Biliary Tract Cancer
Conditions
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.
Interventions
DRUGNivolumab
Intravenous (IV) infusion
DRUGNanoliposomal-Irinotecan
Intravenous (IV) infusion
DRUG5-Fluorouracil
Intravenous (IV) infusion
DRUGLeucovorin
Intravenous (IV) infusion
Sponsors
University of Michigan Rogel Cancer Center
Ipsen
Bristol-Myers Squibb
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Inclusion * 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 Exclusion * 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).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase Ib: Incidence of Dose-limiting Toxicities (DLTs) of Drug Combination Nanoliposomal-Irinotecan, 5-fluorouracil, Leucovorin and Nivolumab | 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.The patients accrued to the phase 2 portion of the trial were also observed for DLT during the first cycle of therapy given the same dose level was used. |
| Median Progression-Free Survival (PFS) | Up to 2 years after last dose of study treatment, average of 4 months | Based on Kaplan-Meier estimates. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Treatment-related Adverse Events | 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. The maximum grade per type, per patient is reported below. |
| Overall Response Rate (ORR) | Up to 2 years after last dose of study treatment, average of 8.5 months | Determined per the combined Response Evaluation Criteria in Solid Tumours (RECISTv1.1) and immune-related RECIST (irRECIST) criteria. Complete Response and Partial Response are included. |
| Median Overall Survival (OS) | Up to 2 years | — |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORVaibhav Sahai, MBBS, MS
University of Michigan
Participant flow
Recruitment details
4 screen fails occured
Pre-assignment details
4 patients enrolled but did not start study treatment. 3 due to declining health and 1 who selected alternative therapy. All patients enrolled experienced the same dosing.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 10 Participants |
| Age, Categorical Between 18 and 65 years | 17 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 10 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants |
| Race (NIH/OMB) White | 25 Participants |
| Region of Enrollment United States | 30 participants |
| Sex: Female, Male Female | 12 Participants |
| Sex: Female, Male Male | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 26 / 30 |
| other Total, other adverse events | 28 / 30 |
| serious Total, serious adverse events | 22 / 30 |
Outcome results
None listed