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.
Conditions
Interventions
Product Name: Acelarin
Product Code: NUC-1031
Pharmaceutical Form: Solution for injection
INN or Proposed INN: Fosgemcitabine palabenamide
CAS Number: 1562406-27-2
Current Sponsor code: NUC-1031
Conce
Sponsors
NuCana plc
Eligibility
Sex/Gender
All
Inclusion criteria
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). Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1
Exclusion criteria
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.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: 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.;Secondary Objective: 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;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.;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. | — |
Secondary
| Measure | Time frame |
|---|---|
| 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).;Timepoint(s) of evaluation of this end point: Progression Free Survival - end the end | — |
Countries
Australia, Canada, Czech Republic, France, Germany, Hungary, Italy, Korea, Republic of, Russian Federation, Spain, Taiwan, Turkey, Ukraine, United Kingdom, United States
Contacts
Public ContactNuCana Clinical Study Information
NuCana plc
Outcome results
None listed