Immune-Based Therapies + Chemotherapy for Pancreatic Cancer

Overseen By Clinical Trials Nurse Navigator

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: HonorHealth Research Institute

Must not be taking: Warfarin, Digoxin

Disqualifiers: CNS metastasis, Active infections, Autoimmune disease, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 12 months

18 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, patients receiving warfarin or digoxin are excluded, and those on certain immunosuppressive medications or corticosteroids may need to adjust their treatment. It's best to discuss your specific medications with the trial team.

What data supports the effectiveness of the drug combination including Balstilimab, AGEN1884, Botensilimab, AGEN1181, Celecoxib, Celebrex, and Chloroquine Phosphate for pancreatic cancer?

Research suggests that combining immune-based therapies with chemotherapy, like the combination of ipilimumab and gemcitabine, may help overcome the resistance of pancreatic cancer to treatment by targeting the tumor's protective environment. ^{1 2 3 4 5}

What safety data exists for immune-based therapies like Balstilimab and Botensilimab in humans?

Immune checkpoint inhibitors, which include drugs like Balstilimab and Botensilimab, have been linked to pancreatic side effects, although the specific details of these effects are not fully understood. Older adults may experience different side effects from these treatments, but they are often not well-represented in clinical trials, making it hard to assess safety for this group. ^{1 6 7 8 9}

What makes the drug Balstilimab and Botensilimab unique for pancreatic cancer?

Balstilimab and Botensilimab are unique because they combine immune-based therapies with chemotherapy, potentially overcoming the resistance seen in pancreatic cancer due to its protective tumor environment. This approach aims to enhance the body's immune response against the cancer, which is different from traditional treatments that often rely solely on chemotherapy. ^{1 4 10 11 12}

What is the purpose of this trial?

The goal of this investigator initiated interventional study is to improve the response to the anticancer treatments (chemotherapy) in people who have previously untreated metastatic pancreas cancer. The main question it aims to answer is: • Do new types of immune-based therapies, called botensilimab, and balstilimab, when given in combination with chemotherapy consisting of nab-paclitaxel + gemcitabine + cisplatin, and oral medications of chloroquine and celecoxib help patients with previously untreated metastatic pancreatic cancer? Participants will be administered two immune-based therapies: * Botensilimab (also referred to as AGEN1811) * Balstilimab (also referred to as AGEN2034) Patients will be evaluated when given in combination with: * Triple chemotherapy (nab-paclitaxel + gemcitabine + cisplatin), plus two oral medications: * chloroquine * celecoxib

Eligibility Criteria

This trial is for adults with untreated metastatic pancreatic cancer who have a life expectancy of at least 3 months, can perform daily activities (ECOG status 0 or 1), and agree to use effective contraception. They must not have had previous cancer treatments or certain health conditions like severe allergies, recent surgeries, active infections, or other cancers within the last two years.

Inclusion Criteria

You are expected to live for at least 3 more months.

You have a visible disease that can be measured using specific criteria.

WOCBP must agree to use highly effective contraceptive measures starting with the screening visit through 6 months after the last dose of study drug(s)

Exclusion Criteria

You have had allergic reactions to sulfonamide medications.

I have had cancer spread to my brain or spinal cord.

Your heart's electrical activity, measured by ECG, shows a QTcf longer than 450 milliseconds.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive a combination of botensilimab, balstilimab, nab-paclitaxel, gemcitabine, cisplatin, chloroquine, and celecoxib to increase ER stress and drive apoptosis in tumor cells.

12 months

Follow-up

Participants are monitored for safety, tolerability, and effectiveness of the treatment, including progression-free survival and overall survival.

up to 2 years

Quality of Life Assessment

Participants' self-reported quality of life and pain levels are evaluated using the MD Anderson Symptom Inventory and Brief Pain Inventory.

up to 3 years

Treatment Details

Interventions

• Balstilimab
• Botensilimab
• Celecoxib
• Chloroquine Phosphate

Trial Overview The study tests if combining new immune therapies botensilimab and balstilimab with chemotherapy (nab-paclitaxel + gemcitabine + cisplatin) and oral drugs chloroquine and celecoxib improves treatment outcomes in metastatic pancreatic cancer patients.

Participant Groups

Group I: Expansion Cohort-Botensilimab+balstilimab+nab-paclitaxel+gemcitabine+cisplatin+chloroquine+celecoxib Experimental Treatment 7 Interventions

Botensilimab (MTD TBD), Balstilimab 240 mg IV, nab-paclitaxel 125 mg/m2 + gemcitabine 1000 mg/m2 +cisplatin 25 mg/m2 IV infusion ; Chloroquine phosphate 500 mg po (300 mg equivalent chloroquine base),Celecoxib 200 mg po twice daily (BID); Famotidine 20 mg po BID Aspirin 81 mg

Group II: DoseEscalationBotensilimab+balstilimab+nab-paclitaxel+gemcitabine+cisplatin +chloroquine + celecoxib Experimental Treatment 7 Interventions

Botensilimab 50 mg IV, Balstilimab 240 mg, nab-paclitaxel 125 mg/m2 + gemcitabine 1000 mg/m2 +cisplatin 25 mg/m2; Chloroquine phosphate 500 mg po (300 mg equivalent chloroquine base); Celecoxib 200 mg po twice daily (BID) on Famotidine 20 mg po BID Aspirin 81 mg

Who Is Running the Clinical Trial?

HonorHealth Research Institute

Lead Sponsor

Trials

26

Recruited

940+

Translational Genomics Research Institute

Collaborator

Trials

36

Recruited

107,000+

University of Arizona

Collaborator

Trials

545

Recruited

161,000+

Agenus Inc.

Industry Sponsor

Trials

58

Recruited

4,900+

Findings from Research

In a phase 3 study involving 800 patients with metastatic pancreatic cancer, ganitumab combined with gemcitabine did not improve overall survival (OS) compared to gemcitabine alone, with median OS of 7.2 months for placebo and similar results for both ganitumab doses (7.0 and 7.1 months).

The combination treatment showed manageable safety with no unexpected toxicities, but circulating biomarkers did not indicate any treatment effect on OS or progression-free survival (PFS).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase 3 randomized, double-blind, placebo-controlled trial of ganitumab or placebo in combination with gemcitabine as first-line therapy for metastatic adenocarcinoma of the pancreas: the GAMMA trial. Fuchs, CS., Azevedo, S., Okusaka, T., et al.[2022]

The combination of cediranib and olaparib did not show clinically meaningful activity in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) who do not have a known BRCA mutation, as no objective responses were observed in the study of 19 patients.

Despite some patients experiencing stable disease for a median of 3.1 months, the overall survival was only 3.4 months, indicating limited efficacy of this treatment combination in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical Activity and Safety of Cediranib and Olaparib Combination in Patients with Metastatic Pancreatic Ductal Adenocarcinoma without BRCA Mutation. Kim, JW., Cardin, DB., Vaishampayan, UN., et al.[2022]

In a phase II clinical trial involving 77 patients with advanced pancreatic cancer, the combination of the BTK inhibitor acalabrutinib and the anti-PD-1 antibody pembrolizumab was well tolerated but showed limited clinical activity, with an overall response rate of only 7.9%.

Despite the low efficacy, the treatment led to consistent reductions in myeloid-derived suppressor cells (MDSCs) in peripheral blood, suggesting a potential mechanism for improving immune response in pancreatic cancer that warrants further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomized phase II study of the Bruton tyrosine kinase inhibitor acalabrutinib, alone or with pembrolizumab in patients with advanced pancreatic cancer. Overman, M., Javle, M., Davis, RE., et al.[2023]

The combination of ipilimumab and gemcitabine was found to be safe and tolerable for treating advanced pancreatic ductal adenocarcinoma (PDAC), with a maximum tolerated dose established at ipilimumab 3 mg/kg and gemcitabine 1,000 mg/m2.

Despite the safety of the regimen, the overall response rate was only 14%, indicating that adding ipilimumab does not significantly enhance the effectiveness compared to gemcitabine alone in advanced PDAC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ipilimumab and Gemcitabine for Advanced Pancreatic Cancer: A Phase Ib Study. Kamath, SD., Kalyan, A., Kircher, S., et al.[2022]

In a study of 41 pancreas cancer patients treated with pembrolizumab, the median overall survival was 7.2 months, which is considered favorable compared to the benchmark of over 4 months.

Patients with specific genetic markers (dMMR, MSI-H, TMB-H, or Lynch syndrome) had a significantly lower risk of death, indicating that these biomarkers may help identify patients who could benefit more from pembrolizumab treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab near the end of life in patients with metastatic pancreatic cancer: a multi-site consecutive series to examine survival and patient treatment burden. Storandt, MH., Tran, N., Martin, N., 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]

A study involving 448 patients with advanced cancers showed that immune checkpoint inhibitors, like anti-PD-1 and anti-CTLA4 therapies, are safe and well tolerated across different age groups, including those aged 75 and older.

Older patients (≥75 years) experienced fewer endocrine toxicities compared to younger patients, while they had a higher incidence of dermatological toxicities, indicating that age does not significantly increase the risk of severe adverse effects from these treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of age on the toxicity of immune checkpoint inhibition. Samani, A., Zhang, S., Spiers, L., et al.[2023]

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]

In a study of 527 patients with advanced nonsmall cell lung cancer receiving PD-1 antibodies, age did not significantly affect the incidence of immune-related adverse events (irAEs) or overall survival, indicating that older patients may tolerate treatment similarly to younger ones.

However, patients aged 75 and older were more likely to have treatment interruptions due to irAEs, which correlated with lower overall survival, suggesting that while age does not affect the likelihood of irAEs, it may impact treatment continuity and outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Association of age with differences in immune related adverse events and survival of patients with advanced nonsmall cell lung cancer receiving pembrolizumab or nivolumab. Ksienski, D., Wai, ES., Croteau, NS., et al.[2021]

In a phase Ib trial involving 22 patients with metastatic pancreatic ductal adenocarcinoma, combinations of avelumab or talazoparib with binimetinib showed higher-than-expected rates of dose-limiting toxicity (DLT), particularly at the 45 mg dose, leading to dose adjustments.

Despite the safety concerns, the overall safety profiles of the combinations were consistent with those of the individual drugs, but no objective tumor responses were observed in the study.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Avelumab or talazoparib in combination with binimetinib in metastatic pancreatic ductal adenocarcinoma: dose-finding results from phase Ib of the JAVELIN PARP MEKi trial. Rodon Ahnert, J., Tan, DS., Garrido-Laguna, I., et al.[2023]

Hedgehog inhibition using IPI-926, when combined with gemcitabine, showed promising tolerance and potential effectiveness in treating pancreatic cancer, with further testing planned in a phase II trial.

The combination of gemcitabine with AZD7762 and the PI3K inhibitor BAY80-6946 both demonstrated acceptable safety profiles, indicating they may be viable options for future studies in pancreatic cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Novel agents for the treatment of pancreatic adenocarcinoma. Highlights from the "2011 ASCO Annual Meeting". Chicago, IL, USA; June 3-7, 2011. Cheng, H., Merika, E., Syrigos, KN., et al.[2011]

In a phase 1b clinical trial involving previously untreated patients with advanced pancreatic ductal adenocarcinoma (PDAC), ibrutinib monotherapy was found to enhance the immune response by increasing activated T cells and monocytes in the blood, indicating its potential to modulate the immune landscape.

However, when ibrutinib was combined with standard chemotherapy (gemcitabine and nab-paclitaxel), these beneficial immune changes were not observed, suggesting that the combination may limit the immunomodulatory effects of ibrutinib.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Modulation of myeloid and T cells in vivo by Bruton's tyrosine kinase inhibitor ibrutinib in patients with metastatic pancreatic ductal adenocarcinoma. Sinha, M., Betts, C., Zhang, L., et al.[2023]

References

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

A phase 3 randomized, double-blind, placebo-controlled trial of ganitumab or placebo in combination with gemcitabine as first-line therapy for metastatic adenocarcinoma of the pancreas: the GAMMA trial. [2022]

2. England pubmed.ncbi.nlm.nih.gov

Clinical Activity and Safety of Cediranib and Olaparib Combination in Patients with Metastatic Pancreatic Ductal Adenocarcinoma without BRCA Mutation. [2022]

3. England pubmed.ncbi.nlm.nih.gov

Randomized phase II study of the Bruton tyrosine kinase inhibitor acalabrutinib, alone or with pembrolizumab in patients with advanced pancreatic cancer. [2023]

4. England pubmed.ncbi.nlm.nih.gov

Ipilimumab and Gemcitabine for Advanced Pancreatic Cancer: A Phase Ib Study. [2022]

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

Pembrolizumab near the end of life in patients with metastatic pancreatic cancer: a multi-site consecutive series to examine survival and patient treatment burden. [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

Impact of age on the toxicity of immune checkpoint inhibition. [2023]

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. Netherlands pubmed.ncbi.nlm.nih.gov

Association of age with differences in immune related adverse events and survival of patients with advanced nonsmall cell lung cancer receiving pembrolizumab or nivolumab. [2021]

10. England pubmed.ncbi.nlm.nih.gov

Avelumab or talazoparib in combination with binimetinib in metastatic pancreatic ductal adenocarcinoma: dose-finding results from phase Ib of the JAVELIN PARP MEKi trial. [2023]

11. Italy pubmed.ncbi.nlm.nih.gov

Novel agents for the treatment of pancreatic adenocarcinoma. Highlights from the "2011 ASCO Annual Meeting". Chicago, IL, USA; June 3-7, 2011. [2011]

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

Modulation of myeloid and T cells in vivo by Bruton's tyrosine kinase inhibitor ibrutinib in patients with metastatic pancreatic ductal adenocarcinoma. [2023]