Immunotherapy + Chemotherapy for Pancreatic Cancer

Overseen By James Cleary, MD, PhD

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: James Cleary, MD, PhD

Must be taking: FOLFIRINOX

Must not be taking: Immunosuppressants, T-cell therapies

Disqualifiers: Autoimmune disease, HIV, Hepatitis, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: Up to 24 months

46 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to test whether a combination of immunotherapy drugs—domvanalimab, zimberelimab, and APX005M—can safely and effectively treat pancreatic cancer that has spread. Immunotherapy boosts the body's immune system to fight cancer cells. The trial will compare these drugs to a standard chemotherapy treatment called FOLFIRI. Individuals diagnosed with metastatic pancreatic cancer who have already undergone several months of first-line treatment might be suitable candidates for this study. 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.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. However, you cannot participate if you have taken certain treatments like cytotoxic chemotherapy or radiotherapy within 2 weeks before starting the study medication, or if you are on immunosuppressive agents above a certain dose.

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

Research is testing the safety of combining three treatments—domvanalimab, zimberelimab, and APX005M—for people with cancer. These treatments are a type of immunotherapy, which helps the body's immune system fight cancer cells.

Previous studies have shown that these drugs are generally well-tolerated. In research with other types of cancer, zimberelimab and domvanalimab did not cause severe side effects for most people. Common side effects included tiredness, nausea, and mild skin reactions. APX005M, when used with chemotherapy, also did not show major safety issues in earlier studies.

Since this trial is in the early stages, the main focus is on ensuring the treatment is safe for humans. Researchers closely monitor for any side effects and adjust doses if needed. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for pancreatic cancer because they combine immunotherapy and chemotherapy, which is a novel approach for this condition. Unlike the standard chemotherapy regimen FOLFIRI, which targets cancer cells directly, the combination of domvanalimab, zimberelimab, and APX005M enhances the body's immune response to fight cancer. Domvanalimab and zimberelimab are antibodies designed to block specific proteins that inhibit the immune system, potentially allowing it to attack the tumor more effectively. APX005M is another immunotherapy agent that boosts immune cell activity. This multi-faceted strategy aims to improve outcomes for patients with pancreatic cancer, a condition notoriously difficult to treat with conventional methods alone.

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

This trial will evaluate the combination of three drugs—domvanalimab, zimberelimab, and APX005M—as one of the treatment arms for pancreatic cancer. Studies have shown promising results for this combination in treating other cancers, indicating that it can help the immune system find and attack cancer cells. Specifically, one study found that patients with advanced gastroesophageal adenocarcinomas who received this treatment lived for a median of 26.7 months. Although this study focused on a different cancer type, it suggests potential benefits for similar cancers. Additionally, past studies combining APX005M with chemotherapy showed enhanced immune system attacks on pancreatic cancer cells. These findings offer hope for patients considering this treatment option. Another arm of this trial will use the FOLFIRI chemotherapy regimen, which includes leucovorin, fluorouracil, and irinotecan. Participants in the FOLFIRI arm who experience disease progression may have the option to crossover to receive the domvanalimab, zimberelimab, and APX005M combination. ^{1 3 4 5 6}

Who Is on the Research Team?

James M. Cleary

Principal Investigator

Dana-Farber Cancer Institute

Are You a Good Fit for This Trial?

This trial is for adults with metastatic pancreatic cancer who've had stable disease or better after 4-6 months of FOLFIRINOX treatment. They must have measurable disease, be willing to use contraception, and able to provide consent. Excluded are those with recent chemotherapy, certain infections (HIV/HBV/HCV), autoimmune diseases, a history of severe allergies to similar drugs, or major surgery within the last month.

Inclusion Criteria

My blood and organ functions meet the trial's required levels.

I can start Stage 2 treatment within 4 weeks after my disease worsens while on the control treatment.

I've completed 4-6 months of FOLFIRINOX treatment with no worsening of my condition.

Exclusion Criteria

I have previously received treatments that boost the immune system.

I have a known blood clotting disorder.

I haven't taken any immunosuppressive drugs in the last 14 days.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive domvanalimab, zimberelimab, and APX005M or leucovorin, fluorouracil, and irinotecan every two weeks through an infusion

Up to 24 months

Bi-weekly visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 months

Crossover

Participants in Arm B who experience disease progression may crossover to receive domvanalimab, zimberelimab, and APX005M

What Are the Treatments Tested in This Trial?

Interventions

• APX005M
• Domvanalimab (AB154)
• Zimberelimab (AB122)

Trial Overview The study tests combining domvanalimab (AB154), zimberelimab (AB122), and APX005M as immunotherapy treatments for advanced pancreatic cancer. It aims to see if these drugs can safely enhance the body's immune response against cancer cells.

How Is the Trial Designed?

Group I: LEAD-IN: DOSE DE-ESCALATION Experimental Treatment 3 Interventions

The lead-in dose de-escalation cohort (Phase 1b) will enroll 6 patients (up to 12 patients in 2 dose levels if needed; 6 patients per DL) to receive zimberelimab, domvanalimab, and APX005M

Group II: CROSSOVER: ZIMBERELIMAB + DOMVANALIMAB + APX005M Experimental Treatment 3 Interventions

Participants in Arm B (control arm) who experience disease progression (as defined by RECIST v1.1) will be given the option to crossover and receive domvanalimab + zimberelimab, + APX005M in the second-line setting, provided they meet eligibility criteria

Group III: ARM A: ZIMBERELIMAB + DOMVANALIMAB + APX005M Experimental Treatment 3 Interventions

Participants will be randomly assigned to one of two groups Arm A will receive domvanalimab, zimberelimab, and APX005M every two weeks through an infusion.

Group IV: ARM B: FOLFIRI Active Control 1 Intervention

Arm B will receive leucovorin, fluorouracil, and irinotecan every two weeks through an infusion

Who Is Running the Clinical Trial?

James Cleary, MD, PhD

Lead Sponsor

Trials

2

Recruited

50+

Lustgarten Foundation

Collaborator

Trials

27

Recruited

5,500+

Arcus Biosciences, Inc.

Industry Sponsor

Trials

44

Recruited

7,500+

Published Research Related to This Trial

In a study of 170 patients with locally recurrent pancreatic cancer, those receiving stereotactic body radiation therapy combined with pembrolizumab and trametinib (SBRT + K + M) had a median overall survival of 17.2 months when they had both PD-L1 positivity and tumor-infiltrating lymphocytes (TIL+), indicating a potential benefit of this combination therapy.

The study suggests that PD-L1, TILs, and mutant KRAS could serve as biomarkers to optimize treatment strategies for pancreatic cancer, particularly when combining immunotherapy with targeted therapies like MEK inhibitors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immune profiling of pancreatic cancer for radiotherapy with immunotherapy and targeted therapy: Biomarker analysis of a randomized phase 2 trial. Zhu, X., Liu, W., Cao, Y., et al.[2023]

In a study involving 153 patients with advanced pancreatic cancer, the FAM-S chemotherapy regimen showed a response rate of only 11%, indicating limited effectiveness against this type of cancer.

The Phase II agents tested (MGBG, DHAD, and AZQ) also demonstrated poor response rates, with MGBG showing a 6% response, while DHAD and AZQ had no responses, suggesting that new treatment options are needed for pancreatic cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evaluation of combination chemotherapy and phase II agents in pancreatic adenocarcinoma. A Southwest Oncology Group study. Bukowski, RM., Fleming, TR., Macdonald, JS., et al.[2019]

The combination of APX005M (sotigalimab) with gemcitabine and nab-paclitaxel, with or without nivolumab, was found to be tolerable in patients with metastatic pancreatic adenocarcinoma, with a recommended phase 2 dose of 0.3 mg/kg for APX005M established during the study.

Clinical activity was observed, with 58% of patients showing responses, suggesting that this treatment regimen could potentially replace the current chemotherapy-only standard of care for this aggressive cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CD40 agonistic monoclonal antibody APX005M (sotigalimab) and chemotherapy, with or without nivolumab, for the treatment of metastatic pancreatic adenocarcinoma: an open-label, multicentre, phase 1b study. O'Hara, MH., O'Reilly, EM., Varadhachary, G., et al.[2022]

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]

Immunotherapy shows promise in treating pancreatic cancer by activating T cells to target tumor-specific antigens, which is crucial since conventional therapies have limited effectiveness.

Preclinical studies suggest that combining immunotherapy with chemotherapy or targeted therapy may enhance treatment outcomes, leading to ongoing trials focused on finding effective and less toxic treatment combinations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immunotherapy for pancreatic cancer. Kotteas, E., Saif, MW., Syrigos, K.[2023]

In the NIVACOR trial, a phase II study involving 10 patients with metastatic colorectal cancer, the combination of nivolumab with FOLFOXIRI/bevacizumab was found to be well tolerated, with no treatment-related deaths reported.

While 70% of patients experienced adverse events primarily related to the chemotherapy regimen, the overall toxicity profile was considered acceptable, indicating potential for further investigation in this treatment approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FOLFOXIRI/Bevacizumab Plus Nivolumab as First-Line Treatment in Metastatic Colorectal Cancer RAS/BRAF Mutated: Safety Run-In of Phase II NIVACOR Trial. Damato, A., Bergamo, F., Antonuzzo, L., et al.[2022]

In a study of 49 patients with advanced pancreatic cancer, dendritic cell-based immunotherapy combined with chemotherapy (gemcitabine and/or S-1) showed promising results, with 2 patients achieving complete remission and a median survival of 360 days.

The treatment was found to be safe, as none of the patients experienced severe adverse events (grade 3 or worse), indicating a favorable safety profile for this combination therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical and immunologic evaluation of dendritic cell-based immunotherapy in combination with gemcitabine and/or S-1 in patients with advanced pancreatic carcinoma. Kimura, Y., Tsukada, J., Tomoda, T., et al.[2022]

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]

In a phase II study involving 44 patients with gemcitabine-refractory pancreatic cancer, FOLFOX4 demonstrated an objective response rate of 11.4% and a tumor stabilization rate of 40.9%, indicating its potential efficacy as a rescue therapy.

FOLFOX4 was generally well-tolerated, but significant hematologic toxicities were observed, including grade 3 or 4 neutropenia in 43.2% of patients, highlighting the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Folfox4 as a rescue chemotherapy for gemcitabine-refractory pancreatic cancer. Chung, JW., Jang, HW., Chung, MJ., et al.[2022]

Citations

1. investors.arcusbio.com investors.arcusbio.com/investors-and-media/press-releases/press-release-details/2025/Anti-TIGIT-Domvanalimab-Plus-Anti-PD-1-Zimberelimab-and-Chemotherapy-Showed-26-7-Months-of-Median-Overall-Survival-as-First-Line-Treatment-of-Unresectable-or-Advanced-Gastroesophageal-Adenocarcinomas-in-the-Phase-2-EDGE-Gastric-Study/default.aspx

Anti-TIGIT Domvanalimab Plus Anti-PD-1 Zimberelimab ... Anti-TIGIT Domvanalimab Plus Anti-PD-1 Zimberelimab and Chemotherapy Showed 26.7 Months of Median Overall Survival as First-Line Treatment of ...

2. withpower.com withpower.com/trial/phase-2-pancreatic-neoplasms-10-2022-9b8ba

Immunotherapy + Chemotherapy for Pancreatic Cancer Research shows that combining APX005M (a type of immunotherapy) with chemotherapy can help the body's immune system attack pancreatic cancer cells, leading to ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT04791839

Study Details | NCT04791839 | Safety and Efficacy of ... Safety and Efficacy of Zimberelimab (AB122) in Combination With Domvanalimab (AB154) ... domvanalimab, etrumadenant, or other agents used in the study ...

4. clinicaltrials.eu clinicaltrials.eu/inn/zimberelimab/

ZIMBERELIMAB: A Promising Immunotherapy Drug Zimberelimab is an innovative immunotherapy drug currently being studied in clinical trials for the treatment of various types of cancer.

5. dana-farber.org dana-farber.org/clinical-trials/22-141

Phase Ib Open-Label, Multicenter, Study Evaluating the ... This study is being done to test the safety and effectiveness of combining domvanalimab (AB154), zimberelimab (AB122), and APX005M with pancreatic cancer ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT05419479

NCT05419479 | Switch Maintenance in Pancreatic This study is being done to test the safety and effectiveness of combining domvanalimab (AB154), zimberelimab (AB122), and APX005M with pancreatic cancer ...