Combination Therapy for Pancreatic Cancer

(AIRPanc Trial)

Recruiting at 4 trial locations

Overseen By Research Nurse Navigator

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Gulam Manji

Must be taking: mFOLFIRINOX

Must not be taking: Immune checkpoint inhibitors

Disqualifiers: Autoimmune disease, HIV, Hepatitis B, others

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

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 4

Duration: 7 weeks

60 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new approach to treating pancreatic cancer by combining standard radiation therapy with drugs that boost the immune system against cancer cells. The trial explores different drug combinations, such as zimberelimab (an immunotherapy drug), quemliclustat, and etrumadenant, to determine if they enhance the effectiveness of radiation before surgery. The goal is to assess the safety of these treatments and their ability to help the immune system fight cancer more effectively. Individuals with pancreatic cancer who have completed certain chemotherapy cycles and are ready for surgery might be suitable candidates for this trial. As a Phase 2 trial, this research focuses on measuring the treatment's effectiveness in an initial, smaller group of participants.

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.

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

Studies have shown that using zimberelimab and quemliclustat together is generally safe and well-tolerated. In the ARC-8 study, patients with advanced pancreatic cancer received these drugs with chemotherapy. The results indicated that adding quemliclustat and zimberelimab did not cause significantly more side effects than chemotherapy alone.

For the combination of zimberelimab, quemliclustat, and etrumadenant, earlier research on similar drug combinations also suggests safety. While specific side effects weren't detailed, the trials did not report any severe unexpected problems, indicating that patients generally tolerate these drug combinations well.

The current trial is in Phase 2. By this stage, treatments have already passed initial safety tests, meaning any major safety concerns have likely been addressed. However, like any treatment, side effects can still occur, and this trial will help researchers understand them better. ^{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 utilize a combination of innovative immunotherapy agents. Zimberelimab (AB122) is an immune checkpoint inhibitor that targets PD-1, helping the immune system recognize and attack cancer cells more effectively. When combined with quemliclustat (AB680), which inhibits the CD73 enzyme, and etrumadenant (AB928), an adenosine receptor antagonist, these drugs work together to enhance the body's immune response against tumors. Unlike standard chemotherapy options like FOLFIRINOX, this combination aims to improve outcomes by leveraging the body's own defenses to combat cancer, offering a potentially more targeted and less toxic approach.

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

In this trial, participants will receive different combinations of treatments to evaluate their effectiveness against pancreatic cancer. Research has shown that zimberelimab, one of the treatments in this trial, has promising results in treating various types of cancer. For example, in one study, patients with advanced gastroesophageal cancer lived for a median of 26.7 months when zimberelimab was combined with chemotherapy. Quemliclustat, another drug being tested, also shows potential. Specifically, in a study, patients with pancreatic cancer lived for a median of 15.7 months when treated with quemliclustat, which is encouraging. Etrumadenant, also part of this trial, targets a specific pathway that helps tumors evade the immune system. Early studies suggest it could enhance the immune system's ability to fight cancer. Together, these treatments aim to strengthen the body's natural defenses to combat cancer more effectively. ^{6 7 8 9 10}

Who Is on the Research Team?

Gulam A. Manji

Principal Investigator

Columbia University

Are You a Good Fit for This Trial?

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.

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

• Etrumadenant
• Modified FOLFIRINOX
• Quemliclustat
• Stereotactic Body Radiotherapy (SBRT)
• Zimberelimab

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

Citations

1. clinicaltrialsarena.com clinicaltrialsarena.com/comment/arcus-phase-ib-ii-etrumadenant-has-intriguing-mechanism-for-1l-pancreatic-cancer/

Arcus' Phase Ib/II etrumadenant has intriguing mechanism ... Arcus Biosciences' Phase Ib/II adenosine receptor antagonist AB928 has a logical mechanism in first-line pancreatic ductal adenocarcinoma.

2. ascopubs.org ascopubs.org/doi/10.1200/JCO.2021.39.3_suppl.TPS150

ARC-9: Phase Ib/II study to evaluate etrumadenant (AB928) ARC-9 is a phase 1b/2, multicohort, open-label, randomized platform study designed to evaluate safety and clinical activity of etrumadenant (150 mg orally once ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9726885/

Impact of the selective A2AR and A2BR dual antagonist ... Conclusions. Together our results suggest that combination therapy with AB928 represents a promising approach to improve adoptive cell therapy. Subject terms: ...

4. investors.arcusbio.com investors.arcusbio.com/investors-and-media/press-releases/press-release-details/2021/Arcus-Biosciences-Presents-Updated-Data-for-Etrumadenant-in-Third-Line-Metastatic-Colorectal-Cancer-and-New-Data-on-its-HIF-2-Program-at-the-AACR-2021-Annual-Meeting/default.aspx

Press Release Details - Investors & Media - Arcus Biosciences Phase 1/1b results for the etrumadenant combination demonstrated a 4.2 month PFS, approximately double the 2 months reported for current ...

5. onclive.com onclive.com/view/dr-cecchini-on-etrumadenant-based-combinations-in-previously-treated-mcrc

Dr Cecchini on Etrumadenant-Based Combinations in ... Michael Cecchini, MD, discusses findings from the ARC-9 trial investigating an etrumadenant-based combination in patients with previously treated mCRC.

6. clinicaltrials.gov clinicaltrials.gov/study/NCT04104672

A Study to Evaluate the Safety and Tolerability of AB680 ... Participants with advanced pancreatic cancer naïve to any prior treatment will receive AB680 combined with zimberelimab and NP-Gem chemotherapy regimen.

7. ascopubs.org ascopubs.org/doi/10.1200/JCO.2024.42.3_suppl.665

ARC-8: Phase 1/1b randomized study of quemliclustat + ... Results from ARC-8 demonstrate the addition of Q 100 mg ± Z to G/nP was safe and tolerable, with no significant added toxicity to GnP.

8. investors.arcusbio.com investors.arcusbio.com/investors-and-media/press-releases/press-release-details/2024/Data-from-a-Phase-1b-Study-of-Quemliclustat-Based-Regimens-Showed-Promising-Overall-Survival-in-Treatment-Nave-Metastatic-Pancreatic-Cancer/default.aspx

Data from a Phase 1b Study of Quemliclustat-Based ... Median Overall Survival was 15.7 months for all patients treated with 100 mg quemliclustat-based regimens in the ARC-8 study, which exceeds ...

9. asco.org asco.org/abstracts-presentations/ABSTRACT321257

Phase I/Ib study to evaluate safety and tolerability of AB680 ... ARC-8: Phase I/Ib study to evaluate safety and tolerability of AB680 + chemotherapy + zimberelimab (AB122) in patients with treatment-naive metastatic ...

10. uclahealth.org uclahealth.org/clinical-trials/zimberelimab-and-quemliclustat-combination-with-chemotherapy

Zimberelimab and Quemliclustat in Combination With ... This phase I/II study tests how well zimberelimab and quemliclustat work in combination with chemotherapy (mFOLFIRINOX) in treating patients pancreatic ...