Clinical trial NCT04163900: Comparing NUC-1031 Plus Cisplatin to Gemcitabine Plus Cisplatin in Patients With Advanced Biliary Tract Cancer
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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Biliary Tract Cancer
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
Lead sponsor: NuCana plc
Sponsor class: OTHER
First posted: 2019-11-15
Enrollment: 773
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: 1:1 randomization model to either Arm A or Arm B
Primary purpose: TREATMENT

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


Eligibility 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 (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.

Primary outcomes:
measure: Objective Response Rate (ORR)
timeFrame: 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.
measure: Overall Survival (OS)
timeFrame: From the date of randomization until the date of death from any cause, assessed up to 12 months on average
Secondary outcomes:
Other outcomes:
Locations:
city: Tucson
country: United States
facility: Arizona Oncology Associates , PC - HOPE
state: Arizona
city: Tucson
country: United States
facility: University of Arizona Cancer Center
state: Arizona
city: Whittier
country: United States
facility: The Oncology Institute of Hope and Innovation
state: California
city: Aurora
country: United States
facility: Rocky Mountain Cancer Centers, LLP- Aurora
state: Colorado
city: Miami
country: United States
facility: Baptist Health Medical Group Oncology, LLC
state: Florida
city: Orlando
country: United States
facility: Orlando Health, Inc.
state: Florida
city: Columbus
country: United States
facility: IACT Health
state: Georgia
city: Chicago Ridge
country: United States
facility: Affiliated Oncologists LLC
state: Illinois
city: Westwood
country: United States
facility: University of Kansas Medical Center Research Institute, Inc.
state: Kansas
city: Louisville
country: United States
facility: Norton Cancer Institute
state: Kentucky
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Boston
country: United States
facility: Beth Israel Deaconess Medical Center
state: Massachusetts
city: Detroit
country: United States
facility: Henry Ford Medical Group
state: Michigan
city: Minneapolis
country: United States
facility: Minnesota Oncology Hemtology
state: Minnesota
city: Minneapolis
country: United States
facility: Regents of the University of Minnesota
state: Minnesota
city: Rochester
country: United States
facility: University of Rochester Medical Center - Strong Memorial Hospital
state: New York
city: Stony Brook
country: United States
facility: The Research Foundation for The State University of New York
state: New York
city: Winston-Salem
country: United States
facility: Wake Forest University Health Sciences
state: North Carolina
city: Columbus
country: United States
facility: The Ohio State University James Cancer Hospital and Solove Research Institute
state: Ohio
city: Philadelphia
country: United States
facility: Corporal Michael J. Crescenz VA Medical Center
state: Pennsylvania
city: Greenville
country: United States
facility: Prisma Health Upstate
state: South Carolina
city: Austin
country: United States
facility: Texas Oncology, P.A. - Austin
state: Texas
city: Dallas
country: United States
facility: Baylor Charles A. Sammons Cancer Center
state: Texas
city: Lubbock
country: United States
facility: Joe Arrington Cancer Research and Treatment Center
state: Texas
city: Tyler
country: United States
facility: Texas Oncology, P.A. - Tyler
state: Texas
city: Seattle
country: United States
facility: Virginia Mason Medical Center
state: Washington
city: Vancouver
country: United States
facility: Northwest Cancer Specialists, P.C.-Vancouver
state: Washington
city: Wenatchee
country: United States
facility: Wenatchee Valley Hospital and Clinics
state: Washington
city: Milwaukee
country: United States
facility: The Medical College of Wisconsin, Inc.
state: Wisconsin
city: Camperdown
country: Australia
facility: Chris O'Brien Lifehouse
state: New South Wales
city: Kogarah
country: Australia
facility: St George Hospital
state: New South Wales
city: Newcastle
country: Australia
facility: Newcastle Private Hospital
state: New South Wales
city: Westmead
country: Australia
facility: Westmead Hospital
state: New South Wales
city: Townsville
country: Australia
facility: Townsville Cancer Centre
state: Queensland
city: Heidelberg
country: Australia
facility: Warringal Medical Centre
state: Victoria
city: Melbourne
country: Australia
facility: The Alfred Hospital
state: Victoria
city: Murdoch
country: Australia
facility: Fiona Stanley Hospital
state: Western Australia
city: Nedlands
country: Australia
facility: Sir Charles Gairdner Hospital
state: Western Australia
city: Calgary
country: Canada
facility: Tom Baker Cancer Centre
state: Alberta
city: Halifax
country: Canada
facility: Nova Scotia Health Authority
state: Nova Scotia
city: Barrie
country: Canada
facility: Royal Victoria Regional Health Centre
state: Ontario
city: Ottawa
country: Canada
facility: The Ottawa Hospital Cancer Centre
state: Ontario
city: Toronto
country: Canada
facility: Sunnybrook Research Institute
state: Ontario
city: Toronto
country: Canada
facility: Princess Margaret Cancer Centre
state: Ontario
city: Montréal
country: Canada
facility: CHUM Centre de Recherche
state: Quebec
city: Montréal
country: Canada
facility: SMBD Jewish General Hospital
state: Quebec
city: Brno
country: Czechia
facility: Fakultní nemocnice Brno
city: Hradec Králové
country: Czechia
facility: Fakultní nemocnice Hradec Králové
city: Olomouc
country: Czechia
facility: Fakultní nemocnice Olomouc
city: Prague
country: Czechia
facility: Thomayerova nemocnice
city: Prague
country: Czechia
facility: Nemocnice Na Homolce
city: Dijon
country: France
facility: Centre Georges François Leclerc
city: Grenoble
country: France
facility: CHU de Grenoble - Hôpital Nord
city: Levallois-Perret
country: France
facility: Institut Hospitalier Franco-Britannique
city: Paris
country: France
facility: Hôpital Cochin
city: Saint Herblain
country: France
facility: ICO - Site René Gauducheau
city: Heidelberg
country: Germany
facility: Universitaetsklinikum Heidelberg
state: Baden Wuerttemberg
city: Berlin
country: Germany
facility: Vivantes Klinikum Neukoelln
city: Freiburg
country: Germany
facility: Universitaetsklinikum Freiburg
city: Hanover
country: Germany
facility: Medizinische Hochschule Hannover
city: Tuebingen
country: Germany
facility: Universitaetsklinikum Tuebingen
city: Budapest
country: Hungary
facility: Semmelweis Egyetem
city: Budapest
country: Hungary
facility: Del-pesti Centrumkorhaz - Orszagos Hematologiai es Infektologiai Intezet
city: Budapest
country: Hungary
facility: Orszagos Onkologiai Intezet
city: Debrecen
country: Hungary
facility: Debreceni Egyetem
city: Miskolc
country: Hungary
facility: Borsod-Abauj-Zemplen Megyei Kozponti Korhaz es Egyetemi Oktatokorhaz
city: Szolnok
country: Hungary
facility: Jasz-Nagykun-Szolnok Megyei Hetenyi Geza Korhaz-Rendelointezet
city: Genova
country: Italy
facility: Ospedale Policlinico San Martino
city: Milano
country: Italy
facility: IEO Istituto Europeo di Oncologia
city: Napoli
country: Italy
facility: Istituto Nazionale Tumori Fondazione G. Pascale
city: Padova
country: Italy
facility: IOV - Istituto Oncologico Veneto IRCCS
city: Pisa
country: Italy
facility: Azienda Ospedaliero Universitaria Pisana
city: Verona
country: Italy
facility: Centro Ricerche Cliniche di Verona S.r.l
city: Seongnam-si
country: Korea, Republic of
facility: CHA Bundang Medical Center, CHA University
state: Gyeonggi-do
city: Hwasun
country: Korea, Republic of
facility: Chonnam National University Hwasun Hospital
state: Jeollanam-do
city: Pusan
country: Korea, Republic of
facility: Dong-A University Hospital
city: Seongnam-si
country: Korea, Republic of
facility: Seoul National University Bundang Hospital
city: Seoul
country: Korea, Republic of
facility: Korea University Anam Hospital
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center
city: Seoul
country: Korea, Republic of
facility: Korea University Guro Hospital
city: Seoul
country: Korea, Republic of
facility: Severance Hospital, Yonsei University
city: Seoul
country: Korea, Republic of
facility: Asan Medical Center
city: Moscow
country: Russian Federation
facility: FSBSI "Russian Oncological Scientific Center n.a. N.N. Blokhin"
city: Moscow
country: Russian Federation
facility: FSBSI Russian Oncological Scientific Center n.a. N.N. Blokhin
city: Moscow
country: Russian Federation
facility: "VitaMed" LLC
city: Saint Petersburg
country: Russian Federation
facility: State Budget Institution of Healthcare "Leningrad Regional Clinical Oncology Dispensary"
city: Saint Petersburg
country: Russian Federation
facility: Pavlov First Saint Petersburg State Medical University
city: Saint Petersburg
country: Russian Federation
facility: SPb SBIH "City Clinical Oncological Dispensary"
city: Tyumen
country: Russian Federation
facility: Medicinskiy gorod
city: Barcelona
country: Spain
facility: Hospital Universitari Vall d'Hebron
city: Barcelona
country: Spain
facility: Hospital Clinic de Barcelona
city: Barcelona
country: Spain
facility: Hospital de la Santa Creu i Sant Pau
city: L'Hospitalet De Llobregat
country: Spain
facility: ICO l'Hospitalet - Hospital Duran i Reynals
city: Madrid
country: Spain
facility: Hospital General Universitario Gregorio Marañon
city: Madrid
country: Spain
facility: Hospital Universitario Clinico San Carlos
city: Madrid
country: Spain
facility: Hospital Universitario HM Madrid Sanchinarro
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen Macarena
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen del Rocio
city: Changhua
country: Taiwan
facility: Changhua Christian Medical Foundation Changhua Christian Hospital
city: Taichung
country: Taiwan
facility: China Medical University Hospital
city: Taipei
country: Taiwan
facility: National Taiwan University Hospital
city: Taipei
country: Taiwan
facility: MacKay Medical Foundation The Presbyterian Church in Taiwan MacKay Memorial Hospital
city: Taipei
country: Taiwan
facility: Taipei Veterans General Hospital
city: Adana
country: Turkey
facility: Acibadem Adana Hospital
city: Adana
country: Turkey
facility: Baskent University Adana Application and Research Center
city: Antalya
country: Turkey
facility: Akdeniz University Medical Faculty
city: Edirne
country: Turkey
facility: Trakya University Medical Faculty
city: Istanbul
country: Turkey
facility: Istanbul University Cerrahpasa - Cerrahpasa Medical Faculty
city: Malatya
country: Turkey
facility: Dr. Abdurrahman Yurtaslan Oncology Teaching and Research Hospital
city: Malatya
country: Turkey
facility: Inonu University Medical Facility
city: Chernivtsi
country: Ukraine
facility: CI Chernivtsi RC Oncological Dispensary
city: Kharkiv
country: Ukraine
facility: Communal Non-profit Enterprise Regional Center of Oncology, Kharkiv NMU
city: Kharkiv
country: Ukraine
facility: CI of Healthcare Regional Clinical Specialized Dispensary of the Radiation Protection
city: Kyiv
country: Ukraine
facility: Kyiv City Clinical Oncological Center
city: Kyiv
country: Ukraine
facility: SI "Shalimov's National Institute of Surgery and Transplantation" of NAMSU
city: Luts'k
country: Ukraine
facility: Treatment-Prevention Institution Volyn Regional Oncological Dispensary
city: Odesa
country: Ukraine
facility: Communal Institution Odesa Regional Clinical Hospital
city: Sumy
country: Ukraine
facility: RCI Sumy Regional Clinical Oncological Dispensary
city: London
country: United Kingdom
facility: Guy's Hospital
state: Greater London
city: Manchester
country: United Kingdom
facility: The Christie
state: Greater Manchester
city: Edinburgh
country: United Kingdom
facility: Western General Hospital
city: Glasgow
country: United Kingdom
facility: Beatson West of Scotland Cancer Centre
city: Torquay
country: United Kingdom
facility: Torbay Hospital
city: Wirral
country: United Kingdom
facility: The Clatterbridge Cancer Centre
Study officials:
affiliation: Professor of Medicine, University of Toronto
name: Jennifer Knox, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: McNamara MG, Goyal L, Doherty M, Springfeld C, Cosgrove D, Sjoquist KM, Park JO, Verdaguer H, Braconi C, Ross PJ, Gramont A, Zalcberg JR, Palmer DH, Valle JW, Knox JJ. NUC-1031/cisplatin versus gemcitabine/cisplatin in untreated locally advanced/metastatic biliary tract cancer (NuTide:121). Future Oncol. 2020 Jun;16(16):1069-1081. doi: 10.2217/fon-2020-0247. Epub 2020 May 6.