Study of TRIFLURIDINE/TIPIRACIL in Previously Treated Cholangiocarcinoma

This is a multi-centre, open-label, single arm phase 2 study to assess the efficacy of TRIFLURIDINE/TIPIRACIL, in patients with advanced cholangiocarcinoma as measured by median progression-free survival (PFS).

This study will enroll a total of 47 patients over a 12-month period, according to a two stage enrollment design. Nine patients will be enrolled during the first stage and the trial will be terminated if 4 or more out of the 9 have disease progression. If the trial goes on to the second stage, a total of 47 patients (38 in second stage) will be required.

Patients will be seen prior to enrolment (within 28 days of treatment), every 4 weeks while on treatment, at the end of treatment, and 30 days post-treatment. Patients will remain on long-term follow-up and will be seen every 12 weeks (+/- 14 days) until 1 year post-treatment when they will enter into the survival follow-up period and will be contacted every 12 weeks by phone until progression or toxicity.


Eligibility Criteria:
Inclusion Criteria:

1. Histologically documented locally advanced or metastatic biliary tract cancer (intra or extrahepatic cholangiocarcinoma or gallbladder cancer) previously treated with first line standard chemotherapy (gemcitabine-based chemotherapy at least one cycle). Patients who develop a recurrence after adjuvant capecitabine therapy must have subsequently received at least one cycle of a gemcitabine-based therapy to be eligible. Patients who have received gemcitabine in the adjuvant setting but progressed within 6 months of their last cycle will be eligible for the study.
2. Presence of measurable disease as assessed by CT scan of the chest, abdomen and pelvis based on RECIST 1.1.
3. ECOG performance status of 0 or 1.
4. Expected life expectancy of ≥ 3 months.
5. Age 18 years and above
6. Able to swallow and retain oral medication.
7. Adequate hematologic function defined by the following laboratory parameter:

   1. Hemoglobin ≥ 9g/dL
   2. Absolute neutrophil count ≥1.5 x 109/L
   3. Platelet count ≥75x 109/L
8. Adequate hepatic and renal function as defined by:

   1. AST and ALT ≤ 3.0 X ULN (≤ 5 if liver metastasis present)
   2. Total bilirubin ≤ 1.5X ULN
   3. Calculated creatinine clearance ≥50 ml/min using Cockcroft-Gault formula
9. Patients who have treated brain metastasis (via local radiation standards or surgical resection or local techniques) and who are either off steroids or on a stable dose of steroids for at least one month (30 days), AND who are off anticonvulsants, AND have radiological documented stability of lesions for at least 3 months may be eligible.
10. Patients must have the ability to read, understand, and sign an informed consent and must be willing to comply with study treatment and procedures.

Exclusion Criteria:

1. Any malignancy related to HIV, history of HIV, history of known HBV surface antigen positivity (subjects with documented laboratory evidence of HBV clearance may be enrolled) or positive HCV antibody. Testing for these diseases is not mandatory unless clinically indicated
2. Chemotherapy, radiotherapy, immunotherapy, or other anti-cancer therapy including investigational drugs within 28 days prior to enrolment.
3. Patients with unresolved Grade 3/4 toxicities from prior therapies.
4. Any major surgery within the last four weeks.
5. Previous or concurrent malignancies, excluding curatively treated in situ carcinoma of the cervix or uterus or non-melanoma skin cancer or in-situ carcinoma of the prostate (Gleason score ≤ 7, with all treatment being completed 6 months prior to enrollment, unless at least 5 years have elapsed since last treatment and the patient is considered cured)
6. Patients with locally or centrally known FGFR2 fusion (Sunnybrook, Ottawa and PMCC sites only).
7. Female patients of childbearing potential and men able to father children who do not agree to use adequate methods of contraception from time of enrolment until 6 months after the last date of treatment administration.
8. Women who are breastfeeding
9. Patients with suspected or documented leptomeningeal disease.