Results of a Phase 1/2 Study for KW-0761, a Monoclonal Antibody Directed Against CC Chemokine Receptor Type 4 (CCR4), In CTCL Patients

KW-0761 is a defucosylated, humanized, monoclonal antibody with enhanced antibody dependent cellular cytotoxicity (ADCC; Potelligent®) that binds to CC chemokine receptor 4 (CCR4). CCR4 is over expressed in PTCL and CTCL, and is a potential target for anti-neoplastic therapy in these disorders.

This multicenter, open-label, dose escalation phase 1/2 study is in patients with previously treated PTCL and CTCL (including MF and SS). The study is composed of a dose escalation phase (Phase 1) and preliminary assessment of safety and efficacy (Phase 2). The phase 1 portion is a standard 3+3 design at doses of 0.1, 0.3, and 1 mg/kg. In the first treatment course, KW-0761 is administered i.v. once a week for four weeks, followed by a 2-week observation period. Subjects demonstrating a response or maintaining stable disease may receive additional infusions of KW-0761 every other week until progression or withdrawal from study. For CTCL patients, the overall global response score is a composite of response in all compartments (skin, lymph nodes, viscera). For subjects with Sezary Syndrome (SS), response in blood is also considered for overall response. For PTCL patients, the response is based on criteria defined by the International Working Group (IWG).

Forty-two patients who had received at least one prior systemic therapy (median 5; range 1–17) are enrolled. The median age is 67 (range: 35–85) years with more males (57%) than females (43%). A total of 40 patients received at least four doses of KW-0761 at 0.1 mg/kg (n=3), 0.3 mg/kg (n=3) and 1 mg/kg (n=34). There are no dose limiting toxicities (DLT) or drug-related serious adverse events (SAEs) reported in the dose escalation portion of the study. Most observed adverse events (AEs) are mild to moderate in severity. There does not appear to be any dose relationship with the incidence or severity of the AEs. The most frequent AEs are chills, headache, nausea, pyrexia, infusion related reactions and back pain. There does not seem to be an increase in the rate of infections associated with the use of this drug. Six of 42 patients who received at least one dose of KW-0761 developed a new skin eruption not consistent with the patients' underlying disease, including one grade 3 hypersensitivity rash with eosinophils. No significant hematologic AEs have been observed except for lymphopenia which is due to the pharmacologic effect of the drug.

A total of 38 patients (23 with MF; 15 with SS) are evaluable for efficacy (only one subject with PTCL was enrolled and is not included in this analysis). A summary of all patients evaluable for efficacy to date is presented in the table below^a:

KW-0761 is well tolerated at doses of 0.1–1.0 mg/kg. The MTD has not been reached in this study. The overall response rate is 39% for all patients in the phase 1/2 trial with a higher rate in SS patients (47%) versus MF patients (35%). Additionally, 12 of 15 SS patients had a response in the blood, including 7 CRs. These promising results warrant further clinical studies using KW-0761 in refractory or relapsed CTCL patients.

Duvic:Kyowa-kirin-pharma.com: Consultancy, Research Funding. Pinter-Brown:Kyowa-Kirin: Consultancy, Research Funding. Foss:Kyowa-Kirin: Consultancy, Research Funding. Sokol:Kyowa-Kirin: Research Funding. Jorgensen:Kyowa Hakko Kirin Co, Ltd.: Research Funding. Spitalny:Kyowa-Kirin: Employment. Kim:Kyowa-Kirin: Consultancy, Research Funding.