| 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 [pancreaticobiliary subtype only; see exclusion criterion 1] cancers) that is locally advanced, unresectable or metastatic (AJCC edition 8, 2018). |
|
| 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) based on BICR
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 sub-study will be carried out to assess any potential effects of the NUC-1031 + cisplatin combination on cardiac depolarisation. |
|
| 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 [pancreaticobiliary subtype only; see exclusion criterion 1] 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. 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.
• ALT and/or AST <5 × ULN
• Creatinine clearance ≥45 mL/min actual or calculated by the Cockcroft-Gault method.
• International normalised 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. Patients with the presence of bundle branch block for whom a QT calculation cannot be reliably determined should not be included.
10. Human Immunodeficiency Virus (HIV)-infected patients who are healthy and have a low risk of Acquired Immune Deficiency Syndrome-(AIDS) 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 and one of which must be a highly effective form 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 or ampullary cancer of the intestinal
or mixed subtypes.
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 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 nonmelanoma
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 or 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 otherco-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 randomisation.
10. Major surgery within 28 days prior to randomisation; 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 (see Appendix 3).
14. Administration of a live vaccination within 28 days prior to randomisation.
15. Ongoing or recent (≤6 months) hepatorenal syndrome. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Overall survival (OS), defined as median time, in months, from the date of randomization to the date of death from any cause.
Objective response rate (ORR), defined as the peercentage of patients achieving a confirmed complete or partial response to treatment as assessed by blinded independent review according to RECIST v1.1 criteria in patients with measurable disease at baseline. Patients will receive a confirmatory scan 28-42 days after response is first observed. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
OS: Evaluated on an ongoing basis from randomisation, then every 12 weeks from the date of treatment discontinuation until the date of death from any cause, up to a maximum of 18 months after the last patient starts treatment.
ORR: Evaluated every 9 weeks from start of treatment or, where treatment is stopped with no evidence of progression, every 12 weeks until disease progression or death from any cause, up to a maximum of 18 months after the last patient starts treatment.
|
|
| E.5.2 | Secondary end point(s) |
Progression-free survival (PFS), based on blinded independent review according to RECIST v1.1 criteria and defined as the time from randomisation to the first observation of objective tumour progression or death from any cause.
Duration of response (DoR), defined as the time from initial clinical response to the first observation of tumour progression or death from any cause as assessed by blinded independent review.
12-month survival, defined as the proportion of patients still alive at 12 months from randomisation.
18-month survival, defined as the proportion of patients still alive at 18 months from randomisation.
Disease control rate (DCR), based on blinded independent review according to RECIST v1.1, defined as the percentage of patients demonstrating a Best Overall Response of Complete Response, Partial Response or Stable Disease.
Safety and tolerability, assessed by total incidence of Treatment Emergent Adverse Events (TEAEs) according to Common Terminology Criteria for Adverse Events (CTCAE) v5.0.
Pharmacokinetics of NUC-1031, and dFdC and dFdU metabolites characterised by maximum observed plasma concentration (Cmax), area under the plasma concentration-time curve (AUC), elimination half-life (t½), terminal elimination rate constant (λz), clearance and volume of distribution. Blood samples taken within 10 minutes post-end of infusion, 2 hours post-end of infusion (±30 minutes) and 6 hours post-end of infusion (±30 minutes) on Day 1 of Cycle 1.
A robust sub-study will be carried out to assess the effect of the NUC-1031 + cisplatin combination on cardiac repolarisation in a subset of patients. Intensive ECG monitoring will be implemented at a subset of sites to collect QT/QTc data for
74 patients (approximately 37 patients in each treatment group) during the first 2 cycles of
treatment to allow robust analysis of ECG parameters.
Comparison of patient-reported quality of life (QoL) scores in Arm A and Arm B, assessed using the European Organisation for Research and Treatment (EORTC) Quality of Life Questionnaire (QLQ-C30) using 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 |
Efficacy (PFS, 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.
QT/QTc analysis: after completion of the QT sub-study.
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 | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 69 |
| 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 |
| Korea, Republic of |
| Russian Federation |
| Taiwan |
| Turkey |
| Ukraine |
| United States |
| France |
| Germany |
| Hungary |
| Italy |
| Spain |
| United Kingdom |
| Czechia |
|
| 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 at the discretion of the treating physician 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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