Comparing NUC-1031 Plus Cisplatin to Gemcitabine Plus Cisplatin in Patients With Advanced Biliary Tract Cancer

Inclusion Criteria:

1. Written informed consent and authorization to use and disclose health information.
2. Ability to comprehend and willingness to comply with the requirements of thisprotocol, including the QoL questionnaires.
3. Female or male patients aged ≥18 years.
4. Histologically- or cytologically-confirmed adenocarcinoma of the biliary tract (including gallbladder, intra and extra-hepatic biliary ducts and ampullary cancers)that is locally advanced, unresectable or metastatic (AJCC edition 8, 2018). Patientswith measurable (as per RECIST v1.1 criteria) or non-measurable disease are permitted.
5. Life expectancy ≥16 weeks.
6. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.
7. Adequate biliary drainage with no evidence of ongoing infection. If applicable,treatable and clinically-relevant biliary duct obstruction has been relieved byinternal endoscopic drainage/stenting at least 2 weeks previously or by palliativebypass surgery or percutaneous drainage prior to study treatment, and the patient hasno active or suspected uncontrolled infection. Patients fitted with a biliary stentshould be clinically stable and free of signs of infection for ≥2 weeks prior to studytreatment. Patients with improving biliary function who meet all other inclusioncriteria may be re-tested during the screening window.
8. Adequate bone marrow, hepatic, and renal function, as evidenced by:

• Absolute neutrophil count (ANC) ≥1,500/μL without colony-stimulating factorsupport
• Platelet count ≥100,000/μL
• Haemoglobin ≥9 g/dL without need for haematopoietic growth factor or transfusionsupport in prior 2 weeks
• Total bilirubin <2 × upper limit of normal (ULN); does not apply to patients withGilbert's syndrome. Consistent with inclusion criterion 7, patients whose wholebilirubin and biliary function is recovering may be re-tested during thescreening period.
• Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) <5 × ULN
• Creatinine clearance ≥45 mL/min actual or calculated by the Cockcroft-Gaultmethod
• International normalized ratio (INR) <1.5 and activated partial thromboplastintime (aPTT) <1.5 × ULN; does not apply to patients on an anti-coagulant withstable dose 28 days prior to first dose.

9. QTc interval <450 msec (males) or <470 msec (females), in the absence of bundle branchblock. In the presence of bundle branch block with consequent QTc prolongation,patients may be enrolled based on a careful risk-benefit assessment.
10. Human Immunodeficiency Virus-infected patients who are healthy and have a low risk ofAcquired Immunodeficiency Syndrome-related outcomes may be included in this study.
11. Female patients of child-bearing potential (i.e., all women except those who arepost-menopausal for ≥1 year or who have a history of hysterectomy or surgicalsterilization) must have a negative pregnancy test within 3 days prior to the firststudy drug administration. All patients of child-bearing potential must agree topractice true abstinence or to use two highly effective forms of contraception, one ofwhich must be a barrier method of contraception, from the time of screening until 6months after the last dose of study medication.
12. Male patients with a female partner must either have had a successful vasectomy orthey and their female partner meet the criteria above (not of childbearing potentialor practicing highly effective contraceptive methods).

Exclusion Criteria:

1. Combined or mixed hepatocellular/cholangiocarcinoma.
2. Prior systemic therapy for advanced or metastatic biliary tract cancer. However, priorchemotherapy in the adjuvant setting or low-dose chemotherapy given in conjunctionwith radiotherapy in the adjuvant setting and completed at least 6 months prior toenrolment is permitted. The following prior interventions are allowed provided thepatient has fully recovered:

• Surgery: non-curative resection with macroscopic residual disease or palliativebypass surgery. Patients who have previously undergone curative surgery must nowhave evidence of non-resectable disease requiring systemic chemotherapy.
• Radiotherapy: prior radiotherapy (with or without radio-sensitizing low-dosechemotherapy) for localized disease and there is now clear evidence of diseaseprogression requiring systemic chemotherapy.
• Photodynamic therapy: prior photodynamic therapy for localized disease with noevidence of metastatic disease or for localized disease to relieve biliaryobstruction in the presence of metastatic disease provided there is now clearevidence of disease progression requiring systemic chemotherapy.
• Palliative radiotherapy: palliative radiotherapy provided that all adverse eventshave resolved and the patient has measurable disease outside the field ofradiation.

3. Prior treatment with or known hypersensitivity to NUC-1031, gemcitabine, cisplatin orother platinum-based agents or history of allergic reactions attributed to anyparenteral excipients (e.g. dimethylacetamide [DMA], Cremophor EL, Polysorbate 80,Solutol HS 15).
4. Symptomatic central nervous system or leptomeningeal metastases.
5. History of other malignancies, except adequately treated non-melanoma skin cancer,curatively treated in situ cancer of the cervix, surgically excised or potentiallycuratively treated ductal carcinoma in situ of the breast, or low grade prostatecancer or patients after prostatectomy not requiring treatment. Patients with previousinvasive cancers are eligible if treatment was completed more than 3 years prior toinitiating the current study treatment, and the patient has had no evidence ofrecurrence since then.
6. Concurrent serious (as deemed by the Investigator) medical conditions, including, butnot limited to, New York Heart Association class III or IV congestive heart failure,history of congenital prolonged QT syndrome, uncontrolled infection, active hepatitisB or C, or other co-morbid conditions that in the opinion of the Investigator wouldimpair study participation or cooperation.
7. Congenital or acquired immunodeficiency (e.g., serious active infection with HIV). Asper inclusion criterion 10, patients with HIV who are healthy and have a low risk ofAIDS related outcomes are eligible.
8. Other acute or chronic medical, neurological, or psychiatric condition or laboratoryabnormality that may increase the risk associated with study participation orinvestigational product administration or may interfere with the interpretation ofstudy results and, in the judgment of the Investigator, would make the patientinappropriate for entry into this study.
9. Prior exposure to another investigational agent within 28 days prior to randomization.
10. Major surgery within 28 days prior to randomization; patient must have completelyrecovered from any prior surgical or other procedures.
11. Pregnant or breastfeeding.
12. Residual toxicities from prior treatments or procedures which have not regressed toGrade ≤1 severity (CTCAE v5.0), except for alopecia or ≤ Grade 2 peripheralneuropathy.
13. Concomitant use of drugs at doses known to cause clinically relevant prolongation ofQT/QTc interval.
14. Administration of a live vaccination within 28 days prior to randomization.
15. Ongoing or recent (≤6 months) hepatorenal syndrome.