Comparing NUC-1031 Plus Cisplatin to Gemcitabine Plus Cisplatin in Patients With Advanced Biliary Tract Cancer
Condition: Biliary Tract Cancer
MeSH terms: Biliary Tract Neoplasms
Intervention: NUC-1031; Gemcitabine; Cisplatin
Intervention description: IV infusion in 500 mL of 0.9% sterile saline for injection given over 30 minutes; IV infusion in 250 mL of 0.9% sterile saline for injection given in accordance with the package insert; IV in accordance with local institutional practice for biliary tract cancer, including the use of an appropriate hydration protocol
Intervention MeSH terms: Gemcitabine
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: 1:1 randomization model to either Arm A or Arm B
Masking: Single (Outcomes Assessor)
Masking description: Imaging scans will be assessed by blinded independent review according to RECIST v1.1
Enrollment: 773.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Adenocarcinoma; Ampullary; Antineoplastic Agents; Biliary Tract Cancer; Chemotherapy; Cholangiocarcinoma; Cisplatin; Digestive System Neoplasms; Distal Bile Duct; Extrahepatic; First-line Chemotherapy; Gallbladder; Gastrointestinal; Gemcitabine; Hepatobiliary; Intrahepatic; Locally advanced; Metastatic; Neoplasm; NUC-1031; ProTides; Untreated

Summary:

      NuTide:121 compares NUC-1031 with gemcitabine, both in combination with cisplatin, in
      patients with previously untreated advanced biliary tract cancer.

      The primary hypotheses are:

        -  The combination of NUC-1031 plus cisplatin prolongs overall survival compared to the
           gemcitabine plus cisplatin standard of care

        -  The combination of NUC-1031 plus cisplatin increases overall response rate compared to
           the gemcitabine plus cisplatin standard of care
    

Eligibility criteria:

        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 this
             protocol, 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). Patients
             with 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 by
             internal endoscopic drainage/stenting at least 2 weeks previously or by palliative
             bypass surgery or percutaneous drainage prior to study treatment, and the patient has
             no active or suspected uncontrolled infection. Patients fitted with a biliary stent
             should be clinically stable and free of signs of infection for ≥2 weeks prior to study
             treatment. Patients with improving biliary function who meet all other inclusion
             criteria 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 factor
                  support

               -  Platelet count ≥100,000/μL

               -  Haemoglobin ≥9 g/dL without need for haematopoietic growth factor or transfusion
                  support in prior 2 weeks

               -  Total bilirubin <2 × upper limit of normal (ULN); does not apply to patients with
                  Gilbert's syndrome. Consistent with inclusion criterion 7, patients whose whole
                  bilirubin and biliary function is recovering may be re-tested during the
                  screening period.

               -  Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) <5 × ULN

               -  Creatinine clearance ≥45 mL/min actual or calculated by the Cockcroft-Gault
                  method

               -  International normalized ratio (INR) <1.5 and activated partial thromboplastin
                  time (aPTT) <1.5 × ULN; does not apply to patients on an anti-coagulant with
                  stable dose 28 days prior to first dose.

          9. QTc interval <450 msec (males) or <470 msec (females), in the absence of bundle branch
             block. 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 of
             Acquired Immunodeficiency Syndrome-related outcomes may be included in this study.

         11. Female patients of child-bearing potential (i.e., all women except those who are
             post-menopausal for ≥1 year or who have a history of hysterectomy or surgical
             sterilization) must have a negative pregnancy test within 3 days prior to the first
             study drug administration. All patients of child-bearing potential must agree to
             practice true abstinence or to use two highly effective forms of contraception, one of
             which must be a barrier method of contraception, from the time of screening until 6
             months after the last dose of study medication.

         12. Male patients with a female partner must either have had a successful vasectomy or
             they and their female partner meet the criteria above (not of childbearing potential
             or 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, prior
             chemotherapy in the adjuvant setting or low-dose chemotherapy given in conjunction
             with radiotherapy in the adjuvant setting and completed at least 6 months prior to
             enrolment is permitted. The following prior interventions are allowed provided the
             patient has fully recovered:

               -  Surgery: non-curative resection with macroscopic residual disease or palliative
                  bypass surgery. Patients who have previously undergone curative surgery must now
                  have evidence of non-resectable disease requiring systemic chemotherapy.

               -  Radiotherapy: prior radiotherapy (with or without radio-sensitizing low-dose
                  chemotherapy) for localized disease and there is now clear evidence of disease
                  progression requiring systemic chemotherapy.

               -  Photodynamic therapy: prior photodynamic therapy for localized disease with no
                  evidence of metastatic disease or for localized disease to relieve biliary
                  obstruction in the presence of metastatic disease provided there is now clear
                  evidence of disease progression requiring systemic chemotherapy.

               -  Palliative radiotherapy: palliative radiotherapy provided that all adverse events
                  have resolved and the patient has measurable disease outside the field of
                  radiation.

          3. Prior treatment with or known hypersensitivity to NUC-1031, gemcitabine, cisplatin or
             other platinum-based agents or history of allergic reactions attributed to any
             parenteral 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 potentially
             curatively treated ductal carcinoma in situ of the breast, or low grade prostate
             cancer or patients after prostatectomy not requiring treatment. Patients with previous
             invasive cancers are eligible if treatment was completed more than 3 years prior to
             initiating the current study treatment, and the patient has had no evidence of
             recurrence since then.

          6. Concurrent serious (as deemed by the Investigator) medical conditions, including, but
             not limited to, New York Heart Association class III or IV congestive heart failure,
             history of congenital prolonged QT syndrome, uncontrolled infection, active hepatitis
             B or C, or other co-morbid conditions that in the opinion of the Investigator would
             impair study participation or cooperation.

          7. Congenital or acquired immunodeficiency (e.g., serious active infection with HIV). As
             per inclusion criterion 10, patients with HIV who are healthy and have a low risk of
             AIDS related outcomes are eligible.

          8. Other acute or chronic medical, neurological, or psychiatric condition or laboratory
             abnormality that may increase the risk associated with study participation or
             investigational product administration or may interfere with the interpretation of
             study results and, in the judgment of the Investigator, would make the patient
             inappropriate 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 completely
             recovered from any prior surgical or other procedures.

         11. Pregnant or breastfeeding.

         12. Residual toxicities from prior treatments or procedures which have not regressed to
             Grade ≤1 severity (CTCAE v5.0), except for alopecia or ≤ Grade 2 peripheral
             neuropathy.

         13. Concomitant use of drugs at doses known to cause clinically relevant prolongation of
             QT/QTc interval.

         14. Administration of a live vaccination within 28 days prior to randomization.

         15. Ongoing or recent (≤6 months) hepatorenal syndrome.