Pooled Mutant KRAS-Targeted Long Peptide Vaccine with Balstilimab and Botensilimab for the Treatment of Patients with Stage IV Non-MSI-H/dMMR Colorectal Cancer and Pancreatic Ductal Adenocarcinoma

Inclusion Criteria

• Age ≥ 18 years
• Have histologically- or cytologically-proven unresectable or metastatic non-MSIH/dMMR adenocarcinoma of the pancreas (PDAC) or colorectal (CRC). Patients with mixed histology will be excluded. The tumor must have been assessed for microsatellite high (MSI-H) or deficient mismatch repair (dMMR) status
• Have tumor lesions amenable to repeated biopsy, and patient’s acceptance to have a tumor biopsy of an accessible lesion at baseline and on treatment if the lesion can be biopsied with acceptable clinical risk (as judged by the investigator)
• Measurable disease as per Response Evaluation Criteria in Solid Tumors (RECIST 1.1)
• Sufficient and accessible tissue for next generation sequencing (NGS) and immune-phenotyping
• Have one of the KRAS mutations included in the vaccine at the time of vaccination expressed in tumor
• Have received 4-6 months of fluorouracil, irinotecan, leucovorin and oxaliplatin (FOLFIRINOX) or gemcitabine+nab-paclitaxel for the 1st line treatment of metastatic unresectable PDAC or 1st line SOC chemotherapy per National Comprehensive Cancer Network (NCCN) guidelines (FOLFIRINOX, fluorouracil, leucovorin, oxaliplatin [FOLFOX], fluorouracil, leucovorin, irinotecan [FOLFIRI] +/- targeted therapy with VEGF inhibitor [i] or EGFRi) CRC. Patients who have received neoadjuvant or adjuvant chemotherapy > 12 months prior to the diagnosis of unresectable or metastatic disease may be eligible. Other first line regimens can be considered on a case-by case basis with approval from study sponsor
• Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
• Life expectancy greater than 3 months
• Leukocytes ≥ 2,500/mcL
• Lymphocytes (absolute lymphocyte count [ALC]) ≥ 500/mcL
• Neutrophils (absolute neutrophil count [ANC]) ≥ 1250/mcL
• Platelets ≥ 75 × 10^3/uL
• Hemoglobin ≥ 9.0 g/dL * Without transfusion support in the past 2 weeks
• Total bilirubin ≤ 1.5 upper limit of normal (ULN) * Except subjects with Gilbert Syndrome, who can have total bilirubin < 2.5 mg/dL
• Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase [SGOT]) ≤ 1.5 ULN
• Alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) ≤ 1.5 ULN
• Albumin ≥ 3.0 g/dL
• Serum creatinine ≤ 1.5 × ULN
• Creatinine clearance ≥ 40 mL/min * Using the Cockcroft-Gault formula
• Lactate dehydrogenase (LDH) ≤ 1.5 ULN
• Evidence of post-menopausal status or negative serum pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin [HCG]). Postmenopausal woman and woman of child bearing potential (WOCBP) * NOTE: If a patient has a positive or indeterminate serum or urine pregnancy test, then an ultrasound must be done to rule out pregnancy to enroll on trial. * WOCBP must agree to follow instructions for method(s) of contraception: hormonal or barrier method of birth control, including male condom, female condom, or diaphragm with spermicidal gel; abstinence) from the time of enrollment for the duration of treatment with study drugs plus 152 days post study drug treatment completion * Men who are sexually active with WOCBP must agree to follow instructions for method (s) of contraception for the duration of treatment with study drug(s) plus 152 days post study drug treatment completion
• Ability to understand and willingness to sign a written informed consent document

Exclusion Criteria

• Patient is a candidate for definitive surgical resection
• Patient has untreated or symptomatic brain metastases and/or leptomeningeal spread. * Treated brain metastases allowed on study if asymptomatic and therapy was completed at least 2 weeks prior to treatment start and steroid dosing
• Patients with a history of prior treatment with immunotherapy agents (including, but not limited to: IL-2, interferon, anti-PD-1, anti-PD-L1, anti-PD-L2, antiCD137, anti-OX-40, anti-CD40, or anti-CTLA-4 antibodies)
• Patients receiving active immunosuppressive agents or chronic use of systemic corticosteroids within 14 days of vaccine treatment
• History of any autoimmune disease, including any history of inflammatory bowel disease, including ulcerative colitis and Crohn’s Disease, as well as history of symptomatic disease (e.g. rheumatoid arthritis, systemic progressive sclerosis [scleroderma], systemic lupus erythematosus, autoimmune vasculitis [e.g., Wegener’s Granulomatosis]); CNS or motor neuropathy considered of autoimmune origin (e.g., Guillain-Barre Syndrome and Myasthenia Gravis, multiple sclerosis) that has required systemic therapy in the last 5 years or ever required biologic therapy. Patients with thyroid disease will be allowed. Autoimmune diagnoses not listed here must be approved by the Principal Investigator
• Known history of interstitial lung disease, has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis
• Has a pulse oximetry < 95% on room air or requires use of home oxygen
• Has a known history of human immunodeficiency virus (HIV) (HIV1/2 antibodies), hepatitis B, or hepatitis C infection
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina, cardiac arrhythmia, metastatic cancer, or psychiatric illness/social situations that would limit compliance with study requirements
• Patients who have been diagnosed with another cancer or myeloproliferative disorder in the past 5 years except for superficial bladder cancer, non-melanoma skin cancers, or a low-grade prostate cancer not requiring therapy
• Patients who have had surgery within 28 days of dosing of investigational agent, excluding minor procedures (dental work, skin biopsy, etc.), celiac plexus block, and biliary stent placement
• Patients who have received any non-oncology live vaccine therapy used for prevention of infectious diseases within 28 days of study treatment. Examples include, but are not limited to, the following: measles, mumps, rubella, chicken pox, yellow fever, rabies, Bacille Calmette Guerin (BCG), and typhoid vaccine. *Note: ** Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed. However, intranasal influenza vaccines (e.g. Flu-Mist) are live-attenuated vaccines, and are not allowed within 28 days of study treatment. ** COVID-19 vaccines will be allowed. However, COVID vaccines are not allowed within 7 days of study drug treatment
• Patient is, at the time of signing informed consent, a regular user (including “recreational use”) of any illicit drugs or other substance abuse (including alcohol) that could potentially interfere with adherence to study procedures or requirements
• Patient is unwilling or unable to follow the study schedule for any reason
• Patient is pregnant or breastfeeding
• Any radiological or clinical pleural effusions or ascites
• Patients with history of malignant small bowel obstruction
• Patients on parenteral nutrition
• Known or suspected hypersensitivity to Hiltonol