PCI Treatment/Gemcitabine & Chemotherapy vs Chemotherapy Alone in Patients With Inoperable Extrahepatic Bile Duct Cancer (RELEASE)

A Multi-Center Randomised Open-Label Phase 2 Study to Assess the Safety, Tolerability and Efficacy of Fimaporfin-Induced Photochemical Internalisation of Gemcitabine Complemented by Gemcitabine/Cisplatin Chemotherapy Versus Gemcitabine/Cisplatin Alone in Patients With Inoperable Cholangiocarcinoma

This study will assess the safety and effectiveness of fimaporfin-induced photochemical internalisation (PCI) of gemcitabine complemented by systemic gemcitabine/cisplatin chemotherapy compared to gemcitabine/cisplatin alone, in patients with inoperable cholangiocarcinoma (CCA). Participants will be randomly assigned to one of the treatment groups and will receive study treatment for 6 months, followed by assessments every 3 months, as applicable.

Study Overview

• Status: Terminated
• Conditions: Cholangiocarcinoma
• Intervention / Treatment: Drug: Fimaporfin and Gemcitabine; Drug: Gemcitabine/Cisplatin chemotherapy

Detailed Description

Cholangiocarcinoma (CCA) is an uncommon adenocarcinoma arising from cells lining the bile ducts. Standard treatment options for CCA include surgery, radiotherapy and chemotherapy, dependent upon if the CCA is intra- or extra-hepatic. Surgical removal of the tumor is the only potential cure, and CCA is very resistant to standard pharmaceutical drug treatment, though chemotherapy has some effect. Current chemotherapy uses cisplatin plus gemcitabine. Photochemical internalisation (PCI) is a novel technology, where photochemical reactions are used to enhance the effect of drugs by increasing their ability cross cell membranes to interact with their intended target. This study will assess the safety and effectiveness of fimaporfin-induced PCI of gemcitabine complemented by systemic gemcitabine/cisplatin chemotherapy compared to gemcitabine/cisplatin alone, in patients with inoperable CCA.

NOTE: Participants are no longer being recruited to this study.

• Study Type: Interventional
• Enrollment (Actual): 41
• Phase: Phase 2

Contacts and Locations

Study Locations

• Belgium
  • Leuven, Belgium, 3000
    • UZ Leuven
  • Oost-Vlaanderen
    • Gent, Oost-Vlaanderen, Belgium, 9000
      • UZ Gent
• Denmark
  • Odense, Denmark, 5000
    • Odense Universitetshospital
• Finland
  • Tampere, Finland, FI-33520
    • Tampereen yliopistollinen sairaala, Syöpätautien klinikka
• France
  • Limoges, France, 87042
    • CHU Dupuytren, 2 Avenue Martin Luther King
  • Villejuif, France, 94805
    • Institut Gustave Roussy, Département de gastro-entérologie
  • Cedex 09
    • Grenoble, Cedex 09, France, 38043
      • Centre Hospitalier Universitaire Grenoble Alpes - Hopital Albert Michallon
  • Cedex 9
    • Angers, Cedex 9, France, 49933
      • CHU Angers
• Germany
  • Bonn, Germany, 53105
    • Universitatsklinikum Bonn
  • Hamburg, Germany, 20246
    • Universitätsklinikum Hamburg Eppendorf, I. Medizinische Klinik und Poliklinik (Gastroenterologie mit Sektionen Infektiologie und Tropenmediz)
  • Landshut, Germany, 84034
    • Klinikum Landshut
  • Landshut, Germany, 84036
    • LAKUMED Kliniken
  • Leipzig, Germany, 04103
    • Universität Leipzig KöR
  • Mannheim, Germany, 68167
    • Klinikum Mannheim Universitätsklinikum gGmbH
  • Muenchen, Germany, 81377
    • Klinikum der Ludwig-Maximilians-Universität MünchenKlinik
  • Nürnberg, Germany, 90419
    • Klinikum Nürnberg Nord, Medizinische Klinik 6 - (Schwerpunkte Gastroenterologie, Hepatologie, Endokrinologie)
  • Bayern
    • München, Bayern, Germany, 81675
      • Klinikum Rechts Der Isar Der Technischen Universität München
  • Hessen
    • Frankfurt am main, Hessen, Germany, 60590
      • Universitatsklinikum Frankfurt
  • Nordrhein-Westfalen
    • Essen, Nordrhein-Westfalen, Germany, 45122
      • Universitatsklinikum Essen
• Italy
  • Castellana Grotte, Italy, 70013
    • IRCCS Saverio de Bellis, Via Turi, 27
  • Emilia-Romagna
    • Modena, Emilia-Romagna, Italy, 41100
      • Azienda Ospedaliero Universitaria Di Modena Policlinico
• Korea, Republic of
  • Busan, Korea, Republic of, 49241
    • Pusan National University Hospital, 179 Gudeok-ro, Seo-gu
  • Daegu, Korea, Republic of, 41404
    • Kyungpook National University Chilgok Hospital, 807 Hoguk-ro, Buk-gu
  • Seoul, Korea, Republic of, 05505
    • Asan Medical Center, 88 Olympic-ro 43-gil, Songpa-gu
  • Soeul, Korea, Republic of, 03722
    • Severance Hospital Yonsei University Health System, 50-1, Yonsei-Ro, Seodaemun-Gu
  • Soeul, Korea, Republic of, 06591
    • The Catholic University of Korea, Seoul St. Mary's Hospital, 222 Banpo-Daero Seocho-gu
  • Gyeonggido
    • Goyang-si, Gyeonggido, Korea, Republic of, 10408
      • National Cancer Center, 323 Ilsan-ro, Ilsandong-gu
• Norway
  • Oslo, Norway
    • Oslo Universitetssykehus HF Radiumhospitalet
• Poland
  • Poznań, Poland, 60-569
    • Med-Polonia Sp. z o.o.
  • Warminsko-mazurskie
    • Olsztyn, Warminsko-mazurskie, Poland, 10-228
      • Zaklad Opieki Zdrowotnej MSW z Warminsko-Mazurskim Centrum Onkologii
• Spain
  • Barcelona, Spain, 08033
    • Hospital Del Mar
  • Madrid, Spain, 28041
    • Hospital Universitario 12 de Octubre
  • Madrid, Spain, 28050
    • Hospital Universitario HM Sanchinarro - CIOCC
  • Majadahonda, Spain, 28222
    • Hospital Universitario Puerta de Hierro - Majadahonda
  • Sabadell, Spain, 08208
    • Corporació Sanitària Parc Taulí
  • Navarra
    • Pamplona, Navarra, Spain, 31008
      • Clinica Universidad Navarra
• Sweden
  • Stockholms Ian
    • Stockholm, Stockholms Ian, Sweden, SE-17176
      • Karolinska Universitetssjukhuset Solna, P.O Bäckencancer, Karolinska Universitetssjukhuset
• Taiwan
  • Taichung, Taiwan, 40705
    • Taichung Veterans General Hospital, No. 1650 Taiwan Boulevard, Sec. 4
  • Taipei, Taiwan, 11217
    • Taipei Veterans General Hospital, No. 201, Sction 2, Shi-pai Road
  • Taoyuan, Taiwan, 33305
    • Chang Gung Memorial Hospital, Linkou, Dept. of Medical Oncology, 5 Fuxing Street, Guishan
• Ukraine
  • Kharkiv, Ukraine
    • MNPE of Kharkiv Regional Council Regional Clinical Specialized Dispensary of Radiation Protection
  • Kharkiv, Ukraine
    • SI Institute for General and Urgent Surgery n.a. V.T. Zaitseva of NAMS of Uktraine
  • Kyiv, Ukraine
    • SI "National Institute of Surgery and Transplantology n.a. O.O. Shalimov " of NAMS of Ukraine
  • Zaporizhzhya, Ukraine
    • Municipal Nonprofit Enterprise City Hospital #3 of Zaporizhzhia City Council
• United States
  • California
    • Duarte, California, United States, 91010
      • City of Hope National Medical Center
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University Hospital, 1365C Clifton Road NE
  • Illinois
    • Chicago, Illinois, United States, 60637
      • University of Chicago Medical Center, 5841 South Maryland Avenue
  • Kentucky
    • Louisville, Kentucky, United States, 40202
      • University of Louisville
  • Minnesota
    • Rochester, Minnesota, United States, 55902
      • The Mayo Clinic Hospital - Saint Mary's Campus, 1216 Second Street Southwest
  • Texas
    • Houston, Texas, United States, 77096
      • Baylor College of Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Each patient must provide signed and witnessed written informed consent and agree to comply with study protocol requirements.
2. Histopathologically/cytologically verified adenocarcinoma consistent with cholangiocarcinoma (CCA). Must have biliary lesion causing bile obstruction that requires stenting and is accessible for PCI light treatment (ie, extrahepatic CCA [perihilar or distal] only).
3. CCA must be considered inoperable with respect to radical resection.
4. At least 1 radiologically evaluable lesion (measurable and/or non-measurable) that can be assessed at baseline and is suitable for repeated radiological evaluation.
5. If metastatic, metastases must be limited tissues other than bone or the central nervous system.
6. Must have adequate biliary drainage (at least 50% of the liver volume or at least 2 sectors) with no evidence of active uncontrolled infection (patients on antibiotics are eligible).
7. Must have Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
8. Estimated life expectancy of at least 12 weeks.

Exclusion Criteria:

1. Patients who have previously received any anti-tumor (either local or systemic) treatment for CCA, except for previous treatment of up to 2 cycles of gemcitabine/cisplatin.
2. Patients with severe visceral disease other than CCA.
3. A history of frequently recurring septic biliary events.
4. Patients with porphyria or hypersensitivity to porphyrins.
5. Patients with a second primary cancer with a disease-free interval of <5 years. A second primary cancer that has been treated with intent to cure may be allowed after consultation with the study Medical Monitor. Adequately treated basal cell carcinoma, squamous cell carcinoma or other non-melanomatous skin cancer, in-situ carcinoma of the uterine cervix, or prostate cancer that is controlled by hormone therapy (patients may continue hormone therapy while on study) are allowed.
6. Patients not able to undergo contrast-enhanced CT or MRI.
7. Patients currently participating in any other interventional clinical trial.
8. Planned surgery, endoscopic examination or dental treatment in the first 30 days after PCI treatment.
9. Co-existing ophthalmic disease likely to require slit-lamp examination within the first 90 days after PCI treatment.
10. Clinically significant and uncontrolled cardiac disease except for extra systoles or minor conduction abnormalities and controlled and well-treated chronic atrial fibrillation.
11. Known allergy or sensitivity to photosensitisers (active substance and/or any of the excipients); or chronic use of other photosensitising therapies; treatment with amiodarone during the last 12 months.
12. Known hypersensitivity to or contraindication to the use of gemcitabine (active substance and/or any of the excipients).
13. Known hypersensitivity to or contraindication to the use of cisplatin (active substance and/or any of the excipients).
14. Patients with ataxia telangiectasia.
15. Upon the Investigator's discretion, evidence of any other medical conditions (such as psychiatric illness, physical examination or laboratory findings) that may interfere with the planned PCI treatment, affect patient compliance or place the patient at high risk from treatment-related complications.
16. Patients planning to have or who have recently had vaccination with a live vaccine.
17. Patients concurrently receiving treatment with phenytoin.
18. Male patients unwilling to use highly effective contraception or female patients of childbearing potential unwilling to use highly effective form of contraception. Patients must continue the use of contraception during PCI treatment and subsequent chemotherapy for at least 6 months thereafter.
19. Women who are breastfeeding or who have a positive pregnancy test at baseline.
20. Patients with inadequate bone marrow function (absolute neutrophil count <1.5 x 10^9/L; platelet count <100 x 10^9/L; haemoglobin <6 mmol/L [transfusion allowed]).
21. Inadequate liver function despite satisfactory drainage (serum bilirubin persisting at >5 x upper limit of normal for the institution; aspartate aminotransferase or alanine aminotransferase >3.0 x upper limit of normal or >5 x upper limit of normal if liver metastases are present; alkaline phosphatase levels >5.0 x upper limit of normal).
22. Inadequate renal function, as determined by local practice for patients on fractionated platinum-based chemotherapy. Patients with creatinine clearance <45 mL/min (in France: <60 mL/min) must not be included.

Other protocol-defined criteria may apply.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: PCI treatment in conjunction with Standard of Care (SoC); Arm A: Fimaporfin-induced photochemical internalisation (PCI) of gemcitabine complemented by gemcitabine/cisplatin chemotherapy	Drug: Fimaporfin and Gemcitabine; PCI treatment consists of IV administration of Amphinex solution for injection (investigational product) at 0.22 mg/kg dose of fimaporfin, followed 4 days later by a standard dose of gemcitabine infusion (1000 mg/m²) and intraluminal laser light application. Up to 2 PCI treatments will be given.; Other Names: PCI treatment; Drug: Gemcitabine/Cisplatin chemotherapy; Up to 8 cycles of gemcitabine/cisplatin combination chemotherapy will be administered.; Other Names: Standard of care (SoC)
Active Comparator: Standard of Care (SoC); Arm B: Gemcitabine/cisplatin chemotherapy	Drug: Gemcitabine/Cisplatin chemotherapy; Up to 8 cycles of gemcitabine/cisplatin combination chemotherapy will be administered.; Other Names: Standard of care (SoC)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free Survival (PFS)	From date of randomisation to date of objective disease progression or death, whichever comes first (in months)	Up to 18 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Best Overall Response (BOR)	Best response recorded from start of treatment until disease progression/recurrence (according to RECIST 1.1)	Up to 18 months
Duration of Response (DoR)	From first documented tumour response until first documented disease progression, or death in the absence of disease progression (in months)	Up to 24 months
Adverse Events (AEs)/Serious Adverse Events (SAEs)	Number and proportion of patients with AEs/SAEs	Up to 12 months
Health-related Quality of Life (QoL)	QoL assessment. Patients select one of four answers to 22 questions ranging from 1 (not at all) to 4 (very much). Lower total scores indicate a more favorable QoL perception than a higher score.	Up to 18 months
Overall Survival (OS)	From date of randomisation to date of death from any cause (in months)	Up to 24 months
Objective Response Rate (ORR)	Proportion of patients with measurable disease at baseline who have at least one visit response with a complete response (CR) or partial response (PR) noted (according to RECIST 1.1)	Up to 18 months
Overall Disease Control Rate (DCR)	Proportion of patients with BOR of CR, PR or stable disease (SD) (according to RECIST 1.1) at or after the first follow-up scan, partial response or complete response	6 months and 12 months
Change in Tumor Size	Best overall percentage change in tumour size from baseline	Up to 18 months
Loco-regional Tumour-related Events and Biliary Complications	Frequency and severity of loco-regional tumour related events and biliary complications	Up to 12 months
Area Under the Plasma Concentration Curve (AUC) Was Performed for Patients in Arm A.	A non-compartmental analysis (NCA) was applied on the data. AUC from time zero to the last measured concentration (AUC 0-t) was initially estimated by the linear trapezoidal method.	Time Frame AUC calculated from time zero to C5-D8 (3 months from the first PCI treatment)
Maximum Observed Concentration (Cmax) Was Performed for Patients in Arm A.	A non-compartmental analysis (NCA) was applied on the data.	Timepoints for pharmacokinetic (PK) sampling: Day -4 (before, 30m and 4hrs after Amphinex), C1-D1, C1-D8, C2-D8, C3-D8, C4-D8, C4-D18 (before, 30m and 4hrs after Amphinex), C5-D1, and C5-D8
Time to Cmax (Tmax) Was Performed for Patients in Arm A.	A non-compartmental analysis (NCA) was applied on the data as described by Gabrielsson & Weiner (Methods in molecular biology, 929:161-180, 2012).	Timepoints for PK sampling: Day -4 (before, 30 min and 4 hours after Amphinex), C1-D1, C1-D8, C2-D8, C3-D8, C4-D8, C4-D18 (before, 30 min and 4 hours after Amphinex) , C5-D1, and C5-D8

Collaborators and Investigators

• Sponsor: PCI Biotech AS
• Investigators: Study Director: PCI Biotech, PCI Biotech

Study record dates

Study Major Dates

• Study Start (Actual): May 23, 2019
• Primary Completion (Actual): April 28, 2022
• Study Completion (Actual): May 6, 2022

Study Registration Dates

• First Submitted: July 26, 2019
• First Submitted That Met QC Criteria: September 20, 2019
• First Posted (Actual): September 23, 2019

Study Record Updates

• Last Update Posted (Actual): September 11, 2023
• Last Update Submitted That Met QC Criteria: August 15, 2023
• Last Verified: April 1, 2023

More Information

Terms related to this study

• Keywords: Gemcitabine; Safety; PCI; Efficacy; Cisplatin; Chemotherapy; Tolerability; Phase II; Cholangiocarcinoma; CCA; Photodynamic therapy; Inoperable; Standard of care; PDT; Pivotal; First line treatment; Bile duct cancer; Distal; SOC; Extrahepatic; Amphinex; Amphinex-induced Photochemical Internalisation; Perihilar; Fimaporfin; RELEASE; FimaChem; Klatskin; Local treatment
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Cholangiocarcinoma; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Gemcitabine
• Other Study ID Numbers: PCIA 203/18

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No