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Nivolumab, Nal-Irinotecan, Fluorouracil, and Leucovorin as Second Line Therapy in Treating Patients with Advanced Biliary Tract Cancer

Trial Status: Active

This phase Ib / II trial studies the side effects of nivolumab, nal-irinotecan, fluorouracil, and leucovorin and to see how well they work in treating patients with biliary tract cancer that has spread to other places in the body (advanced). Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body’s immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Drugs used in chemotherapy, such as nal-irinotecan, 5-fluorouracil, and leucovorin work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving nivolumab together with chemotherapy (nal-irinotecan, 5-fluorouracil, and leucovorin) may work better in treating patients with biliary tract cancer compared to chemotherapy alone.

Inclusion Criteria

  • Patients must have a pathologically confirmed carcinoma of the biliary tract (intra-hepatic, extra-hepatic [hilar, distal] or gall bladder) that is not eligible for curative resection, transplantation, or ablative therapies. Tumors with mixed hepatocellular and cholangiocarcinoma histology are excluded
  • Patients must have received one and only one prior systemic therapy for advanced disease. Prior therapies must have not included irinotecan or PD1/PD-L1 antibody. Patient should have either progressed on or within 6 months of first-line systemic therapy or deemed intolerant of that therapy
  • Prior surgical resection, radiation, chemoembolization, radioembolization or other local ablative therapies are permitted if completed >= 4 weeks prior to registration AND if patient has recovered to =< grade 1 toxicity
  • Patients must have radiographically measurable disease (as per Response Evaluation Criteria in Solid Tumors [RECIST] version [v]1.1) in at least one site not previously treated with radiation or liver directed therapy (including bland, chemo- or radio-embolization, or ablation) either within the liver or in a metastatic lesion
  • Child-Pugh score of less than 7
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0-1
  • Ability to understand and willingness to sign Institutional Review Board (IRB)-approved informed consent
  • Available archived tissue (formalin-fixed paraffin-embedded [FFPE] block or 20 unstained slides from prior core biopsy or surgery)
  • Must be able to tolerate computed tomography (CT) and/or magnetic resonance imaging (MRI) with contrast
  • Absolute neutrophil count >= 1500/mm^3 (assessed =< 2 weeks prior to registration)
  • Hemoglobin >= 9 g/dL (assessed =< 2 weeks prior to registration)
  • Platelets >= 100,000/mm^3 (assessed =< 2 weeks prior to registration)
  • Serum creatinine =< 1.5 x upper limit of normal (ULN) (assessed =< 2 weeks prior to registration)
  • Albumin >= 3.0 g/dL (assessed =< 2 weeks prior to registration)
  • Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 3.0 x ULN (=< 5 x ULN if liver metastasis (assessed =< 2 weeks prior to registration)
  • Total bilirubin =< 1.5 x ULN (assessed =< 2 weeks prior to registration)
  • Must not have received systemic steroid therapy, or any other form of immunosuppressive therapy within 14 days prior to registration. Short bursts of steroids of 5-7 days (for chronic obstructive pulmonary disease [COPD] exacerbation or other similar indication) are allowed
  • No prior history of solid organ transplantation or brain metastasis (unless treated, asymptomatic and stable)
  • Must not have undergone a major surgical procedure < 4 weeks prior to registration
  • Must not have an active second malignancy other than non-melanoma skin cancer or cervical carcinoma in situ. Patients with history of malignancy are eligible provided primary treatment of that cancer was completed > 1 year prior to registration and the patient is free of clinical or radiologic evidence of recurrent or progressive malignancy
  • Must have no ongoing active, uncontrolled infections (afebrile for > 48 hours off antibiotics)
  • Must not have received a live vaccine within 30 days of registration
  • Must not have a psychiatric illness, other significant medical illness, or social situation which, in the investigator’s opinion, would limit compliance or ability to comply with study requirements
  • Women must not be pregnant or breastfeeding since 5-fluorouracil, nalirinotecan and/or nivolumab may harm the fetus or child. All females of childbearing potential (not surgically sterilized and between menarche and 1- year post menopause) must have a pregnancy test (blood or urine) within 2 weeks prior to registration
  • Women of child-bearing potential and men must agree to use 2 methods of adequate contraception (hormonal plus barrier or 2 barrier forms) OR abstinence prior to study entry, for the duration of study participation, and for 5 months (for women) and 7 months (for men) following completion of study therapy
  • Participants with an active, known or suspected autoimmune disease which may affect vital organ function, or has/may require systemic immunosuppressive therapy for management are excluded. Participants 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
  • Participants with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of registration are excluded. Inhaled, ocular, intra-articular, intra-nasal or topical steroids, and adrenal replacement steroid doses > 10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease
  • No known UGT1A1* variants or Gilbert’s syndrome
  • Prisoners or subjects who are involuntarily incarcerated, or compulsorily detained for treatment of either a psychiatric or physical (e.g. infectious disease) illness would be excluded
  • No known hypersensitivity to 5-fluorouracil, leucovorin, irinotecan, and/or nivolumab
  • Must not have ongoing bowel obstruction
  • No known human immunodeficiency virus (HIV), hepatitis B or hepatitis C infection that is untreated and/or with a detectable viral load
  • Patients must not have uncontrolled intercurrent illness including, but not limited to, interstitial lung disease, symptomatic congestive heart failure, unstable angina pectoris, uncontrolled cardiac arrhythmia
  • No known medical condition (e.g. a condition associated with uncontrolled diarrhea such as ulcerative colitis or acute diverticulitis) that, in the investigator’s opinion, would increase the risk associated with study participation or interfere with the interpretation of safety results
  • Patients must not be on warfarin, strong CYP3A4 inducers (such as phenytoin, phenobarbital, primidone, carbamazepine, rifampin, rifabutin, rifapentine or St. John’s wort), strong CYP3A4 inhibitors (such as ketoconazole, clarithromycin, indinavir, itraconazole, lopinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telaprevir, voriconazole), and strong UGT1A1 inhibitors (such as atazanavir, gemfibrozil, indinavir and ketoconazole)


Ann Arbor
University of Michigan Comprehensive Cancer Center
Status: ACTIVE
Contact: Vaibhav Sahai
Phone: 734-936-4991
Grand Rapids
Cancer and Hematology Centers of Western Michigan
Status: ACTIVE
Contact: Sreenivasa R. Chandana


Salt Lake City
Huntsman Cancer Institute / University of Utah
Status: ACTIVE
Contact: Heloisa Prado Soares


Virginia Mason Medical Center
Status: ACTIVE
Contact: Vincent Joseph Picozzi


University of Wisconsin Hospital and Clinics
Status: ACTIVE
Contact: Dustin Alan Deming


I. Determine the recommended phase 2 dose (RP2D) and dose limiting toxicities (DLTs) of liposomal irinotecan (nal-Irinotecan), fluorouracil (5-fluorouracil), leucovorin and nivolumab in subjects with advanced biliary cancer. (Phase Ib)

II. Determine the median progression free survival (PFS). (Phase II)


I. Evaluate the safety and toxicity of this drug combination in this patient population.

II. Evaluate the overall response rate (ORR) and median overall survival (OS).


I. To explore biomarkers of response and mechanisms of resistance based on the exploratory analysis of tumor tissue obtained through serial biopsies and blood.

Ia. Levels of PD-L1 (B7-H1), PD-L2, CTLA-4, T cell subset, myeloid-derived cell subset infiltration by immunohistochemistry (IHC) at baseline (for all patients), at 2 months and progression (for patients enrolled at University of Michigan).

Ib. Whole exome genomic and transcriptomic (ribonucleic acid sequence [RNAseq]) analysis for tumor biology, deoxyribonucleic acid (DNA) damage response (DDR) and immune signature at baseline and progression.

Ic. Peripheral blood mononuclear cells (PBMC) collection for immune cell subset analysis including serum for future biomarker analysis.


Patients receive leucovorin intravenously (IV) over 90 minutes, liposomal irinotecan IV over 90 minutes, nivolumab IV over 30 minutes, and fluorouracil over 46 hours on day 1. Cycles repeat every 14 days for 2 years in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for up to 2 years from treatment discontinuation or until death, whichever comes first, or 3 years after first date of treatment initiation.

Trial Phase Phase I/II

Trial Type Treatment

Lead Organization
University of Michigan Comprehensive Cancer Center

Principal Investigator
Vaibhav Sahai

  • Primary ID UMCC 2018.101
  • Secondary IDs NCI-2019-04693, CA209-8LF, HUM00151852
  • ID NCT03785873