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Phase Ib/II Trial of Nal-Irinotecan and Nivolumab as Second-Line Treatment in Patients With Advanced Biliary Tract Cancer

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT03785873
Recruitment Status : Active, not recruiting
First Posted : December 24, 2018
Last Update Posted : September 27, 2021
Bristol-Myers Squibb
Information provided by (Responsible Party):
University of Michigan Rogel Cancer Center

Brief Summary:
The purpose of this study is to test the effectiveness (how well the drug works), safety, and tolerability of the investigational drug combination of nivolumab plus nanoliposomal-irinotecan, 5-fluorouracil, and leucovorin for patients with advanced or metastatic biliary tract cancer after progression on first-line systemic therapy.

Condition or disease Intervention/treatment Phase
Biliary Tract Cancer Drug: Nivolumab Drug: Nanoliposomal-Irinotecan Drug: 5-Fluorouracil Drug: Leucovorin Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 34 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Single Arm Phase Ib/II Multi-Center Study of Nivolumab in Combination With Nanoliposomal-Irinotecan, 5-Fluorouracil, and Leucovorin as Second Line Therapy for Patients With Advanced Biliary Tract Cancer
Actual Study Start Date : May 22, 2019
Estimated Primary Completion Date : May 2023
Estimated Study Completion Date : May 2023

Arm Intervention/treatment
Experimental: Nal-Irinotecan and Nivolumab Drug: Nivolumab
Intravenous (IV) infusion
Other Name: Opdivo®, BMS-936558, MDX-1106, ONO-4538

Drug: Nanoliposomal-Irinotecan
Intravenous (IV) infusion
Other Name: Onivyde®

Drug: 5-Fluorouracil
Intravenous (IV) infusion
Other Name: 5-FU

Drug: Leucovorin
Intravenous (IV) infusion

Primary Outcome Measures :
  1. Phase Ib: Incidence of dose-limiting toxicities (DLTs) of drug combination nanoliposomal-Irinotecan, 5-fluorouracil, leucovorin and nivolumab [ Time Frame: At 4 weeks after initiation of study treatment ]
    Adverse events will be graded according to NCI Common Toxicity Criteria for Adverse Events (CTCAE) version 5.0

  2. Phase II: Median Progression-Free Survival (PFS) [ Time Frame: Up to 2 years after last dose of study treatment or 3 years after first date of treatment initiation for those that remain on treatment ]
    Based on Kaplan-Meier estimates.

Secondary Outcome Measures :
  1. Incidence of adverse events [ Time Frame: Until discontinuation of study treatment, up to approximately 2 years after initiating study treatment or 3 years after first date of treatment initiation for those that remain on treatment ]
    Reportable adverse events are defined by the study protocol and graded according to the NCI Common Toxicity Criteria for Adverse Events (CTCAE) v5.0.

  2. Overall Response Rate (ORR) [ Time Frame: Up to 2 years after last dose of study treatment ]
    Determined per the combined Response Evaluation Criteria in Solid Tumours (RECISTv1.1) and immune-related RECIST (irRECIST) criteria

  3. Median Overall Survival (OS) [ Time Frame: Up to 2 years after last dose of study treatment ]

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No


  • 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 PD- 1/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 RECISTv1.1) 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.
  • Age ≥18 years
  • Child-Pugh score of less than 7
  • ECOG performance status of 0-1
  • Ability to understand and willingness to sign IRB-approved informed consent
  • Available archived tissue (FFPE block or 20 unstained slides from prior core biopsy or surgery)
  • Must be able to tolerate CT and/or MRI with contrast
  • Adequate organ function (per protocol) 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 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, nal- irinotecan 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 blood test to rule out pregnancy 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 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).

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT03785873

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United States, Michigan
University of Michigan Rogel Cancer Center
Ann Arbor, Michigan, United States, 48109
Cancer and Hematology Centers of Western Michigan
Grand Rapids, Michigan, United States, 49503
United States, Utah
University of Utah
Salt Lake City, Utah, United States, 84132
United States, Washington
Virginia Mason
Seattle, Washington, United States, 98101
United States, Wisconsin
University of Wisconsin
Madison, Wisconsin, United States, 53705
Sponsors and Collaborators
University of Michigan Rogel Cancer Center
Bristol-Myers Squibb
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Principal Investigator: Vaibhav Sahai, MBBS, MS University of Michigan
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Responsible Party: University of Michigan Rogel Cancer Center Identifier: NCT03785873    
Other Study ID Numbers: UMCC 2018.101
HUM00151852 ( Other Identifier: University of Michigan )
First Posted: December 24, 2018    Key Record Dates
Last Update Posted: September 27, 2021
Last Verified: September 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: IPD that underlie the results published in peer reviewed research articles, after deidentification.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Time Frame: Beginning 9 months and ending 36 months following article publication.
Access Criteria: Investigators whose proposed use of the data is for meta-analysis, and has been approved by an independent review committee identified for this purpose. Proposals should be directed to To gain access, data requestors will need to sign a data access agreement.

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
Additional relevant MeSH terms:
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Biliary Tract Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Biliary Tract Diseases
Digestive System Diseases
Molecular Mechanisms of Pharmacological Action
Antimetabolites, Antineoplastic
Antineoplastic Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antineoplastic Agents, Immunological
Immune Checkpoint Inhibitors
Topoisomerase I Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Protective Agents
Vitamin B Complex