NCT06076837

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

• Status: Active Not Recruiting
• Phase: Phase 1
• Study type: Interventional
• Enrollment: 6 (actual)
• Sponsor: HonorHealth Research Institute · Academic / Other
• Sex: All
• Age: 18 Years
• Healthy volunteers: Not accepted

Summary

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

Detailed description

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.

Conditions

• Pancreatic Cancer Metastatic
• Pancreatic Adenocarcinoma Metastatic

Interventions

Type	Name	Description
DRUG	Botensilimab	an Fc-engineered anti-CTLA-4 (cytotoxic T-lymphocyte antigen 4) monoclonal antibody
DRUG	Balstilimab	a human monoclonal immunoglobulin (Ig) G4 (IgG4) antibody, designed to block programmed cell death protein (PD-1) binding by PD-L1 and PD-L2
DRUG	Chloroquine Phosphate	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
DRUG	Celecoxib	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)
DRUG	Nab paclitaxel	microtubule inhibitor indicated for the treatment of Metastatic adenocarcinoma of the pancreas as first-line treatment, in combination with gemcitabine
DRUG	Gemcitabine	a nucleoside metabolic inhibitor indicated as a single agent for the treatment of pancreatic cancer
DRUG	Cisplatin	platinum-based drug indicated for the treatment of advanced cancers

Timeline

• Start date: 2025-01-09
• Primary completion: 2026-06-01
• Completion: 2026-12-01
• First posted: 2023-10-11
• Last updated: 2026-01-12

Locations

1 site across 1 country: United States

Regulatory

• FDA-regulated drug study