Neoplasms

All Conditions

Rare Diseases

Cholangiocarcinoma

Adenocarcinoma

Carcinoma

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Bile Duct Cancer

Antineoplastic Agents

All Drugs and Chemicals

Gemcitabine

Cisplatin

Antimetabolites

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.

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

Amphinex, Gemcitabine and Cisplatin

Dr Richard Sturgess, MD

This is a Phase I 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 advanced inoperable cholangiocarcinomas.

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.

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).

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

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

From date of registration to reintervention

Skin photosensitivity - protection information- testing information and events

Local tumour responses by assessment of radiological data

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.

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).

PCI Biotech AS

Skin and Connective Tissue Diseases

Symptoms and General Pathology

Breast Neoplasms

Neoplasm Metastasis

Carcinoma, Squamous Cell

Recurrence

Head and Neck Neoplasms

Dermatologic Agents

Anti-Infective Agents

Bleomycin

Photosensitizing Agents

Anti-Bacterial Agents

Antibiotics, Antitubercular

The photosensitiser Amphinex is activated by Laser to enhance the effect of Bleomycin

Amphinex

Laser

Martin Forster, MD

The primary goal of this extension study is to further investigate the tolerability and efficacy in a phase I setting in order to see whether lower doses than the initial study dose of 0.25 mg/kg bw Amphinex in Amphinex-based PCI of bleomycin will show a comparable or improved safety and tolerability profile in combination with comparable signs of efficacy.

Use of Amphinex for the enhancement of Bleomycin at the intracellular target. The photosensitizer Amphinex is activated by Laser Light at 652 nm.

Superficial lesions (cutaneous or subcutaneous) was treated with the laser light after administration of Amphinex and Bleomycin according to time scheduled provided.

Safety and preliminary effect data where evaluated at a lower dose than explored in the preceeding dose escalating study with Amphinex.

Dose Escalating Study for Amphinex-based PCI of Bleomycin.

Dose Escalating Study to Evaluate the Tolerability, Efficacy and Safety of Amphinex 0.125 mg/kg or Lower in Amphinex-based PCI of Bleomycin in Patients With Local Recurrence or Advanced/Metastatic, Cutaneous or Sub-cutaneous Malignancies.

Plasma samples for pharmacokinetic (PK) evaluation will be collected from patients and the presence of Amphinex and/or other unidentified metabolites will be assessed using a validated analytical method

Systematic skin photosensitivity tests will be carried out using a white light source with an emission spectrum that, relatively to the luminance and within +/- 50%, excites Amphinex with the same efficiency as sunlight. The luminance will be 500 lux, which is comparable to bright indoor light, and 100.000 lux, which is comparable to direct sunlight. The phototoxic reaction will be scored at specific time points following the light exposure (see the study flowchart Appendix B). This information will be used to predict the degree of photosensitivity of the skin.

Maximal pain during the procedure will be recorded immediately after the procedure on a 10 centimetre visual analogue scale (VAS). Pain will also be recorded 24 hours after the illumination and on day 4. The end-points of the VAS will be "no pain" and "unbearable pain

A formal efficacy analysis is not appropriate for this trial. The response data will be documented by descriptive summary tables. No statistical comparison of dose levels will be done. Fluorescence measurements over time and lesion response evaluation according to RECIST (see Appendix E) will be presented for APT and PP stratified by dose level.

* Summaries of the adverse event rates and laboratory changes from baseline stratified by dose level.
* Listings and frequency tables categorizing laboratory and non-laboratory adverse events by maximum CTCAE toxicity grade and relationship to study drug.
* Pain measurement, fluorescence measurement, skin photosensitivity measurement

Skin Neoplasms

Skin Diseases

No comparative treatment is given in this open-label phase I, dose escalating safety study

intravenous TPCS2a, followed by standard dose of bleomycin (iv infusion) and illumination with CeramOptec laser.

Amphinex (TPCS2a)

Illumination with CeramOptec laser

Colin Hopper, MD

This study is an open, non- randomized, phase I, dose-escalating study to evaluate the safety and tolerance of Amphinex based PCI of bleomycin in patients with local recurrent or advanced/metastatic, cutaneous or sub-cutaneous malignancies.

Eligible patients will be included in cohorts of 3 patients. The initial starting dose for Amphinex will be given 4 days prior to the fixed dose of bleomycin administered by intravenous infusion. The illumination, with red light (laser 652 nm), to the tumour surface and a margin of 2-3 mm outside the tumour surface, will be performed after bleomycin administration.

There will be no comparative procedure in this study. Dose escalation will proceed according to a modification of Simon's accelerated titration design. The number of patients recruited depends on the DLT experienced. A total of 6 patients will be included at each dose level if no more than 1 patient experiences DLT.

Additional cohorts may be added pending the outcome of the previous cohorts and discussions between the investigators and the Sponsor. The primary goal of the study is to assess the safety and tolerance of the Amphinex and determine the maximal tolerated dose (MTD) of Amphinex as a PCI therapy in combination with bleomycin treatment.

Safety Study of Amphinex Based Photochemical Internalisation (PCI) of Bleomycin in Patients With Cutaneous Cancer

Phase I, Dose-escalating Study to Evaluate Safety and Tolerance of Amphinex Based Photochemical Internalisation (PCI) of Bleomycin in Patients With Local Recurrence or Advanced/Metastatic, Cutaneous or Sub-cutaneous Malignancies

Vaccines

Poly ICLC

Keyhole-limpet hemocyanin

Interferons

Immunologic Factors

Adjuvants, Immunologic

Run-in cohort for selection of fimaporfin starting dose in the main study. Single intradermal dosing of fimaporfin and adjuvant (Hiltonol \[poly-ICLC\]) followed by light application.

Main part: Intradermal dosing of fimaporfin, adjuvant (Hiltonol, poly-ICLC) and antigens (KLH and HPV E7) followed by light application.

Optional part: Assessment of different time interval between intradermal dosing of fimaporfin, adjuvant/antigens and light application.

Fimaporfin (Photosensitizer)

Hiltonol (Poly-ICLC)

HPV E7 (Human Papilloma Virus E7) peptides

KLH (Keyhole Limpet Hemocyanin)

Jim Bush, MBChB, PhD, MRCS, MFPM

Fimaporfin (TPCS2a) is a photosensitiser drug being developed by PCI Biotech AS for use in novel Photochemical Internalisation (PCI) technology. PCI technology is designed to enhance the effects of other drugs in a site-specific, light-directed manner and is used to re-localise endocytosed molecules from endosomes to cytosol. This research study is evaluating the use of the PCI Technology in combination with adjuvant and vaccine antigens for safety and induction of immune responses.

Study to Assess Safety, Tolerability and Immune Response of Fimaporfin-induced Photochemical Internalisation of Antigen/Adjuvant

An Open-label, Phase I/Proof of Principle, Dose Escalation Study to Assess Safety, Tolerability and Immune Response of Fimaporfin-induced Photochemical Internalisation (PCI) of Antigen/Adjuvant in Healthy Male/Female Subjects

Clinical Laboratory, ECG, Vital Signs and Physical Examinations

Local Tolerability (pain, erythema, oedema, induration and ulceration)

Blood samples will be collected prior, during and after treatment for assessment of Antibody Production and T-cell Responses (change from baseline)

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
A Phase I/II Safety and Efficacy Study of PCI of Gemcitabine and Chemotherapy in Patients With Cholangiocarcinomas	NCT01900158	Cholangiocarcin...	Amphinex, Gemci...	18 Years -	PCI Biotech AS
A Phase I/II Safety and Efficacy Study of PCI of Gemcitabine and Chemotherapy in Patients With Cholangiocarcinomas	NCT01900158	Cholangiocarcin...	Amphinex, Gemci...	18 Years -	PCI Biotech AS
Dose Escalating Study for Amphinex-based PCI of Bleomycin.	NCT01872923	Cutaneous or Su...	Amphinex Bleomycin Laser	18 Years -	PCI Biotech AS
Safety Study of Amphinex Based Photochemical Internalisation (PCI) of Bleomycin in Patients With Cutaneous Cancer	NCT00993512	Head and Neck N... Skin Neoplasms	Amphinex (TPCS2... Bleomycin Illumination wi...	18 Years -	PCI Biotech AS
Study to Assess Safety, Tolerability and Immune Response of Fimaporfin-induced Photochemical Internalisation of Antigen/Adjuvant	NCT02947854	Healthy Volunte...	Fimaporfin (Pho... Hiltonol (Poly-... HPV E7 (Human P... KLH (Keyhole Li...	18 Years - 55 Years	PCI Biotech AS

Spots Global Cancer Trial Database for photochemical internalisation