Efficacy and Safety Study of PDT Using Photofrin in Unresectable Advanced Perihilar Cholangiocarcinoma (OPUS)

Study Overview
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Brief Summary
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Photodynamic therapy (PDT) is a combination of a drug, porfimer sodium (Photofrin), which is activated by a light from a laser that emits no heat. This technique works to allow the medical doctor to specifically target and destroy abnormal or cancer cells while limiting damage to surrounding healthy tissue. The activation of the drug is done by lighting the abnormal areas using a fiber optic device (very fine fiber like a fishing line that permits light transmission) inserted into a flexible tube with a light called cholangioscope for the bile duct. The light will activate the porfimer sodium concentrated in the abnormal tissue, leading to its destruction. This research study will evaluate the efficacy and safety of PDT with porfimer sodium administered with Standard Medical Care (SMC) compared to SMC alone on the overall survival time of patients with non-operable advanced cholangiocarcinoma, a rare cancer of the bile ducts. It will involve 200 patients across North America and Europe. Other countries may participate if needed. Participation will last at least 18 months.

Detailed Description
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Photodynamic therapy (PDT) is a combination of a drug, porfimer sodium (Photofrin), which is activated by a light from a laser that emits no heat. This technique works to allow the medical doctor to specifically target and destroy abnormal or cancer cells while limiting damage to surrounding healthy tissue. The activation of the drug is done by lighting the abnormal areas using a fiber optic device (very fine fiber like a fishing line that permits light transmission) inserted into a flexible tube with a light called cholangioscope for the bile duct. The light will activate the porfimer sodium concentrated in the abnormal tissue, leading to its destruction. Cholangiocarcinoma (CCA) is defined as primary malignant tumors of the bile ducts. The exact etiology remains unknown. These cancerous tumors block the bile flow and can be intrahepatic (IH) or extrahepatic (EH). The distinction between IH- and EH-CCA has become increasingly important, as the epidemiological features (i.e., incidence and risk factors), the biologic and pathologic characteristics and the clinical course are largely different. Unfortunately, most subjects are found to have metastases or unresectable disease at the time of diagnosis. Median survival for subjects with unresectable perihilar-CCA varies between five and eight months. The one-year survival is 50%, with 20% surviving at two years and 10% at three years. Unresected CCA is a rapidly fatal process with cholangitis being a significant cause of morbidity and mortality in these subjects. This study was designed to confirm the efficacy of PHOPDT + standard medical care (SMC) defined as stents plus gemcitabine/cisplatin chemotherapy regimen on the overall survival of subjects with unresectable cholestasis perihilar Bismuth type III or IV - tumor TNM stage III or IVa CCA.

Official Title
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Multicenter, Open-label, Randomized, Controlled Phase III Clinical Study of the Efficacy and Safety of Photodynamic Therapy Using Porfimer Sodium for Injection as Treatment for Unresectable Advanced Perihilar Cholangiocarcinoma

Conditions
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Hilar Cholangiocarcinoma

Intervention / Treatment
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* Drug: Photodynamic therapy-Photofrin
* Procedure: Stenting procedure
* Drug: Chemotherapy regimen


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males or females aged 18 or older Diagnosed with radiologically and biopsy or cytology confirmed inoperable perihilar cholangiocarcinoma Bismuth Tumor Stage III/IV Non-menopausal or non-sterile female subjects of childbearing potential must have a negative serum beta-HCG and use a medically acceptable form of birth control Able to sign an informed consent Exclusion Criteria: Diagnostic of cholangiocarcinoma made more than 45 days prior to randomization Cholangiocarcinoma with extra-hepatic metastasis or concurrent non-solid malignancy Presence or history of other neoplasms (treated during the last five years prior to study entry) other than carcinoma in situ of the cervix or basal carcinoma of the skin Previously received photodynamic therapy for cholangiocarcinoma Previously undergone surgical resection of the cholangiocarcinoma Previously undergone chemotherapy, brachytherapy, or radiotherapy prior to entering the study Previously undergone metal stent insertion Porphyria or hypersensitivity to porphyrins (constituents of porfimer sodium), gemcitabine, cisplatin or other platinum-containing compounds Presence of infection other than the infection of the bile duct (cholangitis) Acute or chronic medical or psychological illnesses that prevent endoscopy procedures Abnormal blood test results Severe impairment of your kidney or liver function Decompensated cirrhosis Pregnant or intend to become pregnant, breastfeeding or intend to breast-feed during this study Participated in another drug study within 90 days before this one Unable or unwilling to complete the follow-up evaluations required for the study

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: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Photodynamic therapy-Photofrin plus SMC<br>Photodynamic therapy (PDT) involves the i.v. injection of Photofrin followed by the illumination of the tumor using a fiber optic device. Two days after the injection, a laser light (180 J/cm(2)) will be applied to the tumor. A second light application will be given 96-120 hours after Photofrin injection if PDT could not initially be performed on all sides of the tumor. Post illumination, all patients will undergo stenting as part of standard medical care procedure. Up to 3 additional courses of PDT using a light dose of 120 J/cm(2) may be given at 3-month intervals. Standard Medical Care (SMC) is defined as stenting procedure plus chemotherapy regimen. | Drug: Photodynamic therapy-Photofrin<br>* Photodynamic therapy (PDT) involves the i.v. injection of Photofrin (2 mg/kg) followed by the illumination of the tumor using a fiber optic device during an endoscopic retrograde cholangiopancreatography (ERCP) or percutaneous transhepatic cholangiography (PTC). Two days after the injection, a laser light (180 J/cm(2)) will be applied to the tumor. A second light application will be given 96-120 hours after Photofrin injection if PDT could not initially be performed on all sides of the tumor. Post illumination, all patients will undergo stenting as part of standard medical care procedure. Up to 3 additional courses of PDT using a light dose of 120 J/cm(2) may be given at 3-month intervals.<br>* Other names: PDT-Photofrin;Procedure: Stenting procedure<br>* As per standard medical procedures, stenting procedure consists in the placement of stents above the main tumors of the right and left hepatic bile ducts via endoscopic retrograde cholangiopancreatography (ERCP) or percutaneous transhepatic cholangiography (PTC) when the ERCP approach has been unsuccessful.<br>* Other names: Stents placement;Drug: Chemotherapy regimen<br>* The regimen will comprise gemcitabine (1 000 mg/m(2)) followed by cisplatin (25 mg/m(2)), each administered on days 1 and 8 every 3 weeks (21 day-cycle) for four cycles. An additional 12 weeks of the same chemotherapy regimen may be administered if there is no disease progression or intolerable toxicity.<br>* Other names: Gemcitabine/Cisplatin;|
| Active Comparator: Standard Medical Care (SMC)<br>Standard Medical Care (SMC) is defined as stenting procedure plus chemotherapy regimen. The chemotherapy regimen will comprise gemcitabine (1 000 mg/m(2)) followed by cisplatin (25 mg/m(2)), each administered on days 1 and 8 every 3 weeks (21 day-cycle) for four cycles. An additional 12 weeks of the same chemotherapy regimen may be administered if there is no disease progression or intolerable toxicity. | Procedure: Stenting procedure<br>* As per standard medical procedures, stenting procedure consists in the placement of stents above the main tumors of the right and left hepatic bile ducts via endoscopic retrograde cholangiopancreatography (ERCP) or percutaneous transhepatic cholangiography (PTC) when the ERCP approach has been unsuccessful.<br>* Other names: Stents placement;Drug: Chemotherapy regimen<br>* The regimen will comprise gemcitabine (1 000 mg/m(2)) followed by cisplatin (25 mg/m(2)), each administered on days 1 and 8 every 3 weeks (21 day-cycle) for four cycles. An additional 12 weeks of the same chemotherapy regimen may be administered if there is no disease progression or intolerable toxicity.<br>* Other names: Gemcitabine/Cisplatin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival Time | Time from the date of randomization until the date of death or the last date the subject was known to be alive | Up to 26 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Health-related Quality of Life on the 4- and 7-point EORTC QLQ-C30 | Final European Organisation for Research and Treatment of Cancer (EORTC) scores for multi-item scales and single-item measures will range from 0 to 100. This questionnaire assesses the quality of life of cancer patients. A high score represents a high/healthy level of functioning, basically a high Quality of Life. | Baseline, 41 weeks | 
| Change From Baseline in Health-related Quality of Life on the 4- and 7-point EORTC QLQ-C30 | Final European Organisation for Research and Treatment of Cancer (EORTC) scores for multi-item scales and single-item measures will range from 0 to 100. This questionnaire assesses the quality of life of cancer patients. A high score represents a high/healthy level of functioning, basically a high Quality of Life. | Baseline, 54 weeks | 
| Change From Baseline in Health-related Quality of Life on the 4- and 7-point EORTC QLQ-C30 | Final European Organisation for Research and Treatment of Cancer (EORTC) scores for multi-item scales and single-item measures will range from 0 to 100. This questionnaire assesses the quality of life of cancer patients. A high score represents a high/healthy level of functioning, basically a high Quality of Life. | Baseline, 66 weeks | 
| Change From Baseline in Health-related Quality of Life on the 4- and 7-point EORTC QLQ-C30 | Final European Organisation for Research and Treatment of Cancer (EORTC) scores for multi-item scales and single-item measures will range from 0 to 100. This questionnaire assesses the quality of life of cancer patients. A high score represents a high/healthy level of functioning, basically a high Quality of Life. | Baseline, 78 weeks | 
| Time-to-tumor Progression | From the date of first documented response until the date that tumor progression was assessed | Up to 26 months | 
| Change From Baseline on Karnofsky Performance Scale (KPS) | The Karnofsky Performance Scale scores range from 0% to 100%. The lower the Karnofsky score, the worse likelihood of survival. However, the premature termination of the study does not allow for a meaningful analysis of the scale where 100% means no complaints with no evidence of disease, 80% is normal activity with effort and some signs or symptoms of disease. | Baseline, 7 days | 
| Change From Baseline in Performance Status on the Karnofsky Performance Scale (KPS) | The Karnofsky Performance Scale (KPS) scores range from 0% to 100%. The lower the Karnofsky score, the worse likelihood of survival. A score of 100% means there are no complaints and no evidence of disease. A score of 80% means there is normal activity with effort and some signs or symptoms of disease. A score of 0% means death. | Baseline, up to 4 weeks | 
| Change From Baseline in Performance Status on the Karnofsky Performance Scale (KPS) | The Karnofsky Performance Scale (KPS) scores range from 0% to 100%. The lower the Karnofsky score, the worse likelihood of survival. A score of 100% means there are no complaints and no evidence of disease. A score of 80% means there is normal activity with effort and some signs or symptoms of disease. A score of 0% means death. | Baseline, 13 weeks | 
| Change From Baseline in Performance Status on the Karnofsky Performance Scale (KPS) | The Karnofsky Performance Scale (KPS) scores range from 0% to 100%. The lower the Karnofsky score, the worse likelihood of survival. A score of 100% means there are no complaints and no evidence of disease. A score of 80% means there is normal activity with effort and some signs or symptoms of disease. A score of 0% means death. | Baseline, 16 weeks | 
| Change From Baseline in Performance Status on the Karnofsky Performance Scale (KPS) | The Karnofsky Performance Scale scores range from 0% to 100%. The lower the Karnofsky score, the worse likelihood of survival. However, the premature termination of the study does not allow for a meaningful analysis of the scale where 100% means no complaints with no evidence of disease, 80% is normal activity with effort and some signs or symptoms of disease. | Baseline, 29 weeks | 
| Change From Baseline in Performance Status on the Karnofsky Performance Scale (KPS) | The Karnofsky Performance Scale scores range from 0% to 100%. The lower the Karnofsky score, the worse likelihood of survival. However, the premature termination of the study does not allow for a meaningful analysis of the scale where 100% means no complaints with no evidence of disease, 80% is normal activity with effort and some signs or symptoms of disease. | Baseline, 41 weeks | 
| Change From Baseline in Performance Status on the Karnofsky Performance Scale (KPS) | The Karnofsky Performance Scale scores range from 0% to 100%. The lower the Karnofsky score, the worse likelihood of survival. However, the premature termination of the study does not allow for a meaningful analysis of the scale where 100% means no complaints with no evidence of disease, 80% is normal activity with effort and some signs or symptoms of disease. | Baseline, 54 weeks | 
| Change From Baseline in Performance Status on the Karnofsky Performance Scale (KPS) | The Karnofsky Performance Scale scores range from 0% to 100%. The lower the Karnofsky score, the worse likelihood of survival. However, the premature termination of the study does not allow for a meaningful analysis of the scale where 100% means no complaints with no evidence of disease, 80% is normal activity with effort and some signs or symptoms of disease. | Baseline, 66 weeks | 
| Change From Baseline in Performance Status on the Karnofsky Performance Scale (KPS) | The Karnofsky Performance Scale scores range from 0% to 100%. The lower the Karnofsky score, the worse likelihood of survival. However, the premature termination of the study does not allow for a meaningful analysis of the scale where 100% means no complaints with no evidence of disease, 80% is normal activity with effort and some signs or symptoms of disease. | Baseline, 78 weeks | 
| Change From Baseline in Health-related Quality of Life on the 4- and 7-point European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30) | Final European Organisation for Research and Treatment of Cancer (EORTC) scores for multi-item scales and single-item measures will range from 0 to 100. This questionnaire assesses the quality of life of cancer patients. A high score represents a high/healthy level of functioning, basically a high Quality of Life. | Baseline, 7 days | 
| Change From Baseline in Health-related Quality of Life on the 4- and 7-point EORTC QLQ-C30 | Final European Organisation for Research and Treatment of Cancer (EORTC) scores for multi-item scales and single-item measures will range from 0 to 100. This questionnaire assesses the quality of life of cancer patients. A high score represents a high/healthy level of functioning, basically a high Quality of Life. | Baseline, up to 4 weeks | 
| Change From Baseline in Health-related Quality of Life on the 4- and 7-point EORTC QLQ-C30 | Final European Organisation for Research and Treatment of Cancer (EORTC) scores for multi-item scales and single-item measures will range from 0 to 100. This questionnaire assesses the quality of life of cancer patients. A high score represents a high/healthy level of functioning, basically a high Quality of Life. | Baseline, 13 weeks | 
| Change From Baseline in Health-related Quality of Life on the 4- and 7-point EORTC QLQ-C30 | Final European Organisation for Research and Treatment of Cancer (EORTC) scores for multi-item scales and single-item measures will range from 0 to 100. This questionnaire assesses the quality of life of cancer patients. A high score represents a high/healthy level of functioning, basically a high Quality of Life. | Baseline, 16 weeks | 
| Change From Baseline in Health-related Quality of Life on the 4- and 7-point EORTC QLQ-C30 | Final European Organisation for Research and Treatment of Cancer (EORTC) scores for multi-item scales and single-item measures will range from 0 to 100. This questionnaire assesses the quality of life of cancer patients. A high score represents a high/healthy level of functioning, basically a high Quality of Life. | Baseline, 29 weeks | 
| Time-to-bilirubin Response | From the date of randomization until the date of first documented bilirubin response | Up to 30 days | 
| Best Overall Tumor Response as Measured by the RECIST 1.1 Criteria (Response Evaluation Criteria in Solid Tumors) | From the start of the treatment until disease progression or recurrence the RECIST 1.1 criteria are applied (Response Evaluation Criteria in Solid Tumors) | Up to 26 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CCA, Cholangiocarcinoma, Unresectable perihilar cholangiocarcinoma, Klatskin tumor, Photodynamic therapy, Porfimer sodium, Photofrin, Gemcitabine, Cisplatin, Stents, PDT, Bile duct cancer, Bile duct tumor, Bile duct adenocarcinoma, Chemotherapy