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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Cholangiocarcinoma

Intervention / Treatment
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* Drug: Fimaporfin and Gemcitabine
* Drug: Gemcitabine/Cisplatin chemotherapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Each patient must provide signed and witnessed written informed consent and agree to comply with study protocol requirements. 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). CCA must be considered inoperable with respect to radical resection. At least 1 radiologically evaluable lesion (measurable and/or non-measurable) that can be assessed at baseline and is suitable for repeated radiological evaluation. If metastatic, metastases must be limited tissues other than bone or the central nervous system. 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). Must have Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Estimated life expectancy of at least 12 weeks. Exclusion Criteria: 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. Patients with severe visceral disease other than CCA. A history of frequently recurring septic biliary events. Patients with porphyria or hypersensitivity to porphyrins. 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. Patients not able to undergo contrast-enhanced CT or MRI. Patients currently participating in any other interventional clinical trial. Planned surgery, endoscopic examination or dental treatment in the first 30 days after PCI treatment. Co-existing ophthalmic disease likely to require slit-lamp examination within the first 90 days after PCI treatment. Clinically significant and uncontrolled cardiac disease except for extra systoles or minor conduction abnormalities and controlled and well-treated chronic atrial fibrillation. 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. Known hypersensitivity to or contraindication to the use of gemcitabine (active substance and/or any of the excipients). Known hypersensitivity to or contraindication to the use of cisplatin (active substance and/or any of the excipients). Patients with ataxia telangiectasia. 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. Patients planning to have or who have recently had vaccination with a live vaccine. Patients concurrently receiving treatment with phenytoin. 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. Women who are breastfeeding or who have a positive pregnancy test at baseline. 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]). 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). 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PCI treatment in conjunction with Standard of Care (SoC)<br>Arm A: Fimaporfin-induced photochemical internalisation (PCI) of gemcitabine complemented by gemcitabine/cisplatin chemotherapy | Drug: Fimaporfin and Gemcitabine<br>* 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.<br>* Other names: PCI treatment;Drug: Gemcitabine/Cisplatin chemotherapy<br>* Up to 8 cycles of gemcitabine/cisplatin combination chemotherapy will be administered.<br>* Other names: Standard of care (SoC);|
| Active Comparator: Standard of Care (SoC)<br>Arm B: Gemcitabine/cisplatin chemotherapy | Drug: Gemcitabine/Cisplatin chemotherapy<br>* Up to 8 cycles of gemcitabine/cisplatin combination chemotherapy will be administered.<br>* Other names: Standard of care (SoC);|

What is the study measuring?
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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 |
| --- | --- | --- |
| Overall Survival (OS) | From date of randomisation to date of death from any cause (in months) | Up to 24 months | 
| Best Overall Response (BOR) | Best response recorded from start of treatment until disease progression/recurrence (according to RECIST 1.1) | Up to 18 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 | 
| 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 | 
| 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 | 
| Adverse Events (AEs)/Serious Adverse Events (SAEs) | Number and proportion of patients with AEs/SAEs | 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 | 
| 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PCI, Phase II, Safety, Tolerability, Efficacy, Amphinex-induced Photochemical Internalisation, Amphinex, Gemcitabine, Cisplatin, Inoperable, CCA, Cholangiocarcinoma, Bile duct cancer, Photodynamic therapy, Extrahepatic, Perihilar, Distal, Fimaporfin, Pivotal, RELEASE, PDT, FimaChem, Klatskin, First line treatment, Standard of care, SOC, Chemotherapy, Local treatment