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

Trial Summary

What is the purpose of this trial?

This study is being done to test the safety and effectiveness of combining domvanalimab (AB154), zimberelimab (AB122), and APX005M with pancreatic cancer that has spread to other parts of body. This research study involves immunotherapy. Immunotherapy triggers the body's immune system to fight cancer cells. The names of the study drugs involved in this study are: * Domvanalimab (also known as AB154) * Zimberelimab (also known as AB122) * APX005M

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.

What data supports the effectiveness of the drug combination APX005M, Domvanalimab, and Zimberelimab 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 tumor shrinkage in animal studies. This suggests potential benefits when used with other drugs like Domvanalimab and Zimberelimab. ^{1 2 3 4 5}

What safety data exists for the combination of immunotherapy and chemotherapy in pancreatic cancer treatment?

The combination of APX005M (sotigalimab) with chemotherapy was evaluated for safety in patients with pancreatic cancer, and the study aimed to establish a safe dose for further trials. Additionally, nivolumab combined with chemotherapy was assessed for safety in advanced pancreatic cancer, indicating that these treatments have been studied for their safety profiles in humans. ^{1 2 4 6 7}

How is the drug combination of APX005M, Domvanalimab, and Zimberelimab unique for treating pancreatic cancer?

This drug combination is unique because it combines immunotherapy with chemotherapy, using APX005M to activate the immune system's T-cells to attack cancer cells, which is different from standard chemotherapy that primarily targets cancer cells directly. This approach aims to improve survival by enhancing the body's immune response against pancreatic cancer. ^{1 2 5 8 9}

Research Team

James M. Cleary

Principal Investigator

Dana-Farber Cancer Institute

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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 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]

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]

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]

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]

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]

References

1. England 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. [2022]

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

Open-label, Phase I Study of Nivolumab Combined with nab-Paclitaxel Plus Gemcitabine in Advanced Pancreatic Cancer. [2022]

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

Evaluation of combination chemotherapy and phase II agents in pancreatic adenocarcinoma. A Southwest Oncology Group study. [2019]

4. Greece pubmed.ncbi.nlm.nih.gov

Folfox4 as a rescue chemotherapy for gemcitabine-refractory pancreatic cancer. [2022]

5. Germany pubmed.ncbi.nlm.nih.gov

Immunotherapy for pancreatic cancer. [2023]

6. Switzerland 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. [2022]

7. United States 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. [2022]

8. England 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. [2023]

9. Ireland 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. [2023]