A Phase I/II Study Safety and Efficacy Study of PCI of Gemcitabine and Chemotherapy in Patients With Cholangiocarcinomas
Information source: PCI Biotech AS
ClinicalTrials.gov processed this data on August 20, 2015 Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Cholangiocarcinoma
Intervention: Amphinex and Gemcitabine (Drug); Gemcitabine and Cisplatin (Drug)
Phase: Phase 1/Phase 2
Status: Recruiting
Sponsored by: PCI Biotech AS Official(s) and/or principal investigator(s): Dr Richard Sturgess, MD, Principal Investigator, Affiliation: University Hospital Aintree
Overall contact: Dr. Richard Sturgess, MD, Phone: 0044(0)151 529 8157, Email: RICHARD.STURGESS@aintree.nhs.uk
Summary
This is a Phase I/II Dose Escalation Study in which the safety, tolerability and efficacy of
Amphinex-induced Photochemical Internalisation (PCI) of Gemcitabine followed by
Gemcitabine/Cisplatin Chemotherapy will be assessed in patients with locally advanced
inoperable cholangiocarcinomas.
Clinical Details
Official title: A Phase I/II Dose Escalation Study to Assess the Safety, Tolerability and Efficacy of PCI of Gemcitabine Followed by Gemcitabine/Cisplatin Chemotherapy in Patients With Locally Advanced Inoperable Cholangiocarcinomas
Study design: Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
Primary outcome: Dose limiting Toxicity - Phase I (safety)Efficacy- Phase II (efficacy)
Secondary outcome: Best Overall ResponsePharmacokinetics Disease Control Rate (DC) Overall Response Rate Overall Survival Safety Profile (Phase II)
Detailed description:
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%), hilar (also known as Klatskin tumour -
50%) and extra-hepatic (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 (10). 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 (23).
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 locally 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 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 PhII 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 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, with its
favourable adverse-event profile, is recommended by most recent review articles for
non-resectable patients.
Eligibility
Minimum age: 18 Years.
Maximum age: N/A.
Gender(s): Both.
Criteria:
Inclusion Criteria:
1. Histopathologically/cytologically (C5) verified adenocarcinoma consistent
with locally advanced inoperable
2. Cholangiocarcinoma that is limited to:
Nodal enlargement ≤ to N1 as per CT/MRI assessment Less than 4cm in longest diameter
Perihilar and extrahilar biliary duct region.
3. Adequate biliary drainage (either at least 50% of the liver volume, or at least two
sectors), with no evidence of active uncontrolled infection (patients on antibiotics
are eligible).
4. Age ≥ 18 years.
5. Performance status ECOG ≤ 2
6. Estimated life expectancy of at least 12 weeks.
7. Written informed consent.
Exclusion Criteria:
- Diagnosis and main criteria for inclusion:
Inclusion Criteria:
1. Histopathologically/cytologically (C5) verified adenocarcinoma consistent with
locally advanced inoperable
2. Cholangiocarcinoma that is limited to:
Nodal enlargement ≤ to N1 as per CT/MRI assessment Less than 4cm in longest diameter
Perihilar and extrahilar biliary duct region.
3. Adequate biliary drainage (either at least 50% of the liver volume, or at least two
sectors), with no evidence of active uncontrolled infection (patients on antibiotics
are eligible).
4. Age ≥ 18 years.
5. Performance status ECOG ≤ 2
6. Estimated life expectancy of at least 12 weeks.
7. Written informed consent.
Exclusion Criteria:
1. Any prior anti-cancer (either local or systemic) treatment for cholangiocarcinoma.
2. Patients with a severe visceral disease other than cholangiocarcinoma.
3. Patients with primary sclerosing cholangitis.
4. Patients with porphyria or hypersensibility to porphyrins.
5. Concomitant or prior malignant disease, with exception of adequately treated basal
cell carcinoma, squamous cell carcinoma or other non-melanomatous skin cancer, or
in-situ carcinoma of the uterine cervix.
6. Inability to undergo CT or MRI.
7. Current participation in any other interventional clinical trial.
8. Male patients not willing to use adequate contraception or female patients of
childbearing potential not willing to use an effective form of contraception such as
hormonal birth control, intrauterine device or double barrier method during PCI
treatment and subsequent chemotherapy and for at least 6 months thereafter.
9. Breast feeding women or women with a positive pregnancy test at baseline.
10. Inadequate bone marrow function:
- Absolute Neutrophil Count (ANC): <1. 5 x 109/L, or platelet count <100 x 109/L or
haemoglobin <6 mmol/L (transfusion allowed).
11. Inadequate liver function, defined as:
- Serum (total) bilirubin >1. 5 x the Upper Limit of Normal (ULN) for the
institution.
- Aspartate Amino Transferase (AST) or Alanine Amino Transferase (ALT) >3. 0 x ULN.
- Alkaline phosphatase levels >5. 0 x ULN.
12. Inadequate renal function, defined as:
- Creatinine clearance <60ml/min)
13. Planned surgery, endoscopic examination or dental treatment in the first 30 days
after PCI treatment.
14. Co-existing ophthalmic disease likely to require slit-lamp examination within the
first 90 days after PCI treatment.
15. Clinically significant and uncontrolled cardiac disease including unstable angina,
acute myocardial infarction within six months prior to baseline, congestive heart
failure, and arrhythmia requiring therapy, with the exception of extra systoles or
minor conduction abnormalities and controlled and well treated chronic atrial
fibrillation.
16. Known allergy or sensitivity to photosensitisers.
17. Ataxia telangiectasia.
18. Evidence of any other medical conditions (such as psychiatric illness, infectious
diseases, 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.
19. Significant hearing impairment.
20. Patients concurrently receiving phenytoin.
Locations and Contacts
Dr. Richard Sturgess, MD, Phone: 0044(0)151 529 8157, Email: RICHARD.STURGESS@aintree.nhs.uk
Charité, Campus Mitte, Berlin D-10117, Germany; Recruiting Dr. med. Christian Jürgensen, MD, Phone: 0049 30 450 514 134, Email: Christian.Juergensen@charite.de
National Center for Tumor Diseases, Heidelberg, Baden-Württemberg D-69120, Germany; Active, not recruiting
Universitätsklinikum Ulm, Ulm, Baden-Württemberg 89081, Germany; Not yet recruiting Dr. med. Matthias Dollinger, MD, Phone: +49 49 731 500 44501, Email: matthias.dollinger@uniklinik-ulm.de
Klinikum rechts der Isar, Munich, Bayern 81675, Germany; Recruiting Dr. Bruno Neu, MD, Phone: 0049 89 4140-2902, Email: Bruno.Neu@lrz.tu-muenchen.de
Klinikum der Ludwig-Maximilians-Universität, München, Bayern 81377, Germany; Recruiting Prof. Dr. Jörg Schirra, MD, Phone: +49 89 4400 73031, Email: Joerg.schirra@med.uni-muenchen.de
Hôpital Nord, Marseille, Bouches-du-Rhône 13915 Cedex 20, France; Not yet recruiting Prof. Dr. Marc Barthet, MD, Phone: + 33 4 91 96 46 14, Email: Marc.BARTHET@ap-hm.fr
Klinikum der Johann Wolfgang Goethe-Universität, Frankfurt am Main, Hessen 60590, Germany; Recruiting Prof. Dr. Jörg Trojan, MD, Phone: +49 69 6301 87686, Email: trojan@em.uni-frankfurt.de
University Hospital Aintree, Aintree, Liverpool L9 7AL, United Kingdom; Recruiting Dr Richard Sturgess, MD, Phone: 0044 (0) 151 529 8157, Email: RICHARD.STURGESS@aintree.nhs.uk Dr Dan Palmer, MD, Phone: 0044 (0)151 706 4177, Email: Daniel.Palmer@liverpool.ac.uk
Universitätsklinikum Essen, Essen, Nordrhein-Westfalen 45122, Germany; Recruiting Dr.med. Stefan Kasper, MD, Phone: +49 201 723 1631, Email: stefan.kasper@uk-essen.de Dr.med. Alexander Dechêne, MD, Phone: +49 49 201 723 2390, Email: alexander.dechene@uk-essen.de
Klinikum Ludwigshafen, Ludwigshafen, Rheinland-Pfalz D-67063, Germany; Recruiting Prof. Ralf Jakobs, MD, Phone: 0049 621 503 4100, Email: JAKOBSR@klilu.de
Universitätsklinikum Leipzig, Leipzig, Sachsen 04103, Germany; Active, not recruiting
Additional Information
Sponsor
Starting date: May 2013
Last updated: May 4, 2015
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