title: Disulfonated tetraphenyl chlorin (TPCS2a)-induced photochemical internalisation of bleomycin in patients with solid malignancies: a phase 1, dose-escalation, first-in-man trial.
abstract: BACKGROUND
  Photochemical internalisation, a novel minimally invasive treatment, has shown promising preclinical results in enhancing and site-directing the effect of anticancer drugs by illumination, which initiates localised chemotherapy release. We assessed the safety and tolerability of a newly developed photosensitiser, disulfonated tetraphenyl chlorin (TPCS2a), in mediating photochemical internalisation of bleomycin in patients with advanced and recurrent solid malignancies.
  
  
  METHODS
  In this phase 1, dose-escalation, first-in-man trial, we recruited patients (aged ≥18 to <85 years) with local recurrent, advanced, or metastatic cutaneous or subcutaneous malignancies who were clinically assessed as eligible for bleomycin chemotherapy from a single centre in the UK. Patients were given TPCS2a on day 0 by slow intravenous injection, followed by a fixed dose of 15 000 IU/m(2) bleomycin by intravenous infusion on day 4. After 3 h, the surface of the target tumour was illuminated with 652 nm laser light (fixed at 60 J/cm(2)). The TPCS2a starting dose was 0·25 mg/kg and was then escalated in successive dose cohorts of three patients (0·5, 1·0, and 1·5 mg/kg). The primary endpoints were safety and tolerability of TPCS2a; other co-primary endpoints were dose-limiting toxicity and maximum tolerated dose. The primary analysis was per protocol. This study is registered with ClinicalTrials.gov, number NCT00993512, and has been completed.
  
  
  RESULTS
  Between Oct 3, 2009, and Jan 14, 2014, we recruited 22 patients into the trial. 12 patients completed the 3-month follow-up period. Adverse events related to photochemical internalisation were either local, resulting from the local inflammatory process, or systemic, mostly as a result of the skin-photosensitising effect of TPCS2a. The most common grade 3 or worse adverse events were unexpected higher transient pain response (grade 3) localised to the treatment site recorded in nine patients, and respiratory failure (grade 4) noted in two patients. One dose-limiting toxicity was reported in the 1·0 mg/kg cohort (skin photosensitivity [grade 2]). Dose-limiting toxicities were reported in two of three patients at a TPCS2a dose of 1·5 mg/kg (skin photosensitivity [grade 3] and wound infection [grade 3]); thus, the maximum tolerated dose of TPCS2a was 1·0 mg/kg. Administration of TPCS2a was found to be safe and tolerable by all patients. No deaths related to photochemical internalisation treatment occurred.
  
  
  CONCLUSIONS
  TPCS2a-mediated photochemical internalisation of bleomycin is safe and tolerable. We identified TPCS2a 0·25 mg/kg as the recommended treatment dose for future trials.
  
  
  BACKGROUND
  PCI Biotech.
authors.affiliation: Academic Unit of Oral and Maxillofacial Surgery, UCL Eastman Dental Institute, London, UK.
authors.forename: Ahmed A
authors.initials: AA
authors.lastname: Sultan
authors.affiliation: Division of Surgery and Interventional Science, University College London, London, UK.
authors.forename: Waseem
authors.initials: W
authors.lastname: Jerjes
authors.affiliation: Department of Radiation Biology, Oslo University Hospital, Oslo, Norway.
authors.forename: Kristian
authors.initials: K
authors.lastname: Berg
authors.affiliation: PCI Biotech AS, Oslo, Norway.
authors.forename: Anders
authors.initials: A
authors.lastname: Høgset
authors.affiliation: Division of Surgery and Interventional Science, University College London, London, UK.
authors.forename: Charles A
authors.initials: CA
authors.lastname: Mosse
authors.affiliation: Division of Surgery and Interventional Science, University College London, London, UK.
authors.forename: Rifat
authors.initials: R
authors.lastname: Hamoudi
authors.affiliation: Academic Unit of Oral and Maxillofacial Surgery, UCL Eastman Dental Institute, London, UK.
authors.forename: Zaid
authors.initials: Z
authors.lastname: Hamdoon
authors.affiliation: Cancer Clinical Trials Unit, University College London Hospitals, London, UK.
authors.forename: Celia
authors.initials: C
authors.lastname: Simeon
authors.affiliation: Head and Neck Unit, University College London Hospitals, London, UK.
authors.forename: Dawn
authors.initials: D
authors.lastname: Carnell
authors.affiliation: Head and Neck Unit, University College London Hospitals, London, UK; UCL Cancer Institute, London, UK.
authors.forename: Martin
authors.initials: M
authors.lastname: Forster
authors.affiliation: Academic Unit of Oral and Maxillofacial Surgery, UCL Eastman Dental Institute, London, UK; Head and Neck Unit, University College London Hospitals, London, UK; UCL Cancer Institute, London, UK. Electronic address: c.hopper@ucl.ac.uk.
authors.forename: Colin
authors.initials: C
authors.lastname: Hopper
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001761:Bleomycin / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008027:Light; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000473:pathology; D009367:Neoplasm Staging; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D017319:Photosensitizing Agents / Q000737:chemistry* / Q000493:pharmacokinetics; D011166:Porphyrins / Q000737:chemistry* / Q000493:pharmacokinetics; D011379:Prognosis; D014018:Tissue Distribution
chemical_list: D000970:Antineoplastic Agents; D017319:Photosensitizing Agents; D011166:Porphyrins; C559366:meso-tetraphenyl chlorin disulphonate; D001761:Bleomycin