title: Phase I study of 90Y-CC49 monoclonal antibody therapy in patients with advanced non-small cell lung cancer: effect of chelating agents and paclitaxel co-administration.
abstract: OBJECTIVE
  This trial was designed to evaluate strategies to improve the efficacy of a radiolabeled monoclonal antibody (mCC49) against tumor-associated glycoprotein-72 (TAG-72) in patients with non-small cell lung cancer (NSCLC). The aims of this study were to determine: safety and maximum tolerated dose (MTD) of (90)Y-mCC49 in combination with interferon alpha2beta (IFN); whether calcium disodium versonate (EDTA) or diethylenetriamine penta-acetic acid (DTPA) could reduce myelosuppression; and safety and MTD of paclitaxel (Taxol) in combination with (90)Y-mCC49.
  
  
  METHODS
  Patients with advanced (TAG-72 positive) non-small cell lung cancer were entered in three phases; the first was the dose escalation of a single agent (90)Y-mCC49. In the second phase, the dose escalation of (90)Y-mCC49 was attempted with concurrent EDTA or DTPA chelator therapy. In the third phase, radiosensitization with a continuous infusion of paclitaxel (96-hour) was administered with (90)Y-mCC49. All patients received IFN for TAG-72 up-regulation.
  
  
  RESULTS
  Thirty-four patients were evaluable. Reversible Grade 4 neutropenia and thrombocytopenia were the dose-limiting toxicities (DLTs). The MTD of (90)Y-mCC49/IFN was 14 mCi/m(2). EDTA did not alter toxicity, while there was a modest reduction of myelosuppression with DTPA. The MTD of continuous infusion paclitaxel in combination with 14 mCi/m(2) of (90)Y-CC49 was 60 mg/m(2). There were no objective tumor responses.
  
  
  CONCLUSIONS
  (90)Y-mCC49/IFN was well tolerated at a dose of 14 mCi/m(2). The clinical effect of adjunctive chelating therapy with DTPA was modest. The MTD of coadministered continuous infusion (96-hour) paclitaxel was 60 mg/m(2). Because of the immunogenicity of the murine compound, future studies are planned using a humanized version of CC49.
authors.affiliation: Department of Medicine, Comprehensive Cancer Center, University of Alabama at Birmingham, 1824 Sixth Avenue South, Birmingham, AL 35294-3300, USA. Andres.Forero@cc.uab.edu
authors.forename: Andres
authors.initials: A
authors.lastname: Forero
authors.forename: Ruby F
authors.initials: RF
authors.lastname: Meredith
authors.forename: M B
authors.initials: MB
authors.lastname: Khazaeli
authors.forename: Sui
authors.initials: S
authors.lastname: Shen
authors.forename: William E
authors.initials: WE
authors.lastname: Grizzle
authors.forename: Delicia
authors.initials: D
authors.lastname: Carey
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Busby
authors.forename: Albert F
authors.initials: AF
authors.lastname: LoBuglio
authors.forename: Francisco
authors.initials: F
authors.lastname: Robert
mesh_terms: D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000737:chemistry; D000912:Antibodies, Neoplasm / Q000627:therapeutic use*; D000951:Antigens, Neoplasm / Q000737:chemistry; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy*; D002614:Chelating Agents / Q000008:administration & dosage* / Q000494:pharmacology; D002986:Clinical Trials as Topic; D018450:Disease Progression; D004492:Edetic Acid / Q000494:pharmacology; D005260:Female; D006023:Glycoproteins / Q000737:chemistry; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009503:Neutropenia; D017239:Paclitaxel / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use; D004369:Pentetic Acid / Q000494:pharmacology; D016499:Radioimmunotherapy; D011874:Radiometry; D013921:Thrombocytopenia; D016896:Treatment Outcome; D015854:Up-Regulation; D015021:Yttrium Radioisotopes / Q000627:therapeutic use*
chemical_list: D000911:Antibodies, Monoclonal; D000912:Antibodies, Neoplasm; D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; C091202:B72.3 antibody; D002614:Chelating Agents; D006023:Glycoproteins; D015021:Yttrium Radioisotopes; C047052:tumor-associated antigen 72; D004369:Pentetic Acid; D004492:Edetic Acid; D017239:Paclitaxel