Neoadjuvant mFOLFIRINOX and ELI-002-7P with or without Tislelizumab for the Treatment of KRAS-mutated Borderline Resectable and Resectable Pancreatic Ductal Adenocarcinoma

Inclusion Criteria

• Pathologically confirmed adenocarcinoma of the pancreas
• Presence of one of seven KRAS mutations: G12D, G12V, G12R, G12C, G12A, G12S, or G13D
• Patients must have resectable or borderline resectable localized disease as defined by National Comprehensive Cancer Network (NCCN) Guidelines version (v) 2.2025
• Staging CT or MRI of the chest/abdomen/pelvis at enrollment must be negative for metastatic disease
• Up to 4 doses of neoadjuvant mFOLFIRINOX are allowed prior to enrollment
• No prior systemic or local therapy for PDAC other than mFOLFIRINOX
• Resolution of all toxicities of prior therapy or surgical procedures to baseline or grade 1 (except for hypothyroidism requiring medication, which must have resolved to grade ≤ 2), alopecia, and other toxicities considered clinically nonsignificant and/or stable on supportive therapy as determined by the investigator)
• Age ≥ 18 years
• Eastern Cooperative Oncology Group (ECOG) performance status 0-1
• Not pregnant or breastfeeding
• Evidence of post-menopausal status or a negative urinary or serum pregnancy test for females of child-bearing potential within 28 days prior to initiation of treatment
• Absolute neutrophil count (ANC) ≥ 1,500/mm^3
• Platelets ≥ 100,000/mm^3
• Hemoglobin ≥ 8.0 g/dL
• Creatinine clearance ≥ 50 mL/min (Cockcroft-Gault formula or 24-hour urine collection)
• Total bilirubin ≤ 1.5 x upper limit of normal (ULN) (Gilbert's syndrome allowed up to ≤ 3 x ULN)
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 x ULN
• Albumin: ≤ 2.5 g/dL
• Patients with known cardiac disease or prior exposure to cardiotoxic agents should undergo risk assessment per New York Heart Association (NYHA) classification; patients must be class IIb or better
• Patient is willing and able to comply with protocol procedures, treatment, and follow-up
• Estimated life expectancy of at least 12 weeks per treating physician
• No active infection requiring parenteral antibiotic(s)
• Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial
• No history of allergic reaction to the study agent(s), compounds of similar chemical or biologic composition to the study agent (s) (or any of its excipients)
• Concomitant medication use should only exclude patients when clinically relevant drug-drug interactions or overlapping toxicities are expected to impact safety or efficacy. All concomitant medications from 7 days prior to screening through 12 weeks after the last dose of investigational product must be documented in the medical record. * Permitted Concomitant Medications ** Maintenance therapies: Oral contraceptives, hormone replacement therapy, prophylactic or therapeutic anticoagulation (e.g., low molecular weight heparin [LMWH], warfarin at stable dose), and other maintenance treatments for non-malignant conditions may be continued ** Supportive care: Growth factors (e.g., granulocyte colony-stimulating factor [G-CSF], pegfilgrastim, on-body injectors, romiplostim) may be used as clinically indicated with cytotoxic therapy. Anti-emetics per institutional guidelines are allowed. Acetaminophen, non-steroidal antiinflammatory drugs (NSAIDs), H1/H2 antagonists may be given for infusion-associated symptoms ** Corticosteroids and TNF-alpha inhibitors: Use may attenuate immunologic effects of ELI-002 7P or tislelizumab; alternatives should be considered when feasible. Systemic corticosteroids or TNF-alpha inhibitors may be administered if clinically necessary and must be documented. Corticosteroids are allowed for imaging contrast allergy premedication, adrenal insufficiency (physiologic replacement), orthostatic hypotension, and other non-immunosuppressive indications ** Other permitted uses: Megestrol as appetite stimulant; inhaled corticosteroids; mineralocorticoids * Prohibited Concomitant Medications The following are prohibited due to potential confounding toxicities or drug-drug interactions: ** Concomitant anticancer therapy: Additional chemotherapy, hormonal therapy, immunotherapy, radiotherapy, or herbal cancer therapy is not permitted during study treatment until documented disease progression and discontinuation of protocol therapy ** Live attenuated vaccines (e.g., FluMist, trademark [TM] [MedImmune, Gaithersburg, Maryland [MD]): Prohibited within 4 weeks prior to initiation, during immunotherapy, and for 5 months after the last dose ** Systemic immunostimulatory agents (e.g., IFNs, IL-2): Prohibited within 4 weeks or 5 drug half-lives (whichever is longer) before initiation and throughout study treatment because these agents could potentially increase the risk for autoimmune conditions when given in combination with immunotherapy ** Immunosuppressive agents: Agents such as cyclophosphamide, azathioprine, methotrexate, thalidomide, chloroquine, or hydroxychloroquine are prohibited unless being used for physiologic replacement ** Traditional herbal medicines: Prohibited due to incomplete characterization and risk of unanticipated interactions * Contraception requirements: * Patients of reproductive potential must use highly effective contraception from screening through 90 days after the last dose of immunotherapy * Highly effective methods (failure rate < 1% per year, when used correctly): ** Copper T intrauterine device (IUD) ** Levonorgestrel-releasing intrauterine system (e.g., Mirena, ®) ** Implants (e.g., etonogestrel implant, Implanon®, Norplant®) ** Intravaginal devices (e.g., NuvaRing®) ** Injectable (e.g., medroxyprogesterone acetate, Depo-Provera®) ** Combined oral contraceptive pill (standard or low-dose) ** Transdermal patch (e.g., OrthoEvra®) ** Progestogen-only oral contraceptive pill where inhibition of ovulation is the primary mode of action (e.g., desogestrel "mini-pill," Cerazette®) * Methods NOT considered highly effective: ** Male or female condoms (with or without spermicide) ** Female cap, diaphragm, or sponge (with or without spermicide) ** Non-copper IUDs ** Triphasic combined oral contraceptives ** Periodic abstinence, rhythm method, or withdrawal * Female patients of childbearing potential (FCBP): ** Defined as not surgically sterile (bilateral salpingectomy, oophorectomy, or hysterectomy) and not postmenopausal ** Postmenopausal definition: *** Women < 50: ≥ 12 months amenorrheic + postmenopausal labs after cessation of hormones *** Women ≥ 50: ≥ 12 months amenorrheic after cessation of hormones, or ≥ 12 months amenorrheic following chemo/radiation ** FCBP who are sexually active with a non-sterilized male partner must use ≥ 1 highly effective method ** Female patients must not breastfeed during study treatment or within 90 days of the last dose ** Female patients must refrain from egg donation during this period * Male patients with female partners of childbearing potential: ** Must use a condom + spermicide throughout treatment and for 90 days post-treatment ** Partners must also use a highly effective method of contraception ** Periodic abstinence, rhythm, or withdrawal are not acceptable ** Male patients must refrain from sperm donation during this period

Exclusion Criteria

• Locally advanced unresectable PDAC (per NCCN v 2.2025), including unreconstructable venous anatomy, arterial tumor contact ≥ 180° (superior mesenteric, celiac, or hepatic artery), or aortic invasion
• Metastatic PDAC
• Prior treatment with TNF receptor agonists (OX40, CD27, CD137/4-1BB, GITR) or prior checkpoint inhibitor therapy (anti–CTLA-4, anti–PD-1, anti–PD-L1)
• Active infection including tuberculosis, hepatitis A, active hepatitis B virus (HBV) (hepatitis B virus surface antigen [HBsAg]+), or active hepatitis C virus (HCV). Patients with resolved HBV (anti-hepatitis B virus core antibody (HBc)+, HBsAg–) may enroll. HCV antibody (Ab)+ patients are eligible if HCV RNA polymerase chain reaction (PCR) is negative. Successfully treated cholangitis is not exclusionary if no active infection remains
• Known HIV infection not meeting the on-study guideline criteria above
• Active or prior documented autoimmune/inflammatory disorders including: Inflammatory bowel disease (IBD), systemic lupus erythematosus, sarcoidosis, granulomatosis with polyangiitis, Graves’ disease, rheumatoid arthritis, hypophysitis, uveitis, systemic sclerosis, central nervous system (CNS) or motor neuropathy of autoimmune origin (e.g., Guillain-Barré, myasthenia gravis, multiple sclerosis) * Exceptions: vitiligo, alopecia, stable hypothyroidism on replacement, remote (> 5 years) inactive autoimmune disease, or celiac disease controlled by diet
• Uncontrolled intercurrent illness including, but not limited to, symptomatic congestive heart failure (CHF), unstable angina, uncontrolled arrhythmia, uncontrolled hypertension, interstitial lung disease, serious gastrointestinal (GI) conditions with chronic diarrhea, or psychiatric/social situations limiting compliance
• Current or prior systemic immunosuppressive medication within 14 days of first ELI-002 7P dose * Exceptions: intranasal/inhaled/topical steroids, local steroid injections, physiologic replacement doses (≤ 10 mg prednisone/day or equivalent), steroids as premedication for imaging contrast allergy, or limited steroid use as anti-emetic with mFOLFIRINOX
• Receipt of a live attenuated vaccine within 30 days prior to first dose of immunotherapy
• Pregnancy, breastfeeding, or unwillingness to use effective contraception during treatment and for 90 days after last immunotherapy dose
• Allergy or hypersensitivity to study drugs or excipients
• Any other malignancy within 3 years except adequately treated cervical carcinoma in situ, non-muscle-invasive bladder cancer, localized prostate cancer, or non-melanoma skin cancers
• Prior allogeneic organ transplantation