Combination Therapy for Pancreatic Cancer

(AIRPanc Trial)

Recruiting at4 trial locations

Overseen by Gulam A. Manji

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

Sponsor: Gulam Manji

Must be taking: mFOLFIRINOX

Must not be taking: Immune checkpoint inhibitors

Disqualifiers: Autoimmune disease, HIV, Hepatitis B, others

No Placebo Group

Prior Safety Data

Trial Summary

What is the purpose of this trial?

The purpose of this study is to combine standard radiation therapy with drugs that encourages the body's immune system against cancer cells and simultaneously adding drugs which also target the pathway that the tumor uses to evade the immune system (CD73 and A2a/b). The study hopes that these drugs will work in concert with radiation therapy to kill cancer cells. The specific goal of this study is to ensure that treatment with zimberelimab and stereotactic body radiation therapy (SBRT) alone or in combination with quemliclustat (a drug which blocks CD73), with or without etrumadenant (a drug which blocks the A2a/b) given before surgery is safe and if it can further increase the immune response against the tumor.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but it does mention that you cannot be on other investigational agents or anti-neoplastic agents (except hormonal therapy). It's best to discuss your current medications with the trial team to see if they are allowed.

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

Research suggests that combining immunotherapy with other treatments like chemotherapy and radiotherapy may improve outcomes in pancreatic cancer by enhancing the immune response. Although single immunotherapy drugs have been ineffective, combination therapies show promise in achieving better and more lasting results. ^{1 2 3 4 5}

Is the combination therapy for pancreatic cancer generally safe in humans?

The safety of immune checkpoint inhibitors (ICIs), which are part of the combination therapy, has been studied, and they are known to cause some immune-related side effects, including pancreatic issues. However, these side effects are manageable with proper attention and care. ^{6 7 8 9 10}

What makes the drug Zimberelimab unique for treating pancreatic cancer?

Zimberelimab is unique because it is part of a combination therapy approach that aims to enhance the immune system's response against pancreatic cancer, which is typically resistant to single immunotherapy treatments. This drug works by targeting immune checkpoints, potentially improving the effectiveness of other treatments like chemotherapy and radiotherapy. ^{1 3 5 11 12}

Research Team

Gulam A. Manji

Principal Investigator

Columbia University

Eligibility Criteria

This trial is for adults with localized pancreatic ductal adenocarcinoma who've completed 8 cycles of mFOLFIRINOX treatment, can undergo surgery and SBRT, have an ECOG status of 0 or 1, and proper organ function. Excluded are those with autoimmune diseases, uncontrolled hypercalcemia, active infections (HIV/HBV/HCV), significant liver disease, psychiatric/substance abuse issues that affect compliance, prior immune therapy use, or certain allergies.

Inclusion Criteria

I am fully active or can carry out light work.

I am cleared to receive focused radiation therapy.

You have a quantifiable malady according to the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.

Exclusion Criteria

I have previously received treatments that boost the immune system.

I have high calcium levels in my blood that require treatment.

You are not allowed to take any other experimental medications at the same time as this study.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive SBRT and zimberelimab, with or without quemliclustat and etrumadenant, for 7 weeks prior to surgery

7 weeks

4 visits (in-person)

Surgery

Participants undergo surgical resection after the treatment phase

1 week

Follow-up

Participants are monitored for safety and effectiveness after treatment

18 months

Treatment Details

Interventions

• Etrumadenant (A2a/b inhibitor)
• Modified FOLFIRINOX (Chemotherapy)
• Quemliclustat (CD73 inhibitor)
• Stereotactic Body Radiotherapy (SBRT) (Radiation)
• Zimberelimab (Checkpoint Inhibitor)

Trial Overview The study tests if combining standard radiation (SBRT) with zimberelimab (an immunotherapy drug) alone or alongside quemliclustat and/or etrumadenant (drugs targeting tumor evasion pathways) before surgery is safe and boosts the immune response against tumors in patients with pancreatic cancer.

Participant Groups

Group I: Arm D: SBRT, Zimberelimab with AB680 and Etrumadenant (AB928) Experimental Treatment 5 Interventions

Prior to resection: SBRT 40 Gy over 5 fractions, 240 mg IV zimberelimab (AB122) every 2 weeks for 7 weeks (4 doses) prior to surgery in combination with quemliclustat IV at the RTD every 2 weeks for 7 weeks (4 doses) and etrumadenant (AB928) PO at the RTD daily for 7 weeks prior to surgery. After resection: mFOLFIRINOX (4 cycles)

Group II: Arm C: SBRT, Zimberelimab with quemliclustat (AB680) Experimental Treatment 4 Interventions

Prior to resection: SBRT 40 Gy over 5 fractions, 240 mg IV zimberelimab (AB122) every 2 weeks for 7 weeks (4 doses) prior to surgery in combination with quemliclustat IV at the recommended therapeutic dose (RTD)every 2 weeks for 7 weeks (4 doses) prior to surgery. After resection: mFOLFIRINOX (4 cycles)

Group III: Arm A: Safety run-in Experimental Treatment 5 Interventions

Prior to resection: SBRT 40 Gy over 5 fractions, zimberelimab (AB122) 240 mg intravenously (IV) every 2 weeks for 7 weeks (4 doses), quemliclustat (AB680) 100 mg IV every 2 weeks for 7 weeks (4 doses) and etrumadenant (AB928) 150 mg PO daily for 7 weeks. After resection: mFOLFIRINOX (4 cycles)

Group IV: Arm B: SBRT with Zimberelimab (AB122) Alone (Control Arm) Active Control 3 Interventions

Prior to resection: SBRT 40 Gy over 5 fractions, 240 mg IV zimberelimab (AB122) every 2 weeks for 7 weeks (4 doses) prior to surgery. After resection: mFOLFIRINOX (4 cycles)

Who Is Running the Clinical Trial?

Gulam Manji

Lead Sponsor

Trials

5

Recruited

160+

Arcus Biosciences, Inc.

Industry Sponsor

Trials

44

Recruited

7,500+

Findings from Research

Recent advances in targeted therapy and immunotherapy show promise for treating pancreatic ductal adenocarcinoma (PDAC), which is often diagnosed at advanced stages and has limited treatment options.

Combining these new therapies may enhance treatment effectiveness and improve patient outcomes, as supported by current preclinical and clinical evidence.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Translational advances in pancreatic ductal adenocarcinoma therapy. Hosein, AN., Dougan, SK., Aguirre, AJ., et al.[2023]

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]

Despite advances in surgery and chemotherapy, pancreatic cancer prognosis has not improved significantly, highlighting the need for new treatment strategies.

Combination therapies, particularly those that include immunotherapy with chemotherapy and other agents, may enhance treatment effectiveness, especially for immunogenic subtypes of pancreatic cancer, and should be prioritized in early clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immunological combination treatment holds the key to improving survival in pancreatic cancer. Sodergren, MH., Mangal, N., Wasan, H., et al.[2021]

Current systemic therapies for pancreatic cancer offer only marginal survival benefits, highlighting the need for more effective treatment strategies.

Phase III studies of targeted therapies, such as those targeting VEGF and EGFR, have shown disappointing results, with erlotinib providing only statistically significant but clinically minimal improvements; ongoing trials are exploring new combinations and better trial designs to enhance treatment efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeted therapies for pancreatic cancer. Philip, PA.[2022]

Pancreatic cancer is difficult to treat, showing poor responses to standard therapies and low survival rates, which makes exploring new treatment options essential.

Combining immune checkpoint therapies with other treatments like chemotherapy and radiotherapy may improve the effectiveness of immunotherapy in pancreatic cancer by enhancing the body's immune response against the tumor.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immunotherapy in pancreatic cancer: Unleash its potential through novel combinations. Guo, S., Contratto, M., Miller, G., et al.[2023]

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]

Itacitinib, a selective JAK1 inhibitor, combined with nab-paclitaxel and gemcitabine, showed an acceptable safety profile and clinical activity in patients with advanced solid tumors, including pancreatic cancer, with a 24% overall response rate across various doses.

The study indicated that while itacitinib was tolerated at lower doses, treatment-related toxicities such as neutropenia and fatigue were common, leading to dose adjustments; however, the study was terminated early due to negative results from a related phase III trial.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Phase Ib/II Study of the JAK1 Inhibitor, Itacitinib, plus nab-Paclitaxel and Gemcitabine in Advanced Solid Tumors. Beatty, GL., Shahda, S., Beck, T., et al.[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 43-year-old woman with advanced pancreatic cancer experienced immune-related encephalopathy as a side effect of toripalimab combined with chemotherapy, highlighting the potential for serious neurological adverse events during treatment.

The patient's symptoms, including stuttering and MRI findings of cerebral white matter changes, resolved after stopping toripalimab and administering corticosteroids, emphasizing the importance of monitoring for rare neurological side effects in patients receiving immune checkpoint inhibitors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Stuttering as a signal of encephalopathy associated with toripalimab in a pancreatic ductal adenocarcinoma patient: a case report. He, J., Chen, X., Cheng, K., et al.[2023]

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 2012, adjuvant therapy for pancreatic adenocarcinoma primarily involves systemic therapy based on strong evidence and combined chemoradiotherapy based on less robust data.

Current research is focused on whether adding a second agent to gemcitabine or using combined chemoradiotherapy can improve overall survival, but progress in treatment effectiveness has been modest.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adjuvant therapy for pancreas adenocarcinoma. O'Reilly, EM.[2022]

Recent advancements in gene and molecular technology show promise for inhibiting pancreatic cancer development and slowing its progression, highlighting the potential for new treatment strategies.

A range of biological therapies, including signal transduction inhibitors, gene therapy, and immunotherapy, are currently being tested in clinical trials to target various aspects of pancreatic cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Emerging biological therapies for pancreatic carcinoma. Gilliam, AD., Watson, SA.[2019]

References

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

Translational advances in pancreatic ductal adenocarcinoma therapy. [2023]

2. England 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. [2021]

3. Germany pubmed.ncbi.nlm.nih.gov

Immunological combination treatment holds the key to improving survival in pancreatic cancer. [2021]

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

Targeted therapies for pancreatic cancer. [2022]

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

Immunotherapy in pancreatic cancer: Unleash its potential through novel combinations. [2023]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Pancreatic Adverse Events Associated With Immune Checkpoint Inhibitors: A Large-Scale Pharmacovigilance Analysis. [2022]

7. England pubmed.ncbi.nlm.nih.gov

A Phase Ib/II Study of the JAK1 Inhibitor, Itacitinib, plus nab-Paclitaxel and Gemcitabine in Advanced Solid Tumors. [2022]

8. Switzerland pubmed.ncbi.nlm.nih.gov

Pancreatic adverse events of immune checkpoint inhibitors therapy for solid cancer patients: a systematic review and meta-analysis. [2023]

9. England pubmed.ncbi.nlm.nih.gov

Stuttering as a signal of encephalopathy associated with toripalimab in a pancreatic ductal adenocarcinoma patient: a case report. [2023]

10. 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]

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

Adjuvant therapy for pancreas adenocarcinoma. [2022]

12. England pubmed.ncbi.nlm.nih.gov

Emerging biological therapies for pancreatic carcinoma. [2019]