Trial Title:
The Seven Trial: Exploiting the Unfolded Protein Response
NCT ID:
NCT06076837
Condition:
Pancreatic Cancer Metastatic
Pancreatic Adenocarcinoma Metastatic
Conditions: Official terms:
Pancreatic Neoplasms
Chloroquine
Chloroquine diphosphate
Celecoxib
Study type:
Interventional
Study phase:
Phase 1
Overall status:
Not yet recruiting
Study design:
Allocation:
Non-Randomized
Intervention model:
Sequential Assignment
Intervention model description:
(Part 1) Maximum Tolerated Dose (MTD) Safety Group; (Part 2) Expansion Cohort -
Botensilimab MTD from Part 1
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
Botensilimab
Description:
an Fc-engineered anti-CTLA-4 (cytotoxic T-lymphocyte antigen 4) monoclonal antibody
Arm group label:
Dose Escalation - Botensilimab + balstilimab + triplet chemotherapy + chloroquine + celecoxib
Arm group label:
Expansion Cohort - Botensilimab + balstilimab i+ triplet chemotherapy + chloroquine + celecoxib
Other name:
AGEN1811
Intervention type:
Drug
Intervention name:
Balstilimab
Description:
a human monoclonal immunoglobulin (Ig) G4 (IgG4) antibody, designed to block programmed
cell death protein (PD-1) binding by PD-L1 and PD-L2
Arm group label:
Dose Escalation - Botensilimab + balstilimab + triplet chemotherapy + chloroquine + celecoxib
Arm group label:
Expansion Cohort - Botensilimab + balstilimab i+ triplet chemotherapy + chloroquine + celecoxib
Other name:
AGEN2034
Intervention type:
Drug
Intervention name:
Chloroquine Phosphate
Description:
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
Arm group label:
Dose Escalation - Botensilimab + balstilimab + triplet chemotherapy + chloroquine + celecoxib
Arm group label:
Expansion Cohort - Botensilimab + balstilimab i+ triplet chemotherapy + chloroquine + celecoxib
Other name:
Aralen
Intervention type:
Drug
Intervention name:
Celecoxib
Description:
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)
Arm group label:
Dose Escalation - Botensilimab + balstilimab + triplet chemotherapy + chloroquine + celecoxib
Arm group label:
Expansion Cohort - Botensilimab + balstilimab i+ triplet chemotherapy + chloroquine + celecoxib
Other name:
Celebrex
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.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
1. Voluntarily agree to participate by giving signed, dated, and written informed
consent prior to any study-specific procedures.
2. ≥ 18 years of age.
3. Histologically confirmed diagnosis of metastatic pancreatic ductal adenocarcinoma.
4. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 (Appendix A).
5. Life expectancy of at least 3 months.
6. Measurable disease on baseline imaging per RECIST 1.1 criteria.
7. < Grade 2 pre-existing peripheral neuropathy per NCI CTCAE, Version 5.0.
8. 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.
9. Adequate organ function defined as the following laboratory values within 7 days
prior to first dose of study drugs, except where noted below:
1. Neutrophils > 1500/μL (stable off any growth factor within 4 weeks prior to
first dose of study drugs).
2. Platelets > 100 × 103/μL (transfusion to achieve this level is not permitted
within 2 weeks prior to first dose of study drugs).
3. Hemoglobin > 9.0 g/dL (transfusion to achieve this level is not permitted
within 2 weeks prior to first dose of study drugs).
4. Creatinine of < 1.5mg/dL or Creatinine clearance ≥ 45 mL/min (measured or
calculated per institutional standards).
5. Aspartate aminotransferase (AST)/ alanine aminotransferase (ALT) < 3.0 × ULN.
6. Total bilirubin < 1.25 × ULN (except patients with Gilbert syndrome who must
have a total bilirubin level of < 3.0 × ULN).
7. Serum albumin ≥ 3.0 g/dL (must be confirmed within 3 days prior to first dose
of study drugs).
10. Female patients of childbearing potential (WOCBP) must have a negative urine or
serum pregnancy test at screening (within 72 hours of first dose of study drugs).
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). Highly
effective contraception is defined in Appendix B, Guidance on Contraception, or as
stipulated in national or local guidelines. Non-childbearing potential is defined
as:
1. ≥ 50 years of age and has not had menses for greater than 1 year.
2. Amenorrheic for ≥ 2 years without a hysterectomy and/or bilateral oophorectomy
and a follicle-stimulating hormone value in the postmenopausal range upon pre-
study (screening) evaluation.
3. Status is post hysterectomy, bilateral oophorectomy, or bilateral tubal
ligation.
11. Male patients with a female partner(s) of childbearing potential must agree to use
highly effective contraceptive measures throughout the study starting with the
screening visit through 6 months after the last dose of study drug(s) is received.
Males with pregnant partners must agree to use a condom; no additional method of
contraception is required for the pregnant partner.
12. Willing and able to comply with the requirements of the protocol.
Exclusion Criteria:
1. 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.
2. History of central nervous system (CNS) metastasis.
3. 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.
4. QTc Derived From Fridericia's Formula (QTcf) > 450 ms on electrocardiogram (ECG)
5. 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.
6. Active, uncontrolled infections, requiring systemic intravenous anti-infective
treatment within 2 weeks prior to first dose of study drugs.
7. Major surgery within 4 weeks prior to signing of informed consent form (ICF).
8. Prior treatment with an immune checkpoint inhibitor.
9. 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.
10. 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.
11. Clinically significant gastrointestinal (GI) disorders including:
1. GI perforation or unhealed ulcerations < 6 months prior to signing of ICF.
Patients must have documented evidence (e.g., upper endoscopy, colonoscopy) of
completely healed area of prior perforation or ulceration.
2. Clinically significant GI bleeding < 3 months prior to signing of informed
consent.
3. History of active Crohn's disease or ulcerative colitis.
12. Previous severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection
within 10 days for mild or asymptomatic infections or 20 days for severe/critical
illness prior to first dose of study drugs.
13. SARS-CoV-2 vaccine < 7 days prior to first dose of study drugs.
14. Known allergy or hypersensitivity to any of the study drugs or any of the study drug
excipients.
15. Symptomatic interstitial lung disease (ILD), history of ILD, or any lung disease
which may interfere with detection and management of new immune-related pulmonary t
toxicity.
16. History of allogeneic organ transplant.
17. Psychiatric or substance abuse disorders that would interfere with cooperation with
the requirements of the study.
18. Patients with a condition requiring systemic treatment with either corticosteroids
(> 10 mg daily prednisone equivalent) within 14 days or another immunosuppressive
medication within 30 days prior to the first dose of study drugs. Inhaled or topical
steroids, and adrenal replacement steroid doses (≤ 10 mg daily prednisone
equivalent), are permitted in the absence of active autoimmune disease.
19. Active autoimmune disease or history of autoimmune disease that required systemic
treatment within 2 years prior to first dose of study drugs (i.e., with use of
disease- modifying agents or immunosuppressive drugs).
20. Pregnant or breastfeeding patients.
21. Uncontrolled infection with HIV. Patients on stable highly active antiretroviral
therapy ( (HAART) therapy with undetectable viral load and normal CD4 (Cluster of
differentiation 4) counts for at least 6 months prior to signing ICF. Serological
testing for HIV at screening is to be performed at the investigator's discretion
based on individual patient's risk factors.
22. Known to be positive for hepatitis B (HBV) surface antigen, or any other positive
test for HBV indicating acute or chronic infection. Patients who are or have
received anti-HBV therapy are eligible, permitting they have undetectable HBV DNA
for at least 6 months prior to signing ICF. Serological testing for HBV at screening
is to be performed at the investigator's discretion based on the individual
patient's risk factors.
23. Known active hepatitis C (HCV) as determined by positive serology and confirmed by
polymerase chain reaction (PCR). Patients on or having received antiretroviral
therapy are eligible provided they are virus-free by PCR for at least 6 months prior
to signing ICF. Serological testing for HCV at screening is to be performed at the
investigator's discretion based on individual patient's risk factors.
24. Dependence on total parenteral nutrition.
25. Patients with concurrent diarrhea > grade 1 at time of enrollment despite optimal
treatment with standard of care pancreatic enzymes.
26. Known active or latent tuberculosis (testing at screening not required).
27. Any condition in the opinion of the principal investigator that might interfere with
the patient's participation in the study or in the evaluation of the study results.
28. Unwillingness or inability to comply with procedures required in this protocol.
29. History of coronary artery bypass graft.
30. Patients receiving warfarin or digoxin.
31. Presence of retinal or visual field changes of any etiology. Note: An
ophthalmological examination to be performed within the 3 weeks of starting
Chloroquine (C1/D1) to include: best corrected distance visual acuity (BCVA), an
automated threshold visual field (VF) of the central 10 degrees (with retesting if
an abnormality is noted), and spectral domain optical coherence tomography (SD-OCT).
All of these parameters should be within normal parameters.
32. Known hypersensitivity to 4-aminoquinoline compounds (chloroquine,
hydroxychloroquine, and amodiaquine).
33. Glucose-6-phosphate dehydrogenase (G6PD) deficiency.
34. History of asthma, urticaria, or other allergic-type reactions after taking aspirin
or other NSAIDs.
35. Patients who have demonstrated allergic-type reactions to sulfonamides.
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
Clinical Trials Nurse Navigator
Address:
City:
Scottsdale
Zip:
85258
Country:
United States
Start date:
December 2023
Completion date:
December 2025
Lead sponsor:
Agency:
HonorHealth Research Institute
Agency class:
Other
Collaborator:
Agency:
Translational Genomics Research Institute
Agency class:
Other
Collaborator:
Agency:
University of Arizona
Agency class:
Other
Collaborator:
Agency:
Agenus Inc.
Agency class:
Industry
Source:
HonorHealth Research Institute
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT06076837
