A Peptide Vaccine (mBTCvax) Plus Durvalumab and Tremelimumab for the Treatment of Biliary Tract Cancers

Inclusion Criteria

• Age ≥ 18 years.
• Have histologically- or cytologically proven BTC previously treated with gemcitabine/cisplatin (gem/cis) and anti-PD-(L)1 therapy. Note: Patients who are currently on maintenance anti-PD(L)1 after receiving gemcitabine/cisplatin are eligible.
• For patients with evidence of radiological disease, must accept 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 principal investigator). NOTE: patients with no radiological evidence of disease will be allowed upon discussion with principal investigator (PI).
• Have sufficient archival tumor tissue for next-generation sequencing (NGS) and immune-phenotyping.
• Have a BTC containing at least one of the oncogenic mutation/alterations targeted by the vaccine.
• Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.
• Body weight > 30 kg.
• Lymphocytes > 500/mm^3.
• Absolute neutrophil count ≥ 1,000/mcL.
• Platelets ≥ 75 × 10^3/uL.
• Hemoglobin ≥ 9.0 g/dL.
• Total bilirubin ≤ 1.5 × upper limit normal (ULN) OR direct bilirubin ≤ ULN for participants with total bilirubin levels > 1.5 × ULN.
• Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT)(serum glutamic pyruvic transaminase[SGPT]) ≤ 3 × ULN.
• Creatinine ≤ 1.5 × ULN or creatinine clearance (CrCl) ≥ 50 mL/min (if using the Cockcroft-Gault formula).
• Albumin ≥ 2.8 g/dL.
• Participants with controlled hepatitis B are eligible for the study, as long as they meet the following criteria: * Participants with chronic hepatitis B virus (HBV) infection, defined as hepatitis B surface antigen (HBsAg) positive and/or detectable HBV deoxyribonucleic acid (DNA), must be given antiviral therapy for HBV for at least 4 weeks prior to the first dose of study intervention and HBV viral load must be less than 100 IU/mL prior to first dose of study intervention. Participants on active HBV therapy with viral loads under 100 IU/mL should stay on the same therapy throughout study intervention. Antiviral therapy after completion of study intervention should follow local guidelines. * Participants with clinically resolved HBV infection, defined as HBsAg negative and hepatitis B virus core antibody (anti-HBc) positive, and who have an undetectable HBV viral load at screening should be checked every 6 weeks for HBV viral load and treated for HBV if viral load is over 100 IU/mL. Antiviral therapy after completion of study intervention should follow local guidelines. * Do not have a concurrent active hepatitis B (defined as HBsAg positive and/or detectable HBV DNA) and hepatitis D virus infection.
• Participants with active hepatitis C infection on appropriate antiviral therapy are eligible for the study. * NOTE: There is not a defined maximum viral load requirement for study entry.
• Evidence of post-menopausal status or negative serum pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin [HCG]). * 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. * Women of childbearing potential (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 90 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 180 days post study drug treatment completion.
• Must have a life expectancy of at least 12 weeks.
• Ability to understand and willingness to sign a written informed consent document which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.

Exclusion Criteria

• Participation in another clinical study with an investigational product during the last 2 weeks unless it is an observational (non-interventional) clinical study or during the follow-up period of an interventional study.
• Patient is expected to require any other form of systemic or localized antineoplastic therapy while on study. NOTE: Palliative (limited-field) radiation therapy is permitted, but only for pain control and with approval by the PI and investigational new drug (IND) sponsor.
• Any of the following procedures or medications: * Within 2 weeks prior to initiation of study treatment: ** Systemic or topical steroids at immunosuppressive doses (> 10 mg/day of prednisone or equivalent). The following are exceptions to this criterion: *** Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra articular injection). *** Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent. *** Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication). ** 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. Exposure to any non-cytotoxic drug within 4 weeks or 5 half-lives (whichever is shorter) is prohibited. If 5 half-lives is shorter than 4 weeks, agreement with IND sponsor is mandatory. ** Any investigational device. ** Non-oncology vaccines containing live virus. Examples include, but are not limited to, the following: measles, mumps, rubella, chicken pox, yellow fever, rabies, bacillus Calmette-Guérin (BCG), and typhoid vaccine. ** Allergen hyposensitization therapy. ** Growth factors, e.g. granulocyte-colony stimulating factor (G-CSF), granulocyte macrophage-colony stimulating factor (GM-CSF), erythropoietin. ** Major surgery (excludes celiac plexus block, biliary stent placement, and other minor procedures such as dental work, skin biopsy, etc.).
• Any unresolved toxicity National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) grade ≥ 2 from previous anticancer therapy with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria.
• Patients with grade ≥ 2 neuropathy will be evaluated on a case-by-case basis after consultation with the study physician. * Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with durvalumab may be included only after consultation with the study physician. * Patients who have received prior anti–PD-1 or anti PD-L1: Must not have experienced a toxicity that led to permanent discontinuation of prior immunotherapy.
• All adverse events (AEs) while receiving prior immunotherapy must have completely resolved or resolved to baseline prior to screening for this study.
• Must not have experienced a ≥ grade 3 immune-related AE or an immune-related neurologic or ocular AE of any grade while receiving prior immunotherapy. NOTE: Patients with endocrine AE of ≤ grade 3 are permitted to enroll if they are stably maintained on appropriate replacement therapy and are asymptomatic.
• Patients with a history of prior treatment with immunotherapy agents other than anti-PD(L)1 (including, but not limited to: IL-2, interferon, anti-PD-L2, anti-CD137, anti-OX-40, anti-CD40, anti-CTLA-4, or anti-LAG-3 antibodies).
• History of severe hypersensitivity reaction to any monoclonal antibodies or related compounds or to any of their components (e.g., history of severe hypersensitivity reactions to drugs formulated with polysorbate 80). NOTE: patients with history of grade 1-2 infusion reactions to anti-PD(L1) that was managed conservatively and did not require discontinuation are allowed as long as there is evidence of uneventful subsequent infusion with prophylactic premedications and prophylactic premedications should be continued on study.
• History of leptomeningeal carcinomatosis.
• Patient has a known history or evidence of brain metastases. NOTE: Patients with previously treated brain metastases must have stable neurologic status and imaging following local therapy (surgery or radiation) for at least 4 weeks, with no requirement for immunosuppressive doses of systemic corticosteroids (> 10 mg/day prednisone equivalents) for at least 2 weeks prior to study drug administration (stable low dose dexamethasone allowed at discretion of IND sponsor). Brain metastases will not be recorded as Response Evaluation Criteria in Solid Tumors (RECIST) target lesions at baseline.
• Has an active known or suspected autoimmune disease or which has required systemic therapy in the last 5 years. Subjects with type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll. * Patients without active disease in the last 5 years may be included but only after consultation with the study physician. * Patients with celiac disease controlled by diet alone.
• Known history of interstitial lung disease or of (non-infectious) pneumonitis that required 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) (HIV1/2 antibodies) NOTE: No HIV testing is required unless mandated by local health authority. * NOTE: For inclusion on study, HIV-infected participants without history of Kaposi’s sarcoma and/or multicentric Castleman’s disease can be enrolled in the study if they have well-controlled HIV on antiretroviral therapy (ART), defined as: ** Participants on ART must have a CD4+ T-cell count ≥ 350 cells/mm^3 at the time of screening. ** Participants on ART must have achieved and maintained virologic suppression defined as confirmed HIV ribonucleic acid (RNA) level below 50 or the lower limit of quantitation (LLOQ) (below the limit of detection) using the locally available assay at the time of screening and for at least 12 weeks before screening. ** It is advised that participants must not have had any AIDS-defining opportunistic infections within the past 12 months. ** Participants on ART must have been on a stable regimen, without changes in drugs or dose modification, for at least 4 weeks before study entry (day 1) and agree to continue ART throughout the study. * Participants should be comanaged by a HIV specialist and the investigator during the study, including monitoring of HIV viral load, CD4+ T-cell count, and additional supportive care measures.
• Has active co-infection with HBV and hepatitis C virus (HCV) or co-infected with HBV and hepatitis D virus (HDV), namely: HBV positive (presence of HBsAg and/or anti hepatitis B virus core antibody [HBcAb] with detectable HBV DNA); AND * HCV positive (presence of anti-HCV antibodies); OR * HDV positive (presence of anti-HDV antibodies).
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina, computer-aided arrhythmia classification (caac) 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 requiring systemic therapy or expected to require active therapy within the clinical study period, except for superficial bladder cancer, non-melanoma skin cancers or lentigo maligna without evidence of disease, or a low grade prostate cancer not requiring therapy or adequately treated carcinoma in situ without evidence of disease.
• 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 hematopoietic stem cell transplant will be excluded.
• Any other sound medical, psychiatric, and/or social reason as determined by the investigator.
• 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.
• Female patients who are pregnant or breastfeeding or male or female patients of reproductive potential who are not willing to employ effective birth control from screening to 90 days after the last dose of durvalumab monotherapy or 180 days after the last dose of durvalumab and tremelimumab combination therapy.
• Evidence of clinical ascites requiring paracentesis in the last 4 weeks.
• History of malignant bowel obstruction.