Immunotherapy With Durva and Treme With or Without Capecitabine in Adjuvant Treatment for Biliary Tract Cancer

Inclusion Criteria:

1. Capable of giving written informed consent, including participation in optionaltranslational research if applicable, and any locally-required authorization (EUData Privacy Directive in the EU) obtained from the subject prior to performing anyprotocol-related procedures, including screening evaluations.

2. Histologically proven and curatively resected biliary tract cancer (intrahepatic,hilar or distal CCA as well gallbladder carcinoma) without metastatic disease, inthe adjuvant situation (R0/R1) up to 16 weeks from surgery.

3. Men or women* ≥ 18 years at time of study entry.

*There is no data that indicates a specific gender distribution. Therefore, patientsare included regardless of their gender.

4. Performance status (PS) ≤ 1 (ECOG scale),with no deterioration over the previous twoweeks prior to baseline.

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

6. Appropriate hematological, hepatic and renal function:

• Absolute number of neutrophils (ANC) ≥ 1.5 x 109/L

• Platelets ≥ 100 x 109/L

• Hemoglobin ≥ 9 g/dL (5.58 mmol/L)

• Total bilirubin ≤ 1.5 times the upper limit of normal (UNL) or ≤3 x ULN in thepresence of documented Gilbert's syndrome (unconjugated hyperbilirubinemia)

• AST (SGOT) and ALT (SGPT) ≤ 2.5 x UNL

• Serum creatinine ≤ 1.5 x UNL or creatinine clearance (measured by 24h urine) ≥ 40 mL / min (i.e., if the serum creatinine level is > 1.5 x UNL, then a 24-hurine test must be performed to check the creatinine clearance to bedetermined).

7. Adequate coagulability, as determined by the International Normalized Ratio (INR) ≤ 1.5 and partial thromboplastin time (PTT) ≤ 5 seconds above the UNL (unlessanti-coagulation therapy has been given). Patients receiving warfarin /phenoprocoumon must be switched to low molecular weight heparin and before startingstudy-specific procedures.

8. Patients of reproductive age must be prepared to use a suitable contraceptive methodduring the study and up to 3 months after the end of treatment. A suitable method ofcontraception is defined as surgical sterilization (e.g., bilateral fallopian tubeligation, vasectomy), hormonal contraception (implantable, patch, oral), and doublebarrier methods (each two-fold combination of intrauterine pessary, condom for men,or women with spermicidal gel, Diaphragm, contraceptive sponge, cervical cap). Womenof child-bearing potential must have a negative serum pregnancy test within the last 7 days prior to the start of study therapy. Men who are sexually active with WOCBP must use any contraceptive method with afailure rate of less than 1% per year. Men receiving IMP and who are sexually activewith WOCBP will be instructed to adhere to contraception for a period of 7 monthsafter the last dose of investigational products (durvalumab and tremelimumab). Women who are not of childbearing potential (i.e., who are postmenopausal orsurgically sterile) as well as azoospermic men do not require contraception).

9. Subject is willing and able to comply with the protocol (including contraceptivemeasures) for the duration of the study including undergoing treatment and scheduledvisits and examinations including follow up.

Exclusion Criteria:

1. Presence of tumors other than biliary tract cancer or a secondary tumor other thansquamous or basal cell carcinomas of the skin or in situ carcinomas of the cervixwhich have been effectively treated. Patients who have received curative treatmentfor other tumors and have been disease-free for at least 5 years at the time ofscreening are eligible for enrollment.

2. Metastatic biliary tract cancer disease.

3. Simultaneous, ongoing systemic immunotherapy, chemotherapy, or hormone therapy notdescribed in the study protocol.

4. Simultaneous treatment with a different anti-cancer therapy other than that providedfor in the study (excluding palliative radiotherapy only for symptom control)

5. Previous therapy with a PD-1, PD-L1 inhibitor (including durvalumab) or CTLA4inhibitor (including tremelimumab) or classical chemotherapy agents like platinum,fluoropyrimidine or gemcitabine based regimens.

6. 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 basisafter consultation with the LKP.

• Patients with irreversible toxicity not reasonably expected to be exacerbatedby treatment with durvalumab or tremelimumab may be included only afterconsultation with the LKP.

7. Stage B cirrhosis according to Child-Pugh criteria (or worse) or cirrhosis (of anygrade) with a history of hepatic encephalopathy or clinically significant ascitesresulting from cirrhosis. Clinically significant ascites is defined as ascitesresulting from cirrhosis requiring diuretics or paracentesis.

8. Known allergic / hypersensitive reactions to at least one of the treatmentcomponents.

9. Known dihydropyrimidine dehydrogenase (DPD) deficiency.

10. Uncontrolled intercurrent illness, including but not limited to, ongoing or activeinfection, symptomatic congestive heart failure, uncontrolled hypertension, unstableangina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronicgastrointestinal conditions associated with diarrhea, or psychiatric illness/socialsituations that would limit compliance with study requirement, substantiallyincrease risk of incurring AEs or compromise the ability of the patient to givewritten informed consent within the last 12 months prior to the start of the study.

11. Presence of an active, uncontrollable infection.

12. Active or prior documented autoimmune or inflammatory disorders (includinginflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis [withthe exception of diverticulosis], systemic lupus erythematosus, Sarcoidosissyndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease,rheumatoid arthritis, hypophysitis, uveitis, etc.]). The following are exceptions tothis criterion:

• Patients with vitiligo or alopecia

• Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable onhormone replacement

• Any chronic skin condition that does not require systemic therapy

• Patients without active disease in the last 5 years may be included but onlyafter consultation with the study physician

• Patients with celiac disease controlled by diet alone

13. Active disseminated intravascular coagulation.

14. Any other serious concomitant or medical condition that, in the opinion of theinvestigator, presents a high risk of complications to the patient or reduces thelikelihood of clinical effect.

15. Major surgical procedure (as defined by the Investigator) within 28 days prior tothe first dose of IP.

16. Mean QT interval corrected for heart rate using Fridericia's formula (QTcF) ≥470 mscalculated from 3 ECGs (within 15 minutes at 5 minutes apart)

17. History of active primary immunodeficiency

18. Active infection including tuberculosis (clinical evaluation that includes clinicalhistory, physical examination and radiographic findings, and TB testing in line withlocal practice), hepatitis B (known positive HBV surface antigen (HBsAg) result),hepatitis C, Patients with a past or resolved HBV infection (defined as the presenceof hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. Patientspositive for hepatitis C (HCV) antibody are eligible only if polymerase chainreaction is negative for HCV RNA.

19. Current or prior use of immunosuppressive medication within 14 days before the firstdose of durvalumab or tremelimumab. 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)

20. Receipt of live attenuated vaccine within 30 days prior to the first dose of IP.Note: Patients, if enrolled, should not receive live vaccine whilst receiving IP andup to 30 days after the last dose of IP.

21. Female patients who are pregnant or breastfeeding or male or female patients ofreproductive potential who are not willing to employ effective birth control fromscreening to 90 days after the last dose of durvalumab monotherapy or 180 days afterthe last dose of durvalumab + tremelimumab combination therapy.