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
Overview
- Phase
- Phase 1
- Intervention
- Botensilimab
- Conditions
- Pancreatic Cancer Metastatic
- Sponsor
- HonorHealth Research Institute
- Enrollment
- 6
- Locations
- 1
- Primary Endpoint
- Maximum Tolerated Dose (MTD)
- Status
- Active, Not Recruiting
- Last Updated
- 3 months ago
Overview
Brief 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.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Voluntarily agree to participate by giving signed, dated, and written informed consent prior to any study-specific procedures.
- •≥ 18 years of age.
- •Histologically confirmed diagnosis of metastatic pancreatic ductal adenocarcinoma.
- •Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 (Appendix A).
- •Life expectancy of at least 3 months.
- •Measurable disease on baseline imaging per RECIST 1.1 criteria.
- •\< Grade 2 pre-existing peripheral neuropathy per NCI CTCAE, Version 5.
- •Acceptable coagulation status as indicated by an international normalized ratio (INR)
- •1.5 times institutional upper limit of normal (ULN), except patients on anticoagulation who can be included at the discretion of the investigator.
- •Adequate organ function defined as the following laboratory values within 7 days prior to first dose of study drugs, except where noted below:
Exclusion Criteria
- •Patients must have received no previous radiotherapy, surgery, chemotherapy, or investigational therapy for the treatment of metastatic disease. Prior treatments in the adjuvant setting with gemcitabine and/or 5-Fluorouracil (5-FU) or gemcitabine administered as a radiation sensitizer are allowed, provided at least 6 months have elapsed since completion of the last dose and development of metastatic disease and no lingering toxicities are present.
- •History of central nervous system (CNS) metastasis.
- •Concurrent malignancy (present during screening) requiring treatment or history of prior malignancy active within 2 years prior to the first dose of study drugs (i.e., patients with a history of prior malignancy are eligible if treatment was completed at least 2 years prior to first dose of study drugs and the patient has no evidence of disease). Patients with history of prior early-stage basal/squamous cell skin cancer or noninvasive or in situ cancers who have undergone definitive treatment at any time are also eligible.
- •QTc Derived From Fridericia's Formula (QTcf) \> 450 ms on electrocardiogram (ECG)
- •Uncontrolled intercurrent illness, including but not limited to clinically significant (i.e., active) cardiovascular disease: cerebral vascular accident/stroke or myocardial infarction within 6 months of enrollment, unstable angina, congestive heart failure (New York Heart Association class ≥ III), or serious uncontrolled cardiac arrhythmia requiring medication. Patients with history of coronary bypass procedure are ineligible.
- •Active, uncontrolled infections, requiring systemic intravenous anti-infective treatment within 2 weeks prior to first dose of study drugs.
- •Major surgery within 4 weeks prior to signing of informed consent form (ICF).
- •Prior treatment with an immune checkpoint inhibitor.
- •Refractory ascites defined as requiring 2 or more therapeutic paracenteses within the last 4 weeks or ≥ 4 within the last 90 days or ≥ 1 time within the last 2 weeks prior to signing of ICF or requiring diuretics intended to treat ascites within 2 weeks of signing of ICF.
- •Partial or complete bowel obstruction within the last 3 months prior to signing of ICF, signs/symptoms of bowel obstruction, or known radiologic evidence of impending obstruction.
Arms & Interventions
DoseEscalationBotensilimab+balstilimab+nab-paclitaxel+gemcitabine+cisplatin +chloroquine + celecoxib
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
Intervention: Botensilimab
DoseEscalationBotensilimab+balstilimab+nab-paclitaxel+gemcitabine+cisplatin +chloroquine + celecoxib
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
Intervention: Balstilimab
DoseEscalationBotensilimab+balstilimab+nab-paclitaxel+gemcitabine+cisplatin +chloroquine + celecoxib
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
Intervention: Chloroquine Phosphate
DoseEscalationBotensilimab+balstilimab+nab-paclitaxel+gemcitabine+cisplatin +chloroquine + celecoxib
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
Intervention: Celecoxib
DoseEscalationBotensilimab+balstilimab+nab-paclitaxel+gemcitabine+cisplatin +chloroquine + celecoxib
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
Intervention: Nab paclitaxel
DoseEscalationBotensilimab+balstilimab+nab-paclitaxel+gemcitabine+cisplatin +chloroquine + celecoxib
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
Intervention: Gemcitabine
DoseEscalationBotensilimab+balstilimab+nab-paclitaxel+gemcitabine+cisplatin +chloroquine + celecoxib
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
Intervention: Cisplatin
Expansion Cohort-Botensilimab+balstilimab+nab-paclitaxel+gemcitabine+cisplatin+chloroquine+celecoxib
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
Intervention: Botensilimab
Expansion Cohort-Botensilimab+balstilimab+nab-paclitaxel+gemcitabine+cisplatin+chloroquine+celecoxib
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
Intervention: Balstilimab
Expansion Cohort-Botensilimab+balstilimab+nab-paclitaxel+gemcitabine+cisplatin+chloroquine+celecoxib
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
Intervention: Chloroquine Phosphate
Expansion Cohort-Botensilimab+balstilimab+nab-paclitaxel+gemcitabine+cisplatin+chloroquine+celecoxib
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
Intervention: Celecoxib
Expansion Cohort-Botensilimab+balstilimab+nab-paclitaxel+gemcitabine+cisplatin+chloroquine+celecoxib
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
Intervention: Nab paclitaxel
Expansion Cohort-Botensilimab+balstilimab+nab-paclitaxel+gemcitabine+cisplatin+chloroquine+celecoxib
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
Intervention: Gemcitabine
Expansion Cohort-Botensilimab+balstilimab+nab-paclitaxel+gemcitabine+cisplatin+chloroquine+celecoxib
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
Intervention: Cisplatin
Outcomes
Primary Outcomes
Maximum Tolerated Dose (MTD)
Time Frame: 12 months
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).
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).
Time Frame: End of Study (up to 2 years)
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).
Secondary Outcomes
- Complete Response (CR)(End of Study (up to 2 years))
- Overall Response Rate (ORR)(End of Study (up to 2 years))
- Progression free survival (PFS)(End of Study (up to 2 years))
- Overall Survival (OS)(End of Study (up to 2 years))
- Disease Control Rate (CR), Partial Response (PR), and Stable Disease (SD)(12 Weeks)
- CA 19-9 (or CA 125, or CEA if not expressers of CA 19-9)(End of Study (up to 2 years))