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.
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.
Yamamoto
Kazuhito
K
Department of Hematology and Cell Therapy, Aichi Cancer Center, Nagoya, Aichi, Japan. kyamamoto@aichi-cc.jp
Utsunomiya
Atae
A
Tobinai
Kensei
K
Tsukasaki
Kunihiro
K
Uike
Naokuni
N
Uozumi
Kimiharu
K
Yamaguchi
Kazunari
K
Yamada
Yasuaki
Y
Hanada
Shuichi
S
Tamura
Kazuo
K
Nakamura
Shigeo
S
Inagaki
Hiroshi
H
Ohshima
Koichi
K
Kiyoi
Hitoshi
H
Ishida
Takashi
T
Matsushima
Kouji
K
Akinaga
Shiro
S
Ogura
Michinori
M
Tomonaga
Masao
M
Ueda
Ryuzo
R
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
D000888:Antibodies, Anti-Idiotypic; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D054398:Receptors, CCR4; C549035:mogamulizumab