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

PURPOSE:

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).

PATIENTS AND 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.

CONCLUSION:

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: Kazuhito Yamamoto, Atae Utsunomiya, Kensei Tobinai, Kunihiro Tsukasaki, Naokuni Uike, Kimiharu Uozumi, Kazunari Yamaguchi, Yasuaki Yamada, Shuichi Hanada, Kazuo Tamura, Shigeo Nakamura, Hiroshi Inagaki, Koichi Ohshima, Hitoshi Kiyoi, Takashi Ishida, Kouji Matsushima, Shiro Akinaga, Michinori Ogura, Masao Tomonaga, Ryuzo Ueda
• Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology (J Clin Oncol) Vol. 28 Issue 9 Pg. 1591-8 (Mar 20 2010) ISSN: 1527-7755 [Electronic] United States
• PMID: 20177026 (Publication Type: Clinical Trial, Phase I, Journal Article, Multicenter Study)

Chemical References

• Antibodies, Anti-Idiotypic
• Antibodies, Monoclonal
• Antibodies, Monoclonal, Humanized
• Antineoplastic Agents
• Receptors, CCR4
• mogamulizumab

Topics

• Aged
• Antibodies, Anti-Idiotypic (pharmacology, therapeutic use)
• Antibodies, Monoclonal (pharmacokinetics, therapeutic use)
• Antibodies, Monoclonal, Humanized
• Antineoplastic Agents (pharmacokinetics, therapeutic use)
• Dose-Response Relationship, Drug
• Female
• Humans
• Leukemia-Lymphoma, Adult T-Cell (drug therapy)
• Lymphoma, T-Cell, Peripheral (drug therapy)
• Male
• Maximum Tolerated Dose
• Middle Aged
• Neoplasm Recurrence, Local
• Receptors, CCR4 (antagonists & inhibitors)
• Treatment Outcome