Biliary Tract Cancer
Conditions
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
Brief 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
Interventions
DRUGNUC-1031
IV infusion in 500 mL of 0.9% sterile saline for injection given over 30 minutes
DRUGGemcitabine
IV infusion in 250 mL of 0.9% sterile saline for injection given in accordance with the package insert
DRUGCisplatin
IV in accordance with local institutional practice for biliary tract cancer, including the use of an appropriate hydration protocol
Sponsors
NuCana plc
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Masking description
Imaging scans will be assessed by blinded independent review according to RECIST v1.1
Intervention model description
1:1 randomization model to either Arm A or Arm B
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR) | Evaluated at Screening (baseline) then every 9 weeks from treatment start (C1D1), or every 12 weeks if treatment is stopped with no evidence of progression, until disease progression or death from any cause up to the end of study, an average of 6 months. | Percentage of patients achieving a confirmed complete response (CR) or partial response (PR) to treatment as assessed by blinded independent review according to RECIST v1.1 criteria. ORR = patients with CR + patients with PR, where CR = disappearance of all target lesions PR = at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters This outcome was assessed in the population of patients with measurable disease at baseline who were also randomized ≥28 weeks before the data cut-off (ITTMD28). Patients were to receive a confirmatory scan 28-42 days after response is first observed. |
| Overall Survival (OS) | From the date of randomization until the date of death from any cause, assessed up to 12 months on average | The median time, in months, from the date of randomization to the date of death from any cause. For patients who were alive at the time of a data cut-off or were permanently lost to follow up, duration of OS was censored at the date at which they were last known to be alive. |
Countries
Australia, Canada, Czechia, France, Germany, Hungary, Italy, Russia, South Korea, Spain, Taiwan, Turkey (Türkiye), Ukraine, United Kingdom, United States
Participant flow
Recruitment details
A total of 773 patients were recruited between Dec 2019 and March 2022.
Participants by arm
| Arm | Count |
|---|---|
| A - NUC-1031 and Cisplatin 725 mg/m\^2 NUC-1031 administered in combination with 25 mg/m\^2 cisplatin on Days 1 and 8 of a 21-day cycle
NUC-1031: IV infusion in 500 mL of 0.9% sterile saline for injection given over 30 minutes
Cisplatin: IV in accordance with local institutional practice for biliary tract cancer, including the use of an appropriate hydration protocol | 388 |
| B - Gemcitabine and Cisplatin 1000 mg/m\^2 gemcitabine administered in combination with 25 mg/m\^2 cisplatin on Days 1 and 8 of a 21-day cycle
Gemcitabine: IV infusion in 250 mL of 0.9% sterile saline for injection given in accordance with the package insert
Cisplatin: IV in accordance with local institutional practice for biliary tract cancer, including the use of an appropriate hydration protocol | 385 |
| Total | 773 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 78 | 32 |
| Overall Study | Clinical disease progression | 14 | 13 |
| Overall Study | Death | 29 | 16 |
| Overall Study | Lost to Follow-up | 0 | 1 |
| Overall Study | Physician Decision | 17 | 25 |
| Overall Study | Protocol Violation | 3 | 4 |
| Overall Study | Radiological disease progression | 112 | 127 |
| Overall Study | Study closure | 98 | 133 |
| Overall Study | Withdrawal by Subject | 37 | 34 |
Baseline characteristics
| Characteristic | A - NUC-1031 and Cisplatin | B - Gemcitabine and Cisplatin | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 203 Participants | 199 Participants | 402 Participants |
| Age, Categorical Between 18 and 65 years | 185 Participants | 186 Participants | 371 Participants |
| Age, Continuous | 65.0 years | 65.0 years | 65.0 years |
| ECOG performance status 0 | 205 Participants | 186 Participants | 391 Participants |
| ECOG performance status 1 | 178 Participants | 192 Participants | 370 Participants |
| ECOG performance status Unknown | 5 Participants | 7 Participants | 12 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 21 Participants | 31 Participants | 52 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 359 Participants | 337 Participants | 696 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 8 Participants | 17 Participants | 25 Participants |
| Extent of disease Locally advanced | 56 Participants | 65 Participants | 121 Participants |
| Extent of disease Metastatic | 330 Participants | 320 Participants | 650 Participants |
| Extent of disease Unknown | 2 Participants | 0 Participants | 2 Participants |
| Measurable disease No | 21 Participants | 19 Participants | 40 Participants |
| Measurable disease Yes | 367 Participants | 366 Participants | 733 Participants |
| Primary tumour location Ampullary | 19 Participants | 18 Participants | 37 Participants |
| Primary tumour location Extra-hepatic | 80 Participants | 80 Participants | 160 Participants |
| Primary tumour location Gallbladder | 80 Participants | 80 Participants | 160 Participants |
| Primary tumour location Intra-hepatic | 209 Participants | 207 Participants | 416 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 76 Participants | 77 Participants | 153 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants | 5 Participants | 8 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 23 Participants | 28 Participants | 51 Participants |
| Race (NIH/OMB) White | 285 Participants | 274 Participants | 559 Participants |
| Sex: Female, Male Female | 174 Participants | 188 Participants | 362 Participants |
| Sex: Female, Male Male | 214 Participants | 197 Participants | 411 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 188 / 388 | 135 / 385 |
| other Total, other adverse events | 370 / 383 | 369 / 378 |
| serious Total, serious adverse events | 175 / 383 | 126 / 378 |
Outcome results
Primary
Objective Response Rate (ORR)
Percentage of patients achieving a confirmed complete response (CR) or partial response (PR) to treatment as assessed by blinded independent review according to RECIST v1.1 criteria. ORR = patients with CR + patients with PR, where CR = disappearance of all target lesions PR = at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters This outcome was assessed in the population of patients with measurable disease at baseline who were also randomized ≥28 weeks before the data cut-off (ITTMD28). Patients were to receive a confirmatory scan 28-42 days after response is first observed.
Time frame: Evaluated at Screening (baseline) then every 9 weeks from treatment start (C1D1), or every 12 weeks if treatment is stopped with no evidence of progression, until disease progression or death from any cause up to the end of study, an average of 6 months.
Population: Intent-to-treat with measurable disease at baseline randomized ≥28 weeks before the data cut-off (ITTMD28)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| A - NUC-1031 and Cisplatin | Objective Response Rate (ORR) | 53 Participants |
| B - Gemcitabine and Cisplatin | Objective Response Rate (ORR) | 34 Participants |
Primary
Overall Survival (OS)
The median time, in months, from the date of randomization to the date of death from any cause. For patients who were alive at the time of a data cut-off or were permanently lost to follow up, duration of OS was censored at the date at which they were last known to be alive.
Time frame: From the date of randomization until the date of death from any cause, assessed up to 12 months on average
Population: Intent-to-treat
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| A - NUC-1031 and Cisplatin | Overall Survival (OS) | 9.2 Months |
| B - Gemcitabine and Cisplatin | Overall Survival (OS) | 12.6 Months |