Phase I Study of KW-0761, a Humanized Anti-CCR4 Antibody, in Patients (Pts) with Relapsed or Refractory Adult T-Cell Leukemia-Lymphoma (ATLL) and Peripheral T-Cell Lymphoma (PTCL): Preliminary Results.

Introduction: KW-0761 is a defucosylated humanized IgG1 monoclonal antibody against CC chemokine receptor 4 (CCR4). Previous studies revealed that CCR4 was over-expressed on tumor cells from 88% of pts with ATLL and 38% of pts with PTCL. CCR4 expression was associated with unfavorable prognosis in both diseases. These evidences suggest that CCR4 could be a reasonable molecular target for treatment of CCR4-positive ATLL and PTCL. KW-0761 exerted very potent ADCC but not CDC against cultured ATLL cell lines using normal effecter cells. KW-0761 also exhibited potent ADCC against freshly isolated ATLL cells using the auto-effecter cells.

Methods: KW-0761 is being investigated in a Phase I, single-agent, dose-escalation, multicenter study for relapsed or refractory pts with ATLL or PTCL after undergoing the initial chemotherapy. Eligible pts were required to express CCR4 on their tumor cells by FCM and/or IHC. This phase I trial was designed to evaluate toxicity, pharmacokinetics (PK), immunogenicity and anti-tumor activity. Toxicity was evaluated by NCI CTCAE (v3.0). Pts were planned to receive four weekly intravenous injections of KW-0761 at the doses of 0.01, 0.1, 0.5 and 1.0 mg/kg.

Results: As of August 10, 2007, 6 pts (1 PTCL and 5 ATLL) have been treated with KW-0761 at the dose of 0.01 (N=3) and 0.1 mg/kg (N=3). Three pts were evaluable for toxicity, PK, immunogenicity and 4 pts were evaluable for anti-tumor activity. KW-0761 was well tolerated with no dose-limiting toxicities. Reversible grade (G) 3 toxicities were lymphocytopenia and herpes zoster. G1-2 adverse events were; rash, constipation, nausea, EF decrease, neutropenia, thrombocytopenia, eosinophilia, lymphocytopenia, ALP increase and QT prolongation. In one leukemic ATLL pt with swollen lymph nodes (LNs) treated at 0.01 mg/kg, peripheral ATLL cells disappeared and the LNs were decreased in size, attaining PR. In another leukemic ATLL pt with skin involvement treated at 0.1 mg/kg, peripheral ATLL cells disappeared and the skin achieved PR by Physicians Global Assessment of Clinical Conditions (PGA). One ATLL pt with skin and bone involvement at 0.01 mg/kg showed SD. Preliminary PK analysis at 0.01 mg/kg showed that Cmax and T1/2 after the 4th dosing was 323.7 56.7 ng/ml and 244 117 hrs, respectively. KW-0761 did not exhibit immunogenicity at 0.01 mg/kg.

Conclusions: Preliminary phase I data warrant further investigations of KW-0761, a first-in-class humanized anti-CCR4 antibody, against CCR4-positive peripheral T-cell malignancies including ATLL. Patient accrual is ongoing and the updated results will be presented at the meeting.