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Trial record 1 of 1 for:    A Phase III Open-Label, Multi-Centre, Randomized Study Comparing NUC-1031 plus Cisplatin to Gemcitabine plus Cisplatin in Patients with Previously Untreated Locally Advanced or Metastatic Biliary Tract Cancer
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Comparing NUC-1031 Plus Cisplatin to Gemcitabine Plus Cisplatin in Patients With Advanced Biliary Tract Cancer (NuTide:121)

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ClinicalTrials.gov Identifier: NCT04163900
Recruitment Status : Recruiting
First Posted : November 15, 2019
Last Update Posted : January 31, 2020
Sponsor:
Information provided by (Responsible Party):
NuCana plc

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

Condition or disease Intervention/treatment Phase
Biliary Tract Cancer Drug: NUC-1031 Drug: Gemcitabine Drug: Cisplatin Phase 3

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 828 participants
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
Primary Purpose: Treatment
Official Title: A Phase III Open-Label, Multi-Centre, Randomized Study Comparing NUC-1031 Plus Cisplatin to Gemcitabine Plus Cisplatin in Patients With Previously Untreated Locally Advanced or Metastatic Biliary Tract Cancer
Actual Study Start Date : December 24, 2019
Estimated Primary Completion Date : December 2023
Estimated Study Completion Date : December 2023


Arm Intervention/treatment
Experimental: 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
Drug: NUC-1031
IV infusion in 500 mL of 0.9% sterile saline for injection given over 30 minutes
Other Name: fosgemcitabine palabenamide

Drug: Cisplatin
IV in accordance with local institutional practice for biliary tract cancer, including the use of an appropriate hydration protocol
Other Name: CDDP

Active Comparator: 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
Drug: Gemcitabine
IV infusion in 250 mL of 0.9% sterile saline for injection given in accordance with the package insert
Other Names:
  • Difluorodeoxycytidine
  • Gemzar

Drug: Cisplatin
IV in accordance with local institutional practice for biliary tract cancer, including the use of an appropriate hydration protocol
Other Name: CDDP




Primary Outcome Measures :
  1. Overall survival (OS) [ Time Frame: Evaluated on an ongoing basis from randomization, 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 ]
    The median time, in months, from the date of randomization to the date of death from any cause

  2. Objective response rate (ORR) [ Time Frame: 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. ]
    Percentage 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


Secondary Outcome Measures :
  1. Progression-free survival (PFS) [ Time Frame: 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 ]
    Based on blinded independent review according to RECIST v1.1 criteria and defined as the time from randomization to the first observation of objective tumour progression or death from any cause

  2. Duration of response (DoR) [ Time Frame: Evaluated every 9 weeks from initial clinical response 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 ]
    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

  3. 12-month survival [ Time Frame: 12 months from randomization ]
    Proportion of patients still alive at 12 months from randomization

  4. 18-month survival [ Time Frame: 18 months from randomization ]
    Proportion of patients still alive at 18 months from randomization

  5. Disease control rate (DCR) [ Time Frame: 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 ]
    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

  6. Safety and tolerability [ Time Frame: Adverse events that occur from initiation of therapy until 30 day post-treatment will be recorded. Adverse events that are not resolved at this time will be followed until resolution to baseline value. ]
    Safety and tolerability will be assessed by total incidence of Treatment Emergent Adverse Events (TEAEs) according to Common Terminology Criteria for Adverse Events (CTCAE) v5.0

  7. Maximum observed plasma concentration (Cmax) of NUC-1031, dFdC and dFdU will be compared to existing data using simulations in Arm A only [ Time Frame: Day 1 of Cycle 1 (each cycle is 21 days): 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) ]
  8. Area under the plasma concentration-time curve (AUC) of NUC-1031, dFdC and dFdU will be compared to existing data using simulations in Arm A only [ Time Frame: Day 1 of Cycle 1 (each cycle is 21 days): 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) ]
  9. Elimination half-life (t½) of NUC-1031, dFdC and dFdU using descriptive statistics in Arm A only [ Time Frame: Day 1 of Cycle 1 (each cycle is 21 days): 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) ]
  10. Terminal elimination rate constant (λz) of NUC-1031, dFdC and dFdU using descriptive statistics in Arm A only [ Time Frame: Day 1 of Cycle 1 (each cycle is 21 days): 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) ]
  11. Clearance of NUC-1031, dFdC and dFdU will be compared to existing data using simulations in Arm A only [ Time Frame: Day 1 of Cycle 1 (each cycle is 21 days): 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) ]
  12. Volume of distribution of NUC-1031, dFdC and dFdU will be compared to existing data using simulations in Arm A only [ Time Frame: Day 1 of Cycle 1 (each cycle is 21 days): 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) ]
  13. Comparison of patient-reported quality of life (QoL) scores in Arm A and Arm B [ Time Frame: Assessed at screening, on Day 1 of every cycle (each cycle is 21 days), and 30 days post-treatment ]
    Assessed using the European Organisation for Research and Treatment (EORTC) Quality of Life Questionnaire (QLQ-C30) using the QLQ-BIL21 module

  14. Comparison of patient-reported quality of life (QoL) scores in Arm A and Arm B [ Time Frame: Assessed at screening, on Day 1 of every cycle (each cycle is 21 days), and 30 days post-treatment ]
    Assessed using the 5-level EuroQol five-dimension scale (EQ-5D-5L)



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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. 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 ≥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.
    • 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 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 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 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. 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04163900


Contacts
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Contact: Matthew McKellar +44 131 357 3950 Nutide121@nucana.com

Locations
Show Show 73 study locations
Sponsors and Collaborators
NuCana plc
Investigators
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Principal Investigator: Jennifer Knox, MD Professor of Medicine, University of Toronto

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Responsible Party: NuCana plc
ClinicalTrials.gov Identifier: NCT04163900    
Other Study ID Numbers: NuTide:121
2019-001025-28 ( EudraCT Number )
First Posted: November 15, 2019    Key Record Dates
Last Update Posted: January 31, 2020
Last Verified: January 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by NuCana plc:
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
Additional relevant MeSH terms:
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Biliary Tract Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Biliary Tract Diseases
Digestive System Diseases
Gemcitabine
Cisplatin
Antineoplastic Agents
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antiviral Agents
Anti-Infective Agents
Enzyme Inhibitors
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs