| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| 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. |
|
| E.1.1.1 | Medical condition in easily understood language |
| Cancer of the biliary tract |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To compare NUC-1031/cisplatin (Arm A) to the gemcitabine/cisplatin standard of care (Arm B) and to detect a clinically meaningful improvement in Overall Survival and Objective Response Rate. |
|
| E.2.2 | Secondary objectives of the trial |
To compare the following between the two treatment arms:
- Progression-free survival (PFS) based on BICR
- Duration of response (DoR) based on BICR
- 18- and 12-month survival
- Disease control rate (DCR)
To assess the safety and tolerability of NUC-1031
To explore the pharmacokinetics of NUC-1031
To assess changes in patient-reported quality of life |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
| A robust QT substudy will be carried out to assess any potential effects of the NUC-1031 + cisplatin combination on QT interval prolongation. |
|
| E.3 | Principal inclusion criteria |
1. Written informed consent and authorisation 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. Patients with measurable (as per RECIST v1.1 criteria) or non-measurable disease are permitted.
5. Life expectancy ≥16 weeks.
6. 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 entry, 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 entry. 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 ≥10 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.
• ALT and/or AST <5 × ULN
• Serum creatinine ≤1.5 × ULN or creatinine clearance ≥45 mL/min actual or calculated by
the Cockcroft-Gault method.
• International normalised ratio (INR) <1.5 and partial thromboplastin time (PTT)
<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 Immune Deficiency 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 sterilisation) 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).
|
|
| E.4 | Principal 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-sensitising low-dose chemotherapy) for localised disease and there is now clear evidence of disease progression requiring systemic chemotherapy.• Photodynamic therapy: prior photodynamic therapy for localised disease with no evidence of metastatic disease or for localised 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 AEs 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 the excipients contained in NUC-1031 or diluent solution (dimethylacetamide [DMA], Kolliphor ELP, Tween 80).
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, low grade prostate cancer not requiring treatment or other solid tumours curatively treated with no evidence of disease for ≥3 years.
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. 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.
8. Prior exposure to another investigational agent within 28 days prior to randomisation.
9. Major surgery within 28 days prior to randomisation; patient must have completely recovered from any prior surgical or other procedures.
10. Pregnant or breastfeeding.
11. Residual toxicities from prior treatments or procedures which have not regressed to Grade ≤1 severity (CTCAE v5.0), except for alopecia or ≤Grade 1 peripheral neuropathy.
12. Concomitant use of drugs at doses known to cause clinically relevant prolongation of QT/QTc interval.
13. Administration of a live vaccination within 28 days prior to randomisation.
14. Ongoing or recent (≤6 months) hepatorenal syndrome. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
OS, defined as the time from randomisation to the time of death from any cause.
ORR, defined as the percentage of patients achieving a confirmed complete or partial response to treatment as assessed by BICR according to RECIST v1.1 criteria. This will be assessed only in patients with measurable disease at baseline. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Interim Analysis 1 - approx 25.5 months or 418 patients with measurable disease randomised. This will assess ORR for demonstration of efficacy, and assess OS for futility.
Interim Analysis 2 - approx 33.1 months or approx 425 deaths. This will assess ORR and OS for demonstration of efficacy.
Interim Analysis 3 - approx 40 months or 541 deaths. This will assess OS for efficacy.
Final Analysis - approx 48 months or 637 deaths. |
|
| E.5.2 | Secondary end point(s) |
Progression Free Survival
• PFS, based on BICR according to RECIST v1.1 criteria, defined as the time from randomisation to the first observation of objective tumour progression or death from any cause. For patients with non-measurable disease at baseline, refer to the protocol criteria for disease progression.
Efficacy
• DoR, as assessed by BICR, defined as the time from initial clinical response (partial response [PR] or complete response [CR] that is subsequently confirmed) to the first observation of tumour progression or death from any cause
• 18-month survival
• 12-month survival
• DCR, based on BICR according to RECIST v1.1 criteria, defined as the percentage of patients demonstrating CR, PR, or stable disease (SD)
Safety
Safety and tolerability will be assessed by evaluation of the following:
• Treatment-emergent AEs (TEAEs), including TEAEs by severity grade using Common Terminology Criteria for Adverse Events (CTCAE) v5.0
• Serious TEAEs (SAEs)
• Deaths due to TEAEs
• Treatment discontinuations due to TEAEs
• Clinically-significant changes in laboratory parameters
• Changes in Eastern Cooperative Oncology Group (ECOG) status, physical exam, electrocardiogram (ECG) and vital signs
A robust QT analysis substudy will be carried out to assess the effect of the NUC-1031 + cisplatin combination on QT interval prolongation in a subset of patients.
Pharmacokinetics of NUC-1031
Sparse PK sampling will be taken on Cycle 1 Day 1 at the end of infusion, 2 hours after the end of infusion, and 6 hours after the end of infusion, to capture Ctrough and Cmax plasma levels.
Patient-Reported Quality of Life
Patient-reported quality of life will be assessed using the European Organisation for Research and Treatment (EORTC) Quality of Life Questionnaire (QLQ-C30) with the QLQ-BIL21 module and the 5-level EuroQol five-dimension scale (EQ-5D-5L). |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Progression Free Survival - end the end of the study.
Efficacy (DoR, 18/12-month survival, DCR) - at the end of the study.
Safety - after 50 patients have been randomised in total, at every 6 months and at the end of the study.
QTc analysis - after 40 patients have been enrolled into the QT substudy.
Pharmacokinetics of NUC-1031 - end of the study.
Patient-Reported Quality of Life - at the end of the study. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | Yes |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Assessment of archival tumour sample characteristics that may further an understanding of the mechanism(s) through which the clinical activity of NUC-1031 is achieved. |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 70 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Canada |
| Czech Republic |
| France |
| Germany |
| Hungary |
| Italy |
| Korea, Republic of |
| Poland |
| Russian Federation |
| Spain |
| Taiwan |
| Turkey |
| Ukraine |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
The end of study date is defined as the time when 637 deaths have occurred, unless the results for OS meet the pre-specified criterion at an interim analysis to stop for early demonstration of efficacy, or unless the study is terminated early on safety grounds on the recommendation of the IDMC.
Patients who are still receiving benefit from study treatment at the end of study date may continue study treatment until disease progression. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
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