A Phase I/II Study Safety and Efficacy Study of PCI of Gemcitabine and Chemotherapy in Patients With Cholangiocarcinomas

This study is currently recruiting participants. (see Contacts and Locations)
Verified July 2013 by PCI Biotech AS
Sponsor:
Information provided by (Responsible Party):
PCI Biotech AS
ClinicalTrials.gov Identifier:
NCT01900158
First received: May 15, 2013
Last updated: July 22, 2013
Last verified: July 2013
  Purpose

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.


Condition Intervention Phase
Cholangiocarcinoma
Drug: Amphinex and Gemcitabine
Drug: Gemcitabine and Cisplatin
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
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

Resource links provided by NLM:


Further study details as provided by PCI Biotech AS:

Primary Outcome Measures:
  • Dose limiting Toxicity - Phase I (safety) [ Time Frame: up to 9 months ] [ Designated as safety issue: Yes ]
    Dose-limiting toxicities (DLT) and the safety profile

  • Efficacy- Phase II (efficacy) [ Time Frame: Up to 17 months ] [ Designated as safety issue: Yes ]
    Progression Free Survival (PFS)


Secondary Outcome Measures:
  • Best Overall Response [ Time Frame: Up to 24 months. ] [ Designated as safety issue: No ]
    Number and proportion of patients with CR, PR, SD PD and NE

  • Pharmacokinetics [ Time Frame: 3 months ] [ Designated as safety issue: No ]
    Pharmacokinetics profine of Amphinex and Gemcitabine in Plasma

  • Disease Control Rate (DC) [ Time Frame: up to 24 months ] [ Designated as safety issue: No ]
    Proportion of patients with best overall response of CR, PR or SD

  • Overall Response Rate [ Time Frame: up to 24 months ] [ Designated as safety issue: No ]
    Proportion of patients with best overall response rate of CR and PR

  • Overall Survival [ Time Frame: up to 24 months ] [ Designated as safety issue: No ]
  • Safety Profile (Phase II) [ Time Frame: up to 24 months ] [ Designated as safety issue: Yes ]

Other Outcome Measures:
  • Time to re-intervention (Exploratory Endpoint) [ Time Frame: Up to 24 months ] [ Designated as safety issue: No ]
  • Skin photosensitivity (Exploratory Endpoint) [ Time Frame: Up to 4 months ] [ Designated as safety issue: Yes ]

Estimated Enrollment: 61
Study Start Date: May 2013
Estimated Study Completion Date: April 2015
Estimated Primary Completion Date: April 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Amphinex and Gemcitabine
Arm A: Amphinex administration on day 0, followed by gemcitabine administration (1000 mg/m2) intravenously over 30 minutes 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, commencing between 7 and 21 days after the laser light application
Drug: Amphinex and Gemcitabine
Amphinex administration on day 0, followed by gemcitabine administration (1000 mg/m2) intravenously over 30 minutes 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, commencing between 7 and 21 days after the laser light application.
Other Name: Gemzar
Active Comparator: Gemcitabine and Cisplatin
No PCI treatment (stenting only) followed by systemic gemcitabine (1000 mg/m2) intravenously over 30 minutes and cisplatin intravenously over a period of 1 hour (25 mg/m2) given on Day 1 and Day 8 of each 21-day cycle, commencing within 21 days after randomization.
Drug: Gemcitabine and Cisplatin
No PCI treatment (stenting only) followed by systemic gemcitabine (1000 mg/m2) intravenously over 30 minutes and cisplatin intravenously over a period of 1 hour (25 mg/m2) given on Day 1 and Day 8 of each 21-day cycle, commencing within 21 days after randomization.
Other Names:
  • Gemzar
  • Cisplatin

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

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01900158

Contacts
Contact: Dr. Richard Sturgess, MD 0044(0)151 529 8157 RICHARD.STURGESS@aintree.nhs.uk
Contact: Dr Dan Palmer, MD 0044 (0)151 706 4177 Daniel.Palmer@liverpool.ac.uk

Locations
Germany
National Center for Tumor Diseases Recruiting
Heidelberg, Baden-Württemberg, Germany, D-69120
Contact: Dr Jürgen Krauss, MD    0049 6221 56 38696    juergen.krauss@nct-heidelberg.de   
Klinikum rechts der Isar Recruiting
Munich, Bayern, Germany, 81675
Contact: Dr. Bruno Neu, MD    0049 89 4140-2902    Bruno.Neu@lrz.tu-muenchen.de   
Klinikum Ludwigshafen Recruiting
Ludwigshafen, Rheinland-Pfalz, Germany, D-67063
Contact: Prof. Ralf Jakobs, MD    0049 621 503 4100    JAKOBSR@klilu.de   
Charité, Campus Mitte Not yet recruiting
Berlin, Germany, D-10117
Contact: Dr. med. Robert Wentrup, MD    0049 30 450 614 055    robert.wentrup@charite.de   
United Kingdom
University Hospital Aintree Not yet recruiting
Aintree, Liverpool, United Kingdom, L9 7AL
Contact: Dr Richard Sturgess, MD    0044 (0) 151 529 8157    RICHARD.STURGESS@aintree.nhs.uk   
Contact: Dr Dan Palmer, MD    0044 (0)151 706 4177    Daniel.Palmer@liverpool.ac.uk   
Sponsors and Collaborators
PCI Biotech AS
Investigators
Principal Investigator: Dr Richard Sturgess, MD University Hospital Aintree
  More Information

No publications provided

Responsible Party: PCI Biotech AS
ClinicalTrials.gov Identifier: NCT01900158     History of Changes
Other Study ID Numbers: PCI A202/12
Study First Received: May 15, 2013
Last Updated: July 22, 2013
Health Authority: Germany: Federal Institute for Drugs and Medical Devices
United Kingdom: Medicines and Healthcare Products Regulatory Agency

Keywords provided by PCI Biotech AS:
Phase I, Phase II, Dose Escalation, Safety, Tolerability,
Efficacy, AmphinexTM-induced Photochemical Internalisation
(PCI), Gemcitabine, Gemcitabine/Cisplatin Chemotherapy,
Locally Advanced Inoperable Cholangiocarcinomas.

Additional relevant MeSH terms:
Cholangiocarcinoma
Adenocarcinoma
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Gemcitabine
Cisplatin
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Radiation-Sensitizing Agents
Physiological Effects of Drugs
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antiviral Agents
Anti-Infective Agents
Enzyme Inhibitors
Immunosuppressive Agents
Immunologic Factors

ClinicalTrials.gov processed this record on July 23, 2014