Pembrolizumab, a Monoclonal Antibody Against PD-1, in Combination With Capecitabine and Oxaliplatin (CAPOX) in People With Advanced Biliary Tract Carcinoma (BTC)

Background:

- The most compelling argument in favor of testing immune-based strategies (and anti-PD1
therapy in particular) in biliary tract cancers (BTC) is that chronic inflammation
appears to be the most common etiologic factor in the development of biliary tract
cancer.

- Single-agent activity has been shown for PD1-directed therapy in BTC. Given the
potential for oxaliplatin-induced immunogenic cell death we would like to evaluate the
combination of CAPOX chemotherapy with pembrolizumab.

Objective:

To determine the 5-month PFS of Pembrolizumab in combination with CAPOX in patients with
advanced biliary tract carcinoma.

Eligibility:

- Histologically confirmed diagnosis biliary tract carcinoma OR histopathological
confirmation of carcinoma in the setting of clinical and radiological characteristics
which, together with the pathology, are highly suggestive of a diagnosis of biliary
tract carcinoma.

- Patients must have at least one prior chemotherapeutic regimen.

- Patients must have disease that is not amenable to potentially curative resection.

- No prior treatment with oxaliplatin.

Design:

The proposed study is a phase II study of Pembrolizumab in combination with CAPOX in patients
with advanced biliary tract carcinoma

- INCLUSION CRITERIA:

- Patients must have histopathological confirmation of biliary tract carcinoma (BTC) by
the Laboratory of Pathology of the NCI prior to entering this study OR
histopathological confirmation of carcinoma in the setting of clinical and
radiological characteristics which, together with the pathology, are highly suggestive
of a diagnosis of biliary tract carcinoma. The term BTC includes intra- or
extrahepatic cholangiocarcinoma, gallbladder cancer or ampullary cancer.

- Patients must have disease that is not amenable to potentially curative resection.
Patients must have received, been intolerant of or refused at least one line of
chemotherapy.

- Patients must have at least one focus of measurable metastatic disease per RECIST 1.1.

- Patients must have at least one focus of metastatic disease that is amenable to pre-
and on-treatment biopsies. Ideally the biopsied lesion should not be one of the target
measurable lesions, although this can be up to the discretion of the investigators.

- Age greater than or equal to 18 years

- ECOG performance status 0-1

- Patients must have normal organ and marrow function as defined below:

- leukocytes greater than or equal to 3,000/mcL

- absolute neutrophil count greater than or equal to 1,000/mcL

- platelets greater than or equal to 100,000/mcL

- total bilirubin less than or equal to 2 xULN

- Serum albumin greater than or equal to 2.5g/dl

- Patients are eligible with ALT or AST up to 5 x ULN.

- creatinine <1.5X institution upper limit of normal OR creatinine clearance
greater than or equal to 45 mL/min/1.73 m^2 for patients with creatinine levels
above institutional normal

- Patients must have recovered from any acute toxicity related to prior therapy,
including surgery. Toxicity should be less than or equal to grade 1 or returned to
baseline.

- Patients must not have other invasive malignancies within the past 5 years (with the
exception of non-melanoma skin cancers, non-invasive bladder cancer or localized
prostate cancer for whom systemic therapy is not required).

- Patient must be able to understand and willing to sign a written informed consent
document.

- The effects of Pembrolizumab in combination with Capecitabine and Oxaliplatin on the
developing human fetus are unknown. For this reason, women of child-bearing potential
and men must agree to use adequate contraception (hormonal or barrier method of birth
control; abstinence) prior to study entry, for the duration of study participation and
up to 120 days after the last dose of the drug. Should a woman become pregnant or
suspect she is pregnant while she or her partner is participating in this study, she
should inform her treating physician immediately.

EXCLUSION CRITERIA:

- Patients who have had standard of care chemotherapy, large field radiotherapy, or
major surgery must wait 2 weeks prior to entering the study.

- Previous treatment with immune checkpoint inhibitors.

- Patients who have undergone prior liver transplantation are ineligible.

- Patients with known brain metastases will be excluded from this clinical trial because
of their poor prognosis and because they often develop progressive neurologic
dysfunction that would confound the evaluation of neurologic and other adverse events.

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
systemic infection, symptomatic congestive heart failure, unstable angina pectoris,
cardiac arrhythmia (excluding insignificant sinus bradycardia and sinus tachycardia)
or psychiatric illness/social situations that would limit compliance with study
requirements.

- History of (non-infectious) pneumonitis that required steroids, evidence of
interstitial lung disease or active, non-infectious pneumonitis.

- History of chronic autoimmune disease (e.g., Addison s disease, multiple sclerosis,
Graves disease, Hashimoto s thyroiditis, rheumatoid arthritis, hypophysitis, etc.)
with symptomatic disease within the 3 years before randomization. Note: Active
vitiligo or a history of vitiligo will not be a basis for exclusion.

- Dementia or significantly altered mental status that would prohibit the understanding
or rendering of Information and Consent and compliance with the requirements of the
protocol

- Active or history of inflammatory bowel disease (colitis, Crohn s), irritable bowel
disease, celiac disease, or other serious, chronic, gastrointestinal conditions
associated with diarrhea. Active or history of systemic lupus erythematosus or Wegener
s granulomatosis.

- Currently receiving immunosuppressive doses of steroids or other immunosuppressive
medications (inhaled and topical steroids are permitted)

- History of sarcoidosis syndrome.

- Known history of active tuberculosis.

- Patients should not be vaccinated with live attenuated vaccines within 1 month of
starting pembrolizumab treatment.

- Active hepatitis B or C infection.

- HIV-positive patients receiving anti-retroviral therapy are excluded from this study
due to the possibility of pharmacokinetic interactions between antiretroviral
medications and pembrolizumab. HIV positive patients not receiving antiretroviral
therapy are excluded due to the possibility that pembrolizumab may worsen their
condition and the likelihood that the underlying condition may obscure the attribution
of adverse events.

- History of hypersensitivity reaction to human or mouse antibody products.

- Female patients who are pregnant or breastfeeding. Because there is an unknown but
potential risk for adverse events in nursing infants secondary to treatment of the
mother with Pembrolizumab in combination with Capecitabine and Oxaliplatin,
breastfeeding should be discontinued.

- Patients with unhealed surgical wounds for more than 30 days.

- Prior therapy with oxaliplatin