Phase I Study of KW-0761, a Defucosylated Anti-CCR4 Antibody, in Relapsed Patients (Pts) with Adult T-Cell Leukemia-Lymphoma (ATL) or Peripheral T-Cell Lymphoma (PTCL): Updated Results.

Background: KW-0761 produced by POTELLIGENT ^® technology is a defucosylated humanized IgG1 monoclonal antibody against CC chemokine receptor 4 (CCR4). Fucose is demonstrated to be the most critical IgG1 oligosaccharide component for antibody-dependent cellular cytotoxicity (ADCC) activity and KW-0761 composed of defucosylated IgG1 exhibits an enhanced ADCC activity. Previous studies revealed that CCR4 was overexpressed on tumor cells from 88% of pts with ATL and 38% of pts with PTCL unspecified (PTCL-U), and its expression was associated with poor prognosis. CCR4 was also expressed in cutaneous T-cell lymphoma (CTCL) such as mycosis fungoides (MF) and Sezary syndrome, especially its large cell transformant. These results suggest that CCR4 could be a realistic therapeutic target for ATL, CTCL and PTCL-U.

Methods: A multicenter phase I study of KW-0761 has been conducted for relapsed pts with CCR4-positive ATL or PTCL to evaluate its safety, pharmacokinetics (PK), immunogenicity and efficacy. Pts were planned to receive 4 weekly intravenous infusions of KW-0761 at 0.01, 0.1, 0.5, and 1.0 mg/kg. A dose-limiting toxicity (DLT) was defined as any of the following adverse events:

1. ≥ grade (G) 4 hematologic toxicities except for lymphopenia,

2. ≥ G4 acute infusion reaction/cytokine release syndrome or tumor lysis syndrome, or

3. ≥ G3 other non-hematologic toxicities. Plasma KW-0761 levels were assessed in all pts enrolled. Response was assessed by standard response criteria for NHL by each investigator.

Results: As of August 18, 2008, 13 pts including 6 males and 7 females (11 ATL, 1 PTCL-U, 1 MF) were treated with KW-0761 at 0.01 (N=3), 0.1 (N=4), 0.5 (N=3) and 1.0 mg/kg (N=3). Median age was 62 years (range 46 – 69). KW-0761 was well tolerated without any DLT. ≥ G2 toxicities included: hematologic: lymphopenia (G4: N=2, G3: N=6, G2: N=3), neutropenia (G3: N=2, G2: N=3), eosinophilia and thrombocytopenia (G2: N=1, each); and non-hematologic: herpes zoster (3 months after the 4th dosing, G3: N=1), acute infusion reaction/cytokine release syndrome (G3: N=1, G2: N=4), constipation, rash, prolonged QTc, ALT increase, CRP increase, and pain of lymph node (G2: N=1, each). One pt enrolled at 0.1 mg/kg was withdrawn due to early disease progression. PK analysis showed that Cmax at 0.01 and 1.0 mg/kg after the 4th dosing were 324 ± 57 and 43469 ± 3819 ng/mL, respectively, and C_168h at 0.01 and 1.0 mg/kg after the 4th dosing were 152 ± 12 and 21900 ± 3880 ng/mL, respectively. T_1/2 at 0.01 and 1.0 mg/kg after the 4th dosing were 244 ± 117 and 554 ± 125 h, respectively. No anti-KW-0761 antibody has been detected. Complete response (CR) was observed in one ATL pt (0.1 mg/kg) with the disappearance of abnormal blood cells and skin disease, and in one PTCL-U pt (1.0 mg/kg) with the disappearance of abnormal blood cells, skin disease and enlarged lymph node. Overall, investigator-assessed responses for 13 enrolled pts were 31% including 2 CRs, 2 PRs (ATL at 0.01, and 0.1 mg/kg) and 4 SDs (ATL at 0.01, 0.1 and 1.0 mg/kg).

Conclusions: KW-0761 was tolerable across a wide range (0.01 – 1.0 mg/kg) and had clinical activity in relapsed CCR4-positive ATL or PTCL. KW-0761 is a promising new antibody therapy for ATL and PTCL. Patient accrual is ongoing and the updated results will be presented.