title: Phase I study of KW-0761, a defucosylated humanized anti-CCR4 antibody, in relapsed patients with adult T-cell leukemia-lymphoma and peripheral T-cell lymphoma.
abstract: OBJECTIVE
  KW-0761, a defucosylated humanized anti-CC chemokine receptor 4 (CCR4) antibody, exerts a strong antibody-dependent cellular cytotoxic effect. This phase I study assessed the safety, pharmacokinetics, recommended phase II dose and efficacy of KW-0761 in patients with relapsed CCR4-positive adult T-cell leukemia-lymphoma (ATL) or peripheral T-cell lymphoma (PTCL).
  
  
  METHODS
  Sixteen patients received KW-0761 once a week for 4 weeks by intravenous infusion. Doses were escalated, starting at 0.01, 0.1, 0.5, and finally 1.0 mg/kg by a 3 + 3 design.
  
  
  RESULTS
  Fifteen patients completed the protocol treatment. Only one patient, at the 1.0 mg/kg dose, developed grade 3 dose-limiting toxicities, skin rash, and febrile neutropenia, and grade 4 neutropenia. Other treatment-related grade 3 to 4 toxicities were lymphopenia (n = 10), neutropenia (n = 3), leukopenia (n = 2), herpes zoster (n = 1), and acute infusion reaction/cytokine release syndrome (n = 1). Neither the frequency nor severity of toxicities increased with dose escalation. The maximum tolerated dose was not reached. Therefore, the recommended phase II dose was determined to be 1.0 mg/kg. No patients had detectable levels of anti-KW-0761 antibody. The plasma maximum and trough, and the area under the curve of 0 to 7 days of KW-0761, tended to increase dose and frequency dependently. Five patients (31%; 95% CI, 11% to 59%) achieved objective responses: two complete (0.1; 1.0 mg/kg) and three partial (0.01; 2 at 1.0 mg/kg) responses.
  
  
  CONCLUSIONS
  KW-0761 was tolerated at all the dose levels tested, demonstrating potential efficacy against relapsed CCR4-positive ATL or PTCL. Subsequent phase II studies at the 1.0 mg/kg dose are thus warranted.
authors.affiliation: Department of Hematology and Cell Therapy, Aichi Cancer Center, Nagoya, Aichi, Japan. kyamamoto@aichi-cc.jp
authors.forename: Kazuhito
authors.initials: K
authors.lastname: Yamamoto
authors.forename: Atae
authors.initials: A
authors.lastname: Utsunomiya
authors.forename: Kensei
authors.initials: K
authors.lastname: Tobinai
authors.forename: Kunihiro
authors.initials: K
authors.lastname: Tsukasaki
authors.forename: Naokuni
authors.initials: N
authors.lastname: Uike
authors.forename: Kimiharu
authors.initials: K
authors.lastname: Uozumi
authors.forename: Kazunari
authors.initials: K
authors.lastname: Yamaguchi
authors.forename: Yasuaki
authors.initials: Y
authors.lastname: Yamada
authors.forename: Shuichi
authors.initials: S
authors.lastname: Hanada
authors.forename: Kazuo
authors.initials: K
authors.lastname: Tamura
authors.forename: Shigeo
authors.initials: S
authors.lastname: Nakamura
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Inagaki
authors.forename: Koichi
authors.initials: K
authors.lastname: Ohshima
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Kiyoi
authors.forename: Takashi
authors.initials: T
authors.lastname: Ishida
authors.forename: Kouji
authors.initials: K
authors.lastname: Matsushima
authors.forename: Shiro
authors.initials: S
authors.lastname: Akinaga
authors.forename: Michinori
authors.initials: M
authors.lastname: Ogura
authors.forename: Masao
authors.initials: M
authors.lastname: Tomonaga
authors.forename: Ryuzo
authors.initials: R
authors.lastname: Ueda
mesh_terms: D000368:Aged; D000888:Antibodies, Anti-Idiotypic / Q000494:pharmacology / Q000627:therapeutic use*; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000188:drug therapy*; D016411:Lymphoma, T-Cell, Peripheral / Q000188:drug therapy*; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D054398:Receptors, CCR4 / Q000037:antagonists & inhibitors*; D016896:Treatment Outcome
chemical_list: D000888:Antibodies, Anti-Idiotypic; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D054398:Receptors, CCR4; C549035:mogamulizumab