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Botensilimab 50 mg IV D1 of each cycle; Balstilimab 240 mg IV on D 1, 15, and 29 of each cycle; Triplet chemo (nab-paclitaxel 125 mg/m2 + gemcitabine 1000 mg/m2 +cisplatin 25 mg/m2 IV infusion on D 1, 8, 22, and 29 of each cycle; Chloroquine phosphate (Aralen) 500 mg po (300 mg equivalent chloroquine base) on D 1, 8, 15, 22, 29, and 36 of each cycle; Celecoxib 200 mg po twice daily (BID) on D 1 through 5 of each cycle Famotidine 20 mg po BID on D 1 through 5 of each cycle Aspirin 81 mg po every day (QD) thrombotic event prevention

Botensilimab (MTD TBD) D1 of each cycle; Balstilimab 240 mg IV on D 1, 15, and 29 of each cycle; Triplet chemo (nab-paclitaxel 125 mg/m2 + gemcitabine 1000 mg/m2 +cisplatin 25 mg/m2 IV infusion on D 1, 8, 22, and 29 of each cycle; Chloroquine phosphate (Aralen) 500 mg po (300 mg equivalent chloroquine base) on D 1, 8, 15, 22, 29, and 36 of each cycle; Celecoxib 200 mg po twice daily (BID) on D 1 through 5 of each cycle Famotidine 20 mg po BID on D 1 through 5 of each cycle Aspirin 81 mg po every day (QD) thrombotic event prevention

an Fc-engineered anti-CTLA-4 (cytotoxic T-lymphocyte antigen 4) monoclonal antibody

Botensilimab

a human monoclonal immunoglobulin (Ig) G4 (IgG4) antibody, designed to block programmed cell death protein (PD-1) binding by PD-L1 and PD-L2

Balstilimab

an antimalarial agent, that is being used in this patient population to sensitize cancer cells to chemotherapy and leads to anticancer effects through inhibiting autophagy

Chloroquine Phosphate

a second-generation selective Cyclooxygenase 2 (COX-2) inhibitor, is being used in this patient population to enhance the therapeutic effect of cisplatin by inhibiting the expression of COX-2 as well as inhibit anti-apoptotic gene BCL-2 (B-cell lymphoma 2)

Clinical Trials Nurse Navigator

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

This Investigator Initiated Trial (IIT) is proposed based on our experience of obtaining high response rates with chemotherapy or chemotherapy + Programmed cell death protein 1 (PD1) checkpoint inhibitor in patients with previously untreated stage 4 pancreatic adenocarcinoma. However, investigators have hit a barrier as they have not been able to improve the complete response rate above 20% nor improve the 64% 2-year survival rate. For the most part ultimately, the patient's tumor progresses.

Pancreatic cancer relies upon unfolded protein response (UPR) to for survival. The endoplasmic reticulum has stress stressors with a variety of proteins that when activated during stress promote proteostasis and homeostasis which prevents apoptosis. While the UPR is able to achieve homeostasis, under prolonged and unresolved stress, the signaling pathway will lead to apoptosis. In pancreatic cancer, the UPR does play a role as it is upregulated to allow for greater survival. Prior cancer research has been focused on mitigating UPR in cancer through agents such as HSP90 inhibitors but this has not been successful. The hypothesis of this study is that by increasing ER stress and thus UPR that apoptosis occurs in pancreatic cancer by the use of these agents and improve the survival in individuals with advanced pancreatic cancer.

Visually it looks like this with three possibilities when tumor cells are under stress:

1. They survive
2. They go into dormancy
3. They undergo apoptosis

Investigators seek to increase ER stress (UPR) to drive that system to apoptosis. To achieve the apoptosis, the investigators seek the maximum treatment approach with maximum chemo immunotherapy to stress the tumor cells (increase of ER stress /UPR) and use 2 agents to help block escape routes a) block autophagy via chloroquine and b) block microenvironment inflammation via celecoxib.

(Part 1) Maximum Tolerated Dose (MTD) Safety Group; (Part 2) Expansion Cohort - Botensilimab MTD from Part 1

The Seven Trial: Exploiting the Unfolded Protein Response

An Open-label, Phase I Trial With Expansion Cohort of Nab-Paclitaxel + Gemcitabine + Cisplatin + Botensilimab (AGEN1811) + Balsilimab (AGEN2034) + Chloroquine + Celecoxib in Patients With Previously Untreated Metastatic Pancreatic Cancer

To evaluate the participant's self-reported quality of life during this study. Participant's self-reported quality of life and pain levels during this study utilizing the MD Anderson Symptom Inventory (MDASI-GI). This questionnaire asks about severity of symptoms using numbers (0 = not present to 10 = as bad as you can imagine).

To evaluate the participant's self-reported pain levels during this study. Participant's self-reported quality of life and pain levels during this study utilizing the Brief Pain Inventory (BPI). This form asks about severity of pain using numbers (0 = not present to 10 = as bad as you can imagine).

Doubling of levels (over baseline) of 78 KDa Glucose regulated protein (GRP78) stress response marker in plasma.

Measuring the decrease in circulating tumor deoxyribonucleic acid (ctDNA) mutational markers in patients who become minimal residual disease (MRD) negative.

To compare the survival rates based on baseline neutrophil lymphocyte ratio (NLR). NLR ≤5 versus NLR \>5.

Survival is defined as the time from enrollment to date of death.

To determine the maximum tolerated dose (MTD) of botensilimab when given in combination with balstilimab + triplet chemotherapy regimen (consisting of nab-paclitaxel + gemcitabine + cisplatin) + chloroquine + celecoxib to be used in Part 2-Dose Expansion. MTD will be defined at the dose of botensilimab at which no more than 1 of 6 evaluable patients experiences a dose-limiting toxicity (DLT).

To evaluate the safety and tolerability of botensilimab in combination with balstilimab + triplet + chloroquine + celecoxib. Treatment-related toxicities as per National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 (NCI-CTC AE V5.0).

To determine the preliminary efficacy of botensilimab at the MTD + balstilimab + triplet + chloroquine + celecoxib in patients with previously untreated metastatic pancreatic cancer. Complete Response (CR) rate as defined by CT scan using RECIST 1.1 criteria, the overall response rate (ORR), progression free survival (PFS) and overall survival (OS).

To evaluate the disease control rate (CR, PR, and SD at 12 weeks) at the MTD of botensilimab + balstilimab + triplet + chloroquine + celecoxib in patients with previously untreated metastatic pancreatic cancer. Disease control rate (CR, PR, and SD at 12 weeks) using RECIST 1.1 criteria.

To evaluate the change in carbohydrate antigen 19-9 (CA 19-9) (or cancer antigen 125 \[CA 125\], or carcinoembryonic antigen \[CEA\] if not expressers of CA 19-9) in this patient population. Change from start of treatment CA 19-9 (or CA 125, or CEA if not expressers of CA 19-9).

Rates of normalization of CA 19-9 (or CA 125, or CEA if not expressers of CA 19-9).

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
The Seven Trial: Exploiting the Unfolded Protein Response	NCT06076837	Pancreatic Canc... Pancreatic Aden...	Botensilimab Balstilimab Chloroquine Pho... Celecoxib	18 Years -	HonorHealth Research Institute
The Seven Trial: Exploiting the Unfolded Protein Response	NCT06076837	Pancreatic Canc... Pancreatic Aden...	Botensilimab Balstilimab Chloroquine Pho... Celecoxib	18 Years -	HonorHealth Research Institute

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