AGEN2373 in Combination with GVAX or mKRASvax for the Treatment of Patients with Stage I or II Resectable Pancreatic Ductal Adenocarcinoma
This phase I/II study tests the safety, side effects, and best dose of AGEN2373 when given together with balstilimab and either granulocyte-macrophage colony stimulating factor-secreting pancreatic tumor vaccine (GVAX) and cyclophosphamide or with mutant KRAS peptide vaccine (mKRASvax) for the treatment of patients with stage I or II pancreatic ductal adenocarcinoma (PDAC) that can be removed by surgery (resectable). AGEN2373 is an antibody that attaches to and activates a protein called CD137 found on the body’s immune cells. Activating CD137 is believed to improve the ability of the immune system to attack tumor cells. Cyclophosphamide is in a class of medications called alkylating agents. It works by damaging the cell’s deoxyribonucleic acid (DNA) and may kill tumor cells. It may also lower the body’s immune response. GVAX is a vaccine made from other patients’ pancreatic tumor cells. The pancreatic tumor cells were specially treated with radiation in the laboratory so they do not grow or divide into more cells. The cells were also changed in a laboratory to make a protein called granulocyte/macrophage colony stimulating factor (GM-CSF). GM-CSF helps to activate a person’s own immune system cells to recognize and attack their tumor cells. mKRASvax is a vaccine made of small pieces (peptides) of abnormal (mutated) KRAS protein mixed with poly-ICLC (Hiltonol). In tumor cells, this abnormal KRAS protein causes the cancer cells to grow and spread in the body. The KRAS vaccine is used to teach an individual’s immune system to recognize this abnormal protein and mount a response against the tumor cells that have this abnormal protein. Poly-ICLC is a type of compound called an adjuvant that is sometimes used in vaccines to help create a stronger immune response. Balstilimab is a monoclonal antibody that may interfere with the ability of tumor cells to grow and spread. Balstilimab works by attaching to and blocking a protein called PD-1. Antibodies that block PD-1 can potentially prevent PD-1 from shutting down the immune system, allowing immune cells to recognize and help to destroy tumor cells. Giving AGEN2373 together with balstilimab and either GVAX and cyclophosphamide or with mKRASvax may be safe, tolerable, and/or effective in treating patients with stage I or II resectable PDAC.
Inclusion Criteria
- INCLUSION FOR STUDY ENTRY: Able to provide written informed consent and can understand and agree to comply with the requirements of the study and schedule of assessments
- INCLUSION FOR STUDY ENTRY: Age >= 18 years on the day of signing the informed consent
- INCLUSION FOR STUDY ENTRY: Have a newly diagnosed, biopsy-proven adenocarcinoma of the pancreas. If the biopsy is not sufficient for diagnosis, the patient can be considered to meet eligibility if the study team agrees that clinically the patient’s tumor is suspected to be adenocarcinoma
- INCLUSION FOR STUDY ENTRY: Tumor must be deemed resectable by the study team prior to registration. Borderline resectable patients will be excluded
- INCLUSION FOR STUDY ENTRY: Agree to undergo a core biopsy of the pancreatic tumor for both research and diagnosis purposes if a prior diagnostic biopsy was not attempted
- INCLUSION FOR STUDY ENTRY: Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
- INCLUSION FOR STUDY ENTRY: White blood cells (WBC) >= 2,000/uL
- INCLUSION FOR STUDY ENTRY: Absolute neutrophil count (ANC) >= 1,000/uL
- INCLUSION FOR STUDY ENTRY: Absolute lymphocyte count (ALC) >= 500/uL
- INCLUSION FOR STUDY ENTRY: Platelets >= 100 x 10^3/uL
- INCLUSION FOR STUDY ENTRY: Hemoglobin >= 9 g/dL
- INCLUSION FOR STUDY ENTRY: Serum albumin >= 3.0 g/dL
- INCLUSION FOR STUDY ENTRY: Serum creatinine =< 1.5 x ULN or creatinine clearance (CrCl) >= 40 mL/min (if using the Cockcroft-Gault formula)
- INCLUSION FOR STUDY ENTRY: Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 3.5 x ULN
- INCLUSION FOR STUDY ENTRY: Women of childbearing potential (WOCBP) must have a negative pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin [HCG])
- INCLUSION FOR STUDY ENTRY: Agree to follow instructions for method(s) of contraception: * Women of childbearing potential (WOCBP) must agree to use highly effective contraception for the duration of the study and for 4 months after the last dose of study drug * Men who are sexually active with WOCBP must agree to use highly effective contraception for the duration of the study and for 6 months after the last dose of study drug * Women who are not of childbearing potential (i.e., who are postmenopausal or surgically sterile) as well as azoospermic men do not require contraception
- INCLUSION CRITERIA FOR STUDY CONTINUATION: Have a surgically resected (R0 or R1) American Joint Committee on Cancer (AJCC) pathologic stage I or stage II adenocarcinoma of the pancreas. Patients with an R2 resection or with intraoperative findings of metastatic disease will not be eligible for the continuation of the study (prior to study drug administration both post-operatively and post-adjuvant chemotherapy and/or radiation [prior to cycles 2 and 3])
- INCLUSION CRITERIA FOR STUDY CONTINUATION: ECOG performance status of 0-1 (prior to study drug administration both post-operatively and post-adjuvant chemotherapy and/or radiation [prior to cycles 2 and 3])
- INCLUSION CRITERIA FOR STUDY CONTINUATION: WBC >= 2000/uL (prior to study drug administration both post-operatively and post-adjuvant chemotherapy and/or radiation [prior to cycles 2 and 3])
- INCLUSION CRITERIA FOR STUDY CONTINUATION: ANC >= 1000/uL (prior to study drug administration both post-operatively and post-adjuvant chemotherapy and/or radiation [prior to cycles 2 and 3])
- INCLUSION CRITERIA FOR STUDY CONTINUATION: ALC > 500/uL (prior to study drug administration both post-operatively and post-adjuvant chemotherapy and/or radiation [prior to cycles 2 and 3])
- INCLUSION CRITERIA FOR STUDY CONTINUATION: Platelets >= 100 x10^3/uL (prior to study drug administration both post-operatively and post-adjuvant chemotherapy and/or radiation [prior to cycles 2 and 3])
- INCLUSION CRITERIA FOR STUDY CONTINUATION: Hemoglobin >= 9 g/dL (prior to study drug administration both post-operatively and post-adjuvant chemotherapy and/or radiation [prior to cycles 2 and 3])
- INCLUSION CRITERIA FOR STUDY CONTINUATION: Creatinine =< 2 mg/dL (prior to study drug administration both post-operatively and post-adjuvant chemotherapy and/or radiation [prior to cycles 2 and 3])
- INCLUSION CRITERIA FOR STUDY CONTINUATION: Total bilirubin =< 1.5 x ULN (subjects with Gilbert Syndrome can have total bilirubin =< 2.0 × ULN) (prior to study drug administration both post-operatively and post-adjuvant chemotherapy and/or radiation [prior to cycles 2 and 3])
- INCLUSION CRITERIA FOR STUDY CONTINUATION: AST and ALT =< 2 x ULN (prior to study drug administration both post-operatively and post-adjuvant chemotherapy and/or radiation [prior to cycles 2 and 3])
- INCLUSION CRITERIA FOR STUDY CONTINUATION: Alkaline phosphatase (Alk phos) =< 5 x ULN (prior to study drug administration both post-operatively and post-adjuvant chemotherapy and/or radiation [prior to cycles 2 and 3])
- INCLUSION CRITERIA FOR STUDY CONTINUATION: Women of childbearing potential (WOCBP) must have a negative pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) (prior to study drug administration both post-operatively and post-adjuvant chemotherapy and/or radiation [prior to cycles 2 and 3])
- INCLUSION CRITERIA FOR STUDY CONTINUATION: Agree to follow instructions for method(s) of contraception (prior to study drug administration both post-operatively and post-adjuvant chemotherapy and/or radiation [prior to cycles 2 and 3]): * Women of childbearing potential (WOCBP) must agree to use highly effective contraception for the duration of the study and for 4 months after the last dose of study drug * Men who are sexually active with WOCBP must agree to use highly effective contraception for the duration of the study and for 6 months after the last dose of study drug * Women who are not of childbearing potential (i.e., who are postmenopausal or surgically sterile) as well as azoospermic men do not require contraception
Exclusion Criteria
- EXCLUSION FOR STUDY ENTRY: Have received any anti-pancreatic cancer therapy (symptomatic therapies are allowed), or any prior anti-cancer immunotherapy
- EXCLUSION FOR STUDY ENTRY: Have been diagnosed with another malignancy whose natural history or treatment has the potential to interfere with safety or efficacy assessment of this study’s investigational drugs
- EXCLUSION FOR STUDY ENTRY: Any serious or uncontrolled medical or psychosocial disorder that could be exacerbated by the study treatment, impair the ability of the subject to comply with the study schedule, or interfere with interpretation of study results
- EXCLUSION FOR STUDY ENTRY: Active autoimmune disease or history of any autoimmune disease that may relapse. Patients with hypothyroidism managed with hormone replacement alone, vitiligo or psoriasis not requiring systemic treatment, and type I diabetes mellitus will be allowed
- EXCLUSION FOR STUDY ENTRY: Systemic steroid therapy (> 10mg daily prednisone equivalent) or immunosuppressive therapy within 14 days of first dose of study drug administration
- EXCLUSION FOR STUDY ENTRY: Active infection requiring systemic therapy
- EXCLUSION FOR STUDY ENTRY: Known history of human immunodeficiency virus (HIV)
- EXCLUSION FOR STUDY ENTRY: Active or chronic hepatitis B or hepatitis C (HCV antibody positive patients may be enrolled if they are confirmed to have a negative viral load at screening)
- EXCLUSION FOR STUDY ENTRY: Known active tuberculosis. Tuberculosis testing at screening is required
- EXCLUSION FOR STUDY ENTRY: History of interstitial lung disease, non-infectious pneumonitis or uncontrolled lung diseases including pulmonary fibrosis, acute lung diseases, chronic obstructive pulmonary disease (COPD), asthma requiring medication, etc
- EXCLUSION FOR STUDY ENTRY: Prior allogeneic stem cell transplantation or organ transplantation
- EXCLUSION FOR STUDY ENTRY: Any major surgical procedure requiring general anesthesia ≤ 28 days before first dose of study drug
- EXCLUSION FOR STUDY ENTRY: Received a live vaccine =< 28 days before first dose of study drug (seasonal flu vaccines are generally inactivated and are allowed. Intranasal vaccines are not allowed) or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine or booster < 7 days before cycle 1 day 1 (C1D1). For SARS-CoV-2 vaccines requiring more than 1 dose, the full series should be completed prior to C1D1, when feasible. Booster shot not required but also must be administered > 7 days from C1D1 or > 7 days from future cycle on study
- EXCLUSION FOR STUDY ENTRY: History of severe hypersensitivity reaction to any monoclonal antibody
- EXCLUSION FOR STUDY ENTRY: Concurrent participation in another therapeutic clinical study
- EXCLUSION FOR STUDY ENTRY: Pregnant or breastfeeding
- EXCLUSION CRITERIA FOR STUDY CONTINUATION: Radiographic evidence of pancreatic cancer recurrence
- EXCLUSION CRITERIA FOR STUDY CONTINUATION: Not able to start study drug within 10 weeks following the surgery (for cycle 2) or within 12 weeks following last dose of chemotherapy (for cycle 3)
- EXCLUSION CRITERIA FOR STUDY CONTINUATION: Have been diagnosed with another malignancy whose natural history or treatment has the potential to interfere with safety or efficacy assessment of this study’s investigational drugs
- EXCLUSION CRITERIA FOR STUDY CONTINUATION: Any serious or uncontrolled medical or psychosocial disorder that could be exacerbated by the study treatment, impair the ability of the subject to comply with the study schedule, or interfere with interpretation of study results
- EXCLUSION CRITERIA FOR STUDY CONTINUATION: Active autoimmune disease or history of any autoimmune disease that may relapse. Patients with hypothyroidism managed with hormone replacement alone, vitiligo or psoriasis not requiring systemic treatment, and type I diabetes mellitus will be allowed
- EXCLUSION CRITERIA FOR STUDY CONTINUATION: Systemic steroid therapy (> 10mg daily prednisone equivalent) or immunosuppressive therapy within 14 days before of first dose of study drug administration
- EXCLUSION CRITERIA FOR STUDY CONTINUATION: Active infections requiring systemic therapy
- EXCLUSION CRITERIA FOR STUDY CONTINUATION: Known history of human immunodeficiency virus (HIV)
- EXCLUSION CRITERIA FOR STUDY CONTINUATION: Active or chronic hepatitis B or hepatitis C (HCV antibody positive patients may be enrolled if they are confirmed to have a negative viral load at screening)
- EXCLUSION CRITERIA FOR STUDY CONTINUATION: History of interstitial lung disease, non-infectious pneumonitis or uncontrolled diseases including pulmonary fibrosis, acute lung diseases, chronic obstructive pulmonary disease (COPD), asthma requiring medication, etc.
- EXCLUSION CRITERIA FOR STUDY CONTINUATION: Prior allogeneic stem cell transplantation or organ transplantation
- EXCLUSION CRITERIA FOR STUDY CONTINUATION: Any major surgical procedure requiring general anesthesia =< 28 days before first dose of study drug
- EXCLUSION CRITERIA FOR STUDY CONTINUATION: Received a live vaccine =< 28 days before first dose of study drug (seasonal flu vaccines are generally inactivated and are allowed. Intranasal vaccines are not allowed) or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine or booster < 7 days before C1D1. For SARS-CoV-2 vaccines requiring more than 1 dose, the full series should be completed prior to C1D1, when feasible. Booster shot not required but also must be administered > 7 days from C1D1 or > 7 days from future cycle on study
- EXCLUSION CRITERIA FOR STUDY CONTINUATION: History of severe hypersensitivity reaction to any monoclonal antibody
- EXCLUSION CRITERIA FOR STUDY CONTINUATION: Concurrent participation in another therapeutic clinical study
- EXCLUSION CRITERIA FOR STUDY CONTINUATION: Pregnant or breastfeeding
Additional locations may be listed on ClinicalTrials.gov for NCT06782932.
Locations matching your search criteria
United States
Maryland
Baltimore
PRIMARY OBJECTIVES:
I. Determine the optimal dose of AGEN2373 that is safe when given in combination with balstilimab and Pancreatic GVAX Whole Cell Vaccine. (Phase I)
II. Assess safety following treatment with balstimilab and AGEN2373 in combination with GVAX (Arm 1) or mKRASvax (Arm 2). (Phase I and II)
III. Quantify the proportion of patients who form intratumoral tertiary lymphoid structures (TLS) following treatment with balstilimab and AGEN2373 in combination with GVAX (Arm 1) versus the mKRASvax (Arm 2). (Phase I and II)
SECONDARY OBJECTIVES:
I. Determine the pathologic overall response rate (pORR) to the GVAX (Arm 1) and mKRASvax (Arm 2) combinations.
II. Assess changes in intratumoral CD3+CD8+CD137+ T cell density by immunohistochemistry (IHC) in Arm 1 and Arm 2.
III. Determine maximal percent change in peripheral interferon-gamma (IFN-γ) producing mutant KRAS-specific T cells within 13 weeks post-vaccination by enzyme-linked immunosorbent spot assay (ELISPOT) with overnight stimulation for each treatment arm.
EXPLORATORY OBJECTIVES:
I. Correlate clinical endpoints of disease-free survival (DFS) and overall survival (OS) with formation of intratumoral TLS for each treatment arm.
II. Assess changes in peripheral and intratumoral T cell quality using mass cytometry (CyTOF), repertoire diversity (bulk TCR sequencing), and gene expression profiles (RNAseq) and correlate with clinical outcomes for each treatment arm.
III. Measure the spatial distance between immune effector cells and neoplastic cells using imaging mass cytometry (IMC) for each treatment arm.
IV. Determine the durability of peripheral mutant KRAS-specific T cell responses following adjuvant chemotherapy and boosting.
V. Assess changes in intratumoral mutant KRAS-specific T cell trafficking using T-cell receptor (TCR) sequencing of intratumoral and peripheral mKRAS T cells.
OUTLINE: This is a phase I, dose-escalation study of AGEN2373 followed by a phase II study.
PHASE I: Patients receive AGEN2373 intravenously (IV) over 60 minutes on day 1 of cycle 1, balstilimab IV over 30 minutes on day 1 of cycle 1, cyclophosphamide IV over 30 minutes on day 1 of cycle 1, and GVAX intradermally (ID) on day 2 of cycle 1 in the absence of disease progression or unacceptable toxicity. Patients then undergo surgical resection 2 weeks after completion of cycle 1. Beginning 4-10 weeks following surgical resection and 2 weeks prior to standard of care (SOC) chemotherapy and/or radiation therapy patients receive AGEN2373 IV over 60 minutes on day 1 of cycle 2, balstilimab IV over 30 minutes on day 1 of cycle 2, cyclophosphamide IV over 30 minutes on day 1 of cycle 2, and GVAX ID on day 2 of cycle 2 in the absence of disease progression or unacceptable toxicity. Beginning 4-12 weeks after last dose of SOC chemotherapy and/or radiation therapy, patients receive AGEN2373 IV over 60 minutes, balstilimab IV over 30 minutes, and cyclophosphamide IV over 30 minutes on day 1 of cycles 3-6, and GVAX ID on day 2 of cycles 3-6 in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo blood sample collection and computed tomography (CT) or magnetic resonance imaging (MRI) throughout the study and may undergo endoscopic ultrasound (EUS) tumor biopsy during screening and at time of disease re-occurrence.
PHASE II: Patients are assigned to 1 of 2 arms.
ARM I: Patients receive AGEN2373 IV over 60 minutes on day 1 of cycle 1, balstilimab IV over 30 minutes on day 1 of cycle 1, cyclophosphamide IV over 30 minutes on day 1 of cycle 1, and GVAX ID on day 2 of cycle 1 in the absence of disease progression or unacceptable toxicity. Patients then undergo surgical resection 2 weeks after completion of cycle 1. Beginning 4-10 weeks following surgical resection and 2 weeks prior to SOC chemotherapy and/or radiation therapy patients receive AGEN2373 IV over 60 minutes on day 1 of cycle 2, balstilimab IV over 30 minutes on day 1 of cycle 2, cyclophosphamide IV over 30 minutes on day 1 of cycle 2, and GVAX ID on day 2 of cycle 2 in the absence of disease progression or unacceptable toxicity. Beginning 4-12 weeks after last dose of SOC chemotherapy and/or radiation therapy, patients receive AGEN2373 IV over 60 minutes, balstilimab IV over 30 minutes, and cyclophosphamide IV over 30 minutes on day 1 of cycles 3-6, and GVAX ID on day 2 of cycles 3-6 in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo blood sample collection and CT or MRI throughout the study and may undergo EUS tumor biopsy during screening and at time of disease re-occurrence.
ARM II: Patients receive AGEN2373 IV over 60 minutes on day 1 of cycle 1, balstilimab IV over 30 minutes on day 1 of cycle 1, and mKRASvax ID on days 1 and 8 of cycle 1 in the absence of disease progression or unacceptable toxicity. Patients then undergo surgical resection 2 weeks after completion of cycle 1. Beginning 4-10 weeks following surgical resection and 2 weeks prior to SOC chemotherapy and/or radiation therapy patients receive AGEN2373 IV over 60 minutes on day 1 of cycle 2, balstilimab IV over 30 minutes on day 1 of cycle 2, and mKRASvax ID on day 1 of cycle 2 in the absence of disease progression or unacceptable toxicity. Beginning 4-12 weeks after last dose of SOC chemotherapy and/or radiation therapy, patients receive AGEN2373 IV over 60 minutes, balstilimab IV over 30 minutes, and mKRASvax ID on day 1 of cycles 3-6 in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo blood sample collection and CT or MRI throughout the study and may undergo EUS tumor biopsy during screening and at time of disease re-occurrence.
After completion of study treatment, patients are followed up at 90 days and as per SOC.
Trial PhasePhase I/II
Trial Typetreatment
Lead OrganizationJohns Hopkins University/Sidney Kimmel Cancer Center
Principal InvestigatorEric Christenson
- Primary IDJ24146
- Secondary IDsNCI-2025-03838, IRB00465956
- ClinicalTrials.gov IDNCT06782932