A Phase I/II Safety and Efficacy Study of PCI of Gemcitabine and Chemotherapy in Patients With Cholangiocarcinomas
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|ClinicalTrials.gov Identifier: NCT01900158|
Recruitment Status : Completed
First Posted : July 16, 2013
Last Update Posted : October 29, 2019
|Condition or disease||Intervention/treatment||Phase|
|Cholangiocarcinoma||Drug: Amphinex, Gemcitabine and Cisplatin||Phase 1|
Cholangiocarcinoma (CCA) is an uncommon adenocarcinoma arising from the neoplastic transformation of cholangiocytes, the epithelial cells lining the intra-hepatic and extra-hepatic bile ducts. CCA accounts for about 3% of all digestive tumours and 10-15% of the hepatobiliary tumours. It has an annual incidence of 1-2 cases per 100,000 in the Western World, but rates of CCA have been steadily rising worldwide over the past several decades. On a global scale, CCA is the second most common primary hepatic malignancy These tumours have a poor overall survival with a 5-year survival of about 5%. Over 50% of patients present with advanced-stage disease, and the prognosis is poor with the survival of between 6-12 months for unresected patients, even after biliary decompression. CCA may arise anywhere in the biliary tree, from the small, peripheral hepatic ducts to the distal common bile duct. Commonly used classification systems utilise anatomical location to group tumours into three main categories: intra-hepatic (20-25%), perihilar (also including hilar/Klatskin tumour - 50%) and distal (20-25%).
Hilar CCA is an adenocarcinoma of the extrahepatic biliary tree arising from the main left or right hepatic ducts or their confluence. There has a been a growing recognition that hilar CCA disease actually has a distinct biological behaviour and natural history compared to that of (distal) extra-hepatic CCA, and increasing acknowledgment that different therapeutic strategies are required. At initial presentation of patients with extra-hepatic CCA, 30-50% will have local lymph node involvement and 10-20% metastatic spread typically to the liver and peritoneum. With hilar CCA due to the long asymptomatic course, only 20% are resectable at time of diagnosis.
Standard treatment options for CCA include surgery, radiotherapy and chemotherapy, dependent upon if the CCA is intra- or extra-hepatic. Tumour resection is the only potential cure for CCA. Recent advances in transplantation using stringent selection criteria and utilization of neoadjuvant chemoradiation have demonstrated encouraging results with 5 year survival rates of over 70%, with even one series from The Mayo Clinic yielding a 5-year survival rate of 82%. For the 80% who present with unresectable disease, the utility of these modalities combined with biliary decompression interventions only provided a median survival time of 3-6 months from the time of diagnosis.
For these patients with inoperable advanced CCA the main treatment aim is palliative to relieve local symptoms such as pain and jaundice. Surgery for these patients is primarily for creating a bypass in patients who cannot be stented. CCA is remarkably resistant to pharmacological therapy, but activity has been seen using chemotherapy; mainly gemcitabine given either as monotherapy or paired with either a platin derivative or a fluoropyrimidine as a doublet treatment and more recently docetaxel, these give partial response (PR) rates of 0-9% and an average survival advantage of 2-12 months. Concerning biological therapy, the ongoing studies using sorafenib, lapatinib or bevacizumab have yielded some promising results, with sorafenib demonstrating therapeutic benefit in a single arm Phase II study. For patients who are unsuitable for curative resection, the current systemic combination chemotherapy is with cisplatin plus gemcitabine. This was established in the largest randomized phase III study to date in non-operable biliary tract cancer which demonstrated a response rate of 81.4% and a median overall survival (OS) of 11.7 months; notably there was no statistically significant increase in toxicity when compared to gemcitabine monotherapy. The recent advances in interventional and endoscopic technology have seen a rise in highly specialized centres that are able to deliver very precise local control treatments aimed at gaining local control; these include local ablation and embolization, brachytherapy, radio-frequency ablation and, most significantly, photodynamic therapy which (PDT), with its favourable adverse-event profile, is recommended by most recent review articles for non-resectable patients.
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||24 participants|
|Intervention Model:||Sequential Assignment|
|Intervention Model Description:||Phase I Dose escalation study With 4 cohorts of different doses of light and fimaporfin (Dose Escalation) plus and additional cohort With one repeated treatment of the dose selected for one treatment (Extended).|
|Masking:||None (Open Label)|
|Official Title:||A Phase I/II Dose Escalation Study to Assess the Safety, Tolerability and Efficacy of Amphinex®-Induced Photochemical Internalisation (PCI) of Gemcitabine in Patients With Advanced Inoperable Cholangiocarcinomas|
|Actual Study Start Date :||May 2013|
|Actual Primary Completion Date :||February 2019|
|Actual Study Completion Date :||February 2019|
Experimental: Phase I
Experimental PCI treatment in dose escalation cohorts consist of Amphinex injection (at different doses) plus a single standard dose of Gemcitabine (1000 mg/m2) plus intraluminal light at the tumour area (at different doses). In addition up to 8 cycles of standard chemotherapy doses of Gemcitabine (1000 mg/m2) and Cisplatin (25 mg/m2) was provided. In the Extended part of the study (last cohort) an additional PCI treatment was introduced at Cycle 5 in the treatment Schedule.
Drug: Amphinex, Gemcitabine and Cisplatin
Amphinex administration on day 0, followed by gemcitabine administration (1000 mg/m2) and laser light application (652 nm) on day 4 followed by systemic gemcitabine (1000 mg/m2) and cisplatin (25 mg/m2) given on Day 1 and Day 8 of each 21-day cycle, for up to a total of eight cycles. Either one or two PCI treatments (Amphinex, Gemcitabine and intraluminal laser light of 652nm) during the 8 cycles of chemotherapy
- Dose-limiting toxicities (DLT) and the safety profile [ Time Frame: up to 6 months ]
Clinically significant toxicity or abnormal laboratory value assessed as unrelated to the underlying disease, criteria's based on the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.02:
- Photosensitivity Grade 3 outside the treatment area, except for areas exposed for skin sensitivity tests and areas exposed for re-introduction to normal light. Patient compliance with light protection guidelines MUST be followed; noncompliance will be taken into account
- Phototoxicity Grade 4 inside the treatment area (e.g., duodenal ulceration).
- Non-haematological toxicity (excluding nausea and vomiting) ≥Grade 3.
- Neutropenia or thrombocytopenia Grade 4.
- All other Grade 3 toxicities that are clinically unexpected.
- Schedule-limiting toxicities (SLTs) and the safety profile [ Time Frame: up to 6 months ]
Clinically significant toxicity or abnormal laboratory value assessed as unrelated to the underlying disease criteria's based on the NCI CTCAE version 4.02:
- Photosensitivity Grade 3 outside the treatment area, except for areas exposed for skin sensitivity tests and areas exposed for re-introduction to normal light despite following prescribed precautions. Patient compliance with light protection guidelines MUST be followed; noncompliance will be taken into account
- Clinically significant phototoxicity inside the treatment area (e.g., duodenal ulceration, cholangitis or pancreatitis requiring interventional radiology, operative intervention or would lead to such intervention including events that would have life-threatening consequences)
- A toxicity of any grade that is clinically unexpected and considered related to the PCI treatment (changes to cisplatin treatment alone will not be included as part of this assessment).
- Measuring the Amphinex and Gemcitabine concentration in blood plasma [ Time Frame: Up to 8 months ]Cmax, Vss, T1/2, AUC and CL
- Progression-free survival (according to RECIST 1.1 criteria) [ Time Frame: Up to documented disease progression or death (or Database lock) ]
- Best Overall Response (according to RECIST 1.1 criteria) [ Time Frame: Up to Database lock ]
- Time to re-intervention (stent patency) [ Time Frame: Up to 8 months ]From date of registration to reintervention
- Patient questionnaire and "in clinic" evaluations [ Time Frame: Up to 8 months ]Skin photosensitivity - protection information- testing information and events
- Measuring of Amphinex concentration in faeces [ Time Frame: up to 1 week after Amphinex administration ]Quantitative measures
- Local tumor response evaluation [ Time Frame: Up to 8 months ]Local tumour responses by assessment of radiological data
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01900158
|Angers, Maine-et-Loire, France, 49933|
|Klinikum rechts der Isar, Technische Universität München|
|Munich, Bayern, Germany, 81675|
|Klinikum der Ludwig-Maximilians-Universität|
|München, Bayern, Germany, 81377|
|Klinikum der Johann Wolfgang Goethe-Universität|
|Frankfurt am Main, Hessen, Germany, 60590|
|Essen, Nordrhein-Westfalen, Germany, 45122|
|Ludwigshafen, Rheinland-Pfalz, Germany, D-67063|
|Leipzig, Sachsen, Germany, 04103|
|Charité, Campus Mitte|
|Berlin, Germany, D-10117|
|Universitätsklinikum Carl Gustav Carus an der Technischen Universität Dresden|
|Dresden, Germany, 01307|
|Oslo Universtiy Hospital|
|Oslo, Norway, 0310|
|University Hospital Aintree|
|Aintree, Liverpool, United Kingdom, L9 7AL|
|Principal Investigator:||Dr Richard Sturgess, MD||University Hospital Aintree|