title: Clinical experience of treatment of metastatic melanoma and solid tumours adopting a derivative of diphtheria toxin: cross-reacting material 197.
abstract: BACKGROUND
  Diphtheria toxin (DT) has shown anticancer activity in both experimental models and humans but its adverse effects stopped further developments. Cross-reacting Material 197 (CRM197) is the product of a single missense mutation (Gly52 to Glu) within fragment A of DT. It has been shown to induce weak toxicity in some cell strains, but it shares immunological properties with native DT. CRM197 commonly acts as an immunological adjuvant, or as an inhibitor of heparin-binding epidermal growth factor. Recently, CRM197 was shown to have promising antitumor activity. To better-define this property, we planned a phase I-II study.
  
  
  METHODS
  Twenty-nine patients bearing advanced melanoma (18 cases), and other solid tumors (two ovarian cancer, two sarcoma, two gastrointestinal cancers, one urinary bladder carcinoma, one glioblastoma, one neuroblastoma, one ocular melanoma and one primitive neuroectodermal embriogenic tumor (PNET) were evaluated and 19 of them, sub-divided in cohorts, received the following levels of CRM197: Level 1, 0.3 mg; level 2, 1.0 mg; level 3, 2.5 mg; level 4, 3.5 mg; level 5, 5.0 mg; level 6, 7.5 mg. The drug was given once every two days for 4 times and then, after a 2-week rest period, once every 2 days for 4 times. CRM197 was administered subcutaneously in the abdominal wall.
  
  
  RESULTS
  grade 1-2 common toxicities included fever, chills, fatigue, dizziness, nausea, vomiting and headache, neutrophilia and skin painful reactions appeared regularly at levels 3 and 4 (2.5 mg and 3.5 mg). Vomiting and abdominal pain, skin reaction tachycardia and hypotension appeared in two patients at level 5. At 7.5 mg, we observed a severe grade 3 reaction with hypotension, dyspnea and grade 4 myalgia. This was considered the dose-limiting toxicity. Eleven patients (seven with melanoma and four with other tumors) were treated to evaluate anticancer effects at the maximum tolerated dose (5 mg). Only one patient reported a minor response, lasting eight weeks. Ten patients reported progressive disease.
  
  
  CONCLUSIONS
  CRM197, injected subcutaneously at 5 mg, elicited a generic inflammatory response causing toxicity, and did not exert a significant degree of antitumor activity in patients with advanced melanoma and solid tumour.
authors: Department of Oncology-Hematology, Azienda Ospedaliera Ospedali Riuniti Marche Nord, Pesaro, Italy. g.fiorentini@ospedalesansalvatore.it
authors: Giammaria
authors: G
authors: Fiorentini
authors: Roberto
authors: R
authors: Banfi
authors: Patrizia
authors: P
authors: Dentico
authors: Sabina
authors: S
authors: Moriconi
authors: Gina
authors: G
authors: Turrisi
authors: Filippo
authors: F
authors: Pelagotti
authors: Susanna
authors: S
authors: Rossi
authors: Francesco
authors: F
authors: Montagnani
mesh_terms: D000328:Adult; D001426:Bacterial Proteins / Q000009:adverse effects / Q000627:therapeutic use*; D004167:Diphtheria Toxin / Q000009:adverse effects / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D007279:Injections, Subcutaneous; D007558:Italy / Q000453:epidemiology; D008545:Melanoma / Q000188:drug therapy* / Q000401:mortality / Q000556:secondary; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D015996:Survival Rate; D016896:Treatment Outcome
chemical_list: D001426:Bacterial Proteins; D004167:Diphtheria Toxin; C028581:CRM197 (non-toxic variant of diphtheria toxin)