The CLEAN-DUCT / TRITICC-3 trial - Phase IIa, prospective, single arm, open label, non-randomized, multi-center pilot study of durvalumab (MEDI4736) + intraductal radiofrequency ablation (ID-RFA) in extra- and intrahepatic cholangiocarcinoma

Prior treatment

• Patient received previous or simultaneous endobiliary treatment other than RFA (e.g. PDT or brachytherapy).
• Patient has active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection (defined as having a positive hepatitis B surface antigen [HBsAg], HBV core antibody [anti-HBc], or HCV antibody test prior to enrollment). NOTE: Patients with resolved HBV infection (defined as negative HBsAg and a positive anti-HBc test) are eligible. Patients positive for HCV antibody are eligible only if polymerase chain reaction testing is negative for HCV RNA.
• Patient received an administration of a live attenuated vaccine within 30 days prior to start of study treatment, or anticipation that such a live attenuated vaccine will be required during the study or within 90 days after the last dose of durvalumab.
• Patient had a treatment with systemic immunostimulatory agents (including but not limited to interferons or interleukin-2) within four weeks or five half-lives of the drug, whichever is longer, prior to study enrollment.
• Patient has current or prior treatment with systemic corticosteroids or other systemic immunosuppressive medications within 2 weeks prior to initiation of study treatment. The following are exceptions: (a) Intranasal, inhaled, topical steroids or local steroid injections (e.g. intra articular injection); (b) Systemic corticosteroids at physiologic dose not to exceed 10mg/day of prednisone or its equivalent; (c) Steroids as premedication for hypersensitivity reactions (e.g. CT premedication)
• Patient underwent major surgical procedure other than for diagnosis within 4 weeks prior to initiation of study treatment. NOTE: Local RFA plus stent implantation is acceptable.
• Patient received previous systemic therapy with a PD-1, PD-L1 inhibitor (including durvalumab) or CTLA4 inhibitor or classical chemotherapy agents like platinum, fluoropyrimidine or gemcitabine-based regimens in palliative intent.
• Patient has any other serious concomitant or medical condition that, in the opinion of the investigator, presents a high risk of complications to the patient or reduces the likelihood of clinical effect.
• Patient participated in another interventional clinical study within 28 days prior to study enrollment or participation in a clinical study at the same time as this study, unless it is an observational/ non-interventional study or during the follow-up period of an interventional study.
• Patient has taken an investigational drug within 28 days prior to initiation of study drug.
• Patient receives any concurrent chemotherapy, investigational product or hormonal therapy for cancer treatment. Concurrent use of hormonal therapy for non-cancer related conditions (e.g., hormone replace therapy) is acceptable.
• Patient had a prior allogeneic bone marrow or stem cell transplantation or prior solid organ transplantation.

Other illness

• Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronic gastrointestinal conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring AEs or compromise the ability of the patient to give written informed consent.
• Patient is known to have tested positive for human immunodeficiency virus (HIV) (positive HIV 1/2 antibodies) or active tuberculosis infection (clinical evaluation that may include clinical history, physical examination and radiographic findings, or tuberculosis testing in line with local practice).
• Patient has history of leptomeningeal carcinomatosis.
• Patient has known hypersensitivity to any component of the durvalumab formulation as well as a known history of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion protein and/or any known contraindication (including hypersensitivity) to gemcitabine or cisplatin.
• Patient has history of primary immunodeficiency.
• Patient has stage B cirrhosis according to Child-Pugh criteria (or worse) or cirrhosis (of any grade) with a history of hepatic encephalopathy or clinically significant ascites resulting from cirrhosis. Clinically significant ascites is defined as ascites resulting from cirrhosis requiring diuretics or paracentesis.
• Patient has active or history of autoimmune or inflammatory disorders (including, but not limited to, inflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis [with the exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis]) . The following are exceptions: (a) Patients with vitiligo or alopecia; (b) Patients with hypothyroidism (e.g. following Hashimoto syndrome) stable on hormone replacement; (c) Patients with any chronic skin condition that does not require systemic therapy; (d) Patients with celiac disease controlled by diet alone; (e) Patients without active disease in the last 5 years may be included but only after consultation with the Lead Investigator.

Lab values

• Female patients, who are pregnant or breast feeding or planning to become pregnant within and 6 months after the end of treatment. Female patients of childbearing potential must have a negative serum pregnancy test result within 7 days prior to initiation of study treatment.
• Patient has any unresolved NCI CTCAE grade ≥ 2 from previous anticancer therapy with the exception of alopecia, vitiligo, and laboratory values defined in the inclusion criteria; (a) Patients with grade ≥ 2 neuropathy will be evaluated on a case-by-case basis after consultation with the Lead Investigator; (b) Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with durvalumab may be included only after consultation with the Lead Investigator.

Age

• Patient has a history of malignancy other than CCA except for: (a) Malignancy treated with curative intent and with no known active disease ≥ 5 years before the first dose of study treatment and of low potential risk for recurrence; (b) Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease; (c) Adequately treated carcinoma in situ without evidence of disease

Other

• Patient has active disseminated intravascular coagulation.

• Patient* has given written informed consent (*There are no data that indicate special gender distribution. Therefore, patients will be enrolled in the study gender-independently.)
• Female patients defined as women of childbearing potential (WOCBP) or male patients with WOCBP partners must agree to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods that result in a failure rate of <1% per year during the treatment period and for at least 6 months after the last dose of chemotherapy or for at least 3 months after last dose of durvalumab, whatever happens last. Male patients must refrain from donating sperm during this same period. Male patients with a pregnant partner must agree to remain abstinent or to use a condom for the duration of the pregnancy.
• Patient is ≥ 18 years of age at time of signing the written informed consent.
• Patient is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up.
• Patient has been diagnosed with histologically or cytologically confirmed (a) histologically or cytologically confirmed cholangiocarcinoma as adenocarcinoma of pancreatobiliary type; (b) unresectable perihilar and/or ductal extrahepatic cholangiocarcinoma or intrahepatic CCA with perihilar stricture according to Bismuth-Corlette-classification with indication for bile duct stenting and palliative systemic therapy as determined by the local multidisciplinary team (MDT) and already resolved cholestasis due to RFA + stent
• Patient is eligible for palliative systemic therapy based on clinical and laboratory parameters (except hyperbilirubinemia) as determined by the local MDT.
• Patient has a ECOG ≤ 1.
• Patient has life expectancy of ≥ 12 weeks.
• Patient has body weight > 30 kg.
• Adequate blood count, liver-enzymes, and renal function: (a) ANC > 1,500 cells/μL without the use of hematopoietic growth factors; (b) Platelet count ≥ 100 x 109/L (>100,000 per mm3); (c) Hemoglobin ≥ 9 g/dL; (d) Serum total bilirubin ≤ 3x upper normal limit (ULN) (biliary drainage is allowed for biliary obstruction; elevated bilirubin should be caused by obstruction not impaired liver function as assessed by albumin and INR values); (e) Albumin levels ≥ 2.8 g/dL; (f) Patients not receiving therapeutic anticoagulation must have an INR< 2.0 ULN and PTT < 1.5 ULN within 7 days prior to randomization. The use of full dose anticoagulants is allowed as long as the INR or PTT is within therapeutic limits (according to the medical standard in the institution) and the patient has been on a stable dose for anticoagulants for at least three weeks at the time of inclusion; (g) AST (SGOT)/ALT (SGPT) ≤ 2.5 x institutional ULN unless liver metastases are present, in which case it must be ≤ 5x ULN; (h) Serum Creatinine ≤ 1.5 x ULN and a calculated creatinine clearance rate ≥ 60 mL /min