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JOURNAL ONKOLOGIE – STUDIE

NuTide:121 Comparing NUC-1031 Plus Cisplatin to Gemcitabine Plus Cisplatin in Patients With Advanced Biliary Tract Cancer

Rekrutierend

NCT-Nummer:
NCT04163900

Studienbeginn:
Dezember 2019

Letztes Update:
09.12.2020

Wirkstoff:
NUC-1031, Gemcitabine, Cisplatin

Indikation (Clinical Trials):
Biliary Tract Neoplasms

Geschlecht:
Alle

Altersgruppe:
Erwachsene (18+)

Phase:
Phase 3

Sponsor:
NuCana plc

Collaborator:
-

Studienleiter

Jennifer Knox, MD
Principal Investigator
Professor of Medicine, University of Toronto

Kontakt

Studienlocations (3 von 122)

State Budget Institution of Healthcare "Leningrad Regional Clinical Oncology Dispensary"
191104 Saint Petersburg
Russian FederationRekrutierend» Google-Maps
Ansprechpartner:
Andrey Chicherin
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Studien-Informationen

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

Ein-/Ausschlusskriterien

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.

Studien-Rationale

Primary outcome:

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:

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)

Studien-Arme

  • 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
  • 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

Geprüfte Regime

  • NUC-1031 (fosgemcitabine palabenamide):
    IV infusion in 500 mL of 0.9% sterile saline for injection given over 30 minutes
  • Gemcitabine (Difluorodeoxycytidine / Gemzar / ):
    IV infusion in 250 mL of 0.9% sterile saline for injection given in accordance with the package insert
  • Cisplatin (CDDP):
    IV in accordance with local institutional practice for biliary tract cancer, including the use of an appropriate hydration protocol

Quelle: ClinicalTrials.gov


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