Fluorouracil, Leucovorin, and Nanoliposomal Irinotecan for the Treatment of Previously Treated Advanced Biliary Tract Cancer, NAPOLI-2 Study

Inclusion Criteria

• Pathologically-confirmed biliary tract cancer (cholangiocarcinoma or gallbladder adenocarcinoma)
• Disease progression on or intolerance of gemcitabine- and platinum-based chemotherapy
• No more than 1 prior line of chemotherapy for unresectable or metastatic disease (adjuvant therapy does not count)
• Measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-1
• Human immunodeficiency virus (HIV)-positive patients are eligible provided: * Patients are on a stable highly active antiretroviral therapy (HAART) regimen that has not changed in at least 6 months * Patients are not on concurrent prophylactic antibiotics or antifungals * The CD4 count above 250 cells/uL and the viral load is undetectable
• Subjects with no brain metastases or a history of previously treated brain metastases who have been treated by surgery or stereotactic radiosurgery (SRS) at least 4 weeks prior to enrollment and have a baseline magnetic resonance imaging (MRI) that shows no evidence of active intracranial disease and at least 2 weeks off corticosteroids
• Consent to access archived tumor tissue if available (available tissue is not required for enrollment)
• Absolute neutrophil count (ANC) >= 1,500/mm^3
• Platelets >= 100 x 10^9/L
• Hemoglobin >= 9.0 g/dL. Patients may have a transfusion of red blood cells to meet the hemoglobin requirement
• Serum creatinine =< 1.5 x upper normal limit of institution’s normal range or creatinine clearance >= 30 mL/min for subjects with creatinine levels above institutional normal
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 3.0 x the upper normal limit of institution’s normal range. For subjects with liver metastases, AST and ALT < 5 x the upper normal limit of institution’s normal range is acceptable as long as there is no persistent nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, or eosinophilia
• Total bilirubin =< 1.5 x the upper normal limit of institution’s normal range. For subjects with liver metastases, total bilirubin > 1.5 - 3.0 x the upper normal limit of institution’s normal range is acceptable as long as there is no persistent nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, or eosinophilia
• Partial thromboplastin time (PTT) must be =< 1.5 x upper normal limit of institution’s normal range and INR (international normalized ratio) < 1.5. Subjects on anticoagulant (such as warfarin) will be permitted to enroll as long as the INR is in the acceptable therapeutic range as determined by the investigator
• Patients must have fully recovered from all effects of surgery. Patients must have had at least two weeks after minor surgery and four weeks after major surgery before starting therapy. Minor procedures requiring “twilight” sedation such as endoscopies or mediport placement may only require a 24-hour waiting period, but this must be discussed with an investigator
• Women of childbearing potential must have a negative serum pregnancy test within 14 days prior to initiation of treatment and/or postmenopausal women must be amenorrheic for at least 12 months to be considered of non-childbearing potential
• Patient is capable of understanding and complying with parameters as outlined in the protocol and able to sign and date the informed consent, approved by the Institutional Review Board (IRB), prior to the initiation of any screening or study-specific procedures

Exclusion Criteria

• Ampullary adenocarcinoma
• Women who are pregnant or breastfeeding
• Anti-cancer treatment within 3 weeks prior to enrollment
• Prior irinotecan or nanoliposomal irinotecan
• Known concurrent malignancy or other malignancy within 3 years except for non-melanomatous skin cancers, prostate or cervical cancers following curative therapy, superficial bladder cancer, or other noninvasive or indolent malignancy either that has undergone potentially curative treatment or not requiring active treatment as determined by the principal investigator
• Bowel obstruction
• Allergy or hypersensitivity to fluoropyrimidines, irinotecan, or nanoliposomal irinotecan
• Exposure to a strong CYP3A4 inducer, strong CYP3A4 inhibitor, or strong UGT1A1 inhibitor within 2 weeks of study start
• Clinically significant liver disease * Patients with resolved hepatitis B infection are eligible if hepatitis B surface antigen (HbsAg) testing is negative * Patients with resolved hepatitis C infection are eligible if viral ribonucleic acid (RNA) polymerase chain reaction (PCR) is negative
• Severe infections within 4 weeks prior to enrollment
• Major surgery within 4 weeks prior to enrollment
• Psychiatric illness or social situation that would limit compliance with study requirements
• Patient has any other concurrent severe and/or uncontrolled medical condition that would, in the investigator’s judgment, cause unacceptable safety risks, contraindicate patient participation in the clinical study or compromise compliance with the protocol (e.g. chronic pancreatitis, chronic active hepatitis, active untreated or uncontrolled fungal, bacterial or viral infections other than described above, etc.)
• Clinically significant, uncontrolled heart disease and/or cardiac repolarization abnormalities, including any of the following: * History of acute coronary syndromes (including myocardial infarction, unstable angina, coronary artery bypass grafting, coronary angioplasty, or stenting) or symptomatic pericarditis within 6 months prior to screening * History of documented congestive heart failure (New York Heart Association functional classification III-IV) * Documented cardiomyopathy * Clinically significant cardiac arrhythmias (e.g. ventricular tachycardia), complete left bundle branch block, high-grade atrioventricular (AV) block (e.g. bifascicular block, Mobitz type II and third-degree AV block) * Long QT syndrome or family history of idiopathic sudden death or congenital long QT syndrome, or any of the following: * Risk factors for Torsades de Pointes (TdP) including uncorrected hypokalemia or hypomagnesemia, history of cardiac failure, or history of clinically significant/symptomatic bradycardia * Concomitant use of medication(s) with a known risk to prolong the QT interval and/or known to cause Torsades de Pointes that cannot be discontinued (within 5 half-lives or 7 days prior to starting study drug) or replaced by safe alternative medication * Systolic blood pressure (SBP) > 160 mmHg or < 90 mmHg at screening