Targeting Driver Oncogenes With a Peptide Vaccine Plus Durvalumab and Tremelimumab for Patients With Biliary Tract Cancers (BTC)

Inclusion Criteria:

• Age ≥18 years

• Must have a histologically- or cytologically, proven biliary tract cancer (BTC)previously treated with gemcitabine/cisplatin/anti-PD(L)1 therapy.

• Must have evidence of radiological disease, must accept to have a tumor biopsy of anaccessible lesion at baseline and on treatment.

• Must have sufficient archival tumor tissue for next-generation sequencing (NGS) andimmune-phenotyping.

• Have a BTC containing at least one of the oncogenic mutation/alterations targeted bythe vaccine.

• Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.

• Must have body weight of >30 kg.

• Patients must have adequate organ and marrow function defined by study-specifiedlaboratory tests.

• Patients with chronic or acute hepatitis B virus (HBV) or hepatitis C virus (HCV)infection must have disease controlled prior to enrollment.

• Women of childbearing potential (WOCBP) must have a negative urine or serumpregnancy test.

• For both Women and Men, must use acceptable form of birth control while on study.

• Must have a life expectancy of at least 12 weeks.

• Ability to understand and willingness to sign a written informed consent document.

Exclusion Criteria:

• Participation in another clinical study with an investigational product during thelast 2 weeks.

• Patient is expected to require any other form of systemic or localizedantineoplastic therapy while on study.

• Any of the following procedures or medications within 2 weeks prior to initiation ofstudy treatment:

• Systemic or topical steroids at immunosuppressive doses (> 10 mg/day ofprednisone or equivalent). The following are exceptions to this criterion:

• Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intraarticular injection)

• Systemic corticosteroids at physiologic doses not to exceed 10 mg/day ofprednisone or its equivalent

• Steroids as premedication for hypersensitivity reactions (e.g., CT scanpremedication)

• Palliative or adjuvant radiation or gamma knife radiosurgery.

• Chemotherapy or checkpoint inhibitor targeting anti-Pd1/PD-L1.

• Within 4 weeks prior to initiation of study treatment:

• Any investigational cytotoxic drug.

• Any investigational device.

• Non-oncology vaccines containing live virus.

• Allergen hyposensitization therapy.

• Growth factors, e.g. granulocyte-colony stimulating factor (G-CSF), granulocytemacrophage-colony stimulating factor (GM-CSF), erythropoietin.

• Major surgery.

• Any unresolved toxicity NCI CTCAE Grade ≥2 from previous anticancer therapy with theexception of alopecia, vitiligo, and the laboratory values defined in the inclusioncriteria.

• Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basis afterconsultation with the Study Physician.

• All AEs while receiving prior immunotherapy must have completely resolved orresolved to baseline prior to screening for this study.

• Must not have experienced a ≥Grade 3 immune related AE or an immune relatedneurologic or ocular AE of any grade while receiving prior immunotherapy.

• Patients with a history of prior treatment with anti-PD-1 and anti-PD-L1.

• History of severe hypersensitivity reaction to any monoclonal antibodies or relatedcompounds or to any of its components.

• History of leptomeningeal carcinomatosis.

• Patient has a known history or evidence of brain metastases.

• Has an active known or suspected autoimmune disease or which has required systemictherapy in the last 5 years.

• Known history of interstitial lung disease or of (non-infectious) pneumonitis thatrequired steroids or current pneumonitis.

• Has a pulse oximetry < 92% on room air.

• Requires the use of home oxygen.

• Has a known history of Human Immunodeficiency Virus (HIV)/AIDS

• Has active co-infection with HBV (hepatitis B virus) and HCV (hepatitis C virus) orcoinfected with HBV and hepatitis delta virus (HDV)

• Uncontrolled intercurrent illness including, but not limited to, uncontrolledinfection, symptomatic congestive heart failure, unstable angina, cardiacarrhythmia, metastatic cancer, or psychiatric illness/social situations that wouldlimit compliance with study requirements.

• Patients who have been diagnosed with another cancer or myeloproliferative disorderin the past 5 years requiring systemic therapy or expected to require active therapywithin the clinical study period.

• Has a diagnosis of immunodeficiency.

• Presence of any tissue or organ allograft, regardless of need for immunosuppression,including corneal allograft. Patients with a history of allogeneic hematopoieticstem cell transplant will be excluded.

• Any other sound medical, psychiatric, and/or social reason as determined by theInvestigator.

• Patient is at the time of signing informed consent a regular user (including "recreational use") of any illicit drugs or had a recent history (within the lastyear) of substance abuse (including alcohol).

• Patient is unwilling or unable to follow the study schedule for any reason.

• Pregnant or breastfeeding.

• WOCBP and men with female partners (WOCBP) who are not willing to use contraception.

• Evidence of clinical ascites requiring paracentesis in the last 4 weeks.

• History of malignant bowel obstruction.