The incidence of PDAC is increasing and is projected to become the second leading cause of cancer ...

4. clinicaltrials.gov clinicaltrials.gov/study/NCT05102721

NCT05102721 | Trial of Immunotherapy With Avelumab ... This trial will assess the safety and tolerability of Pepinemab in combination with Avelumab in patients with metastatic pancreatic adenocarcinoma that has ...

5. aacrjournals.org aacrjournals.org/cancerres/article/84/17_Supplement_2/A004/747510/Abstract-A004-A-Phase-1B-2-trial-of-second-line

Abstract A004: A Phase 1B/2 trial of second line ... A Phase 1B/2 trial of second line immunotherapy with pepinemab and avelumab for patients with metastatic pancreatic adenocarcinoma [abstract].

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6605872/

Product review: avelumab, an anti-PD-L1 antibody - PMC Its acceptable safety profile and ability to induce durable responses in otherwise deadly tumors provide the rationale for its use in other tumor types and in ...