ALBERT

Description: Abstract 285 Background: 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 expressed on the surfaces of cells comprising several T-cell malignancies such as ATL, peripheral T-cell lymphoma (PTCL) and cutaneous T-cell lymphoma (CTCL). A phase I study of KW-0761 in patients with CCR4-positive ATL and PTCL demonstrated that 4 weekly intravenous infusions of KW-0761 were well tolerated up to 1.0 mg/kg and it showed encouraging clinical activity with an overall response rate (ORR) of 31.3% (4 of 13 ATL and 1 of 3 PTCL) in 16 patients (J Clin Oncol 2010;28:1591-8). Methods: A multicenter phase II study of KW-0761 has been conducted for relapsed patients with CCR4-positive ATL to evaluate its efficacy, pharmacokinetics (PK), safety and immunogenicity. Patients were planned to receive 8 weekly intravenous infusions of KW-0761 at 1.0 mg/kg. The primary endpoint was ORR. Objective responses were assessed after the 4th and 8th infusions of KW-0761 according to the response criteria for ATL (J Clin Oncol 2009;27:453-9) by each investigator and the independent efficacy assessment committee. The number of patients required was estimated to be 25, for 90% power to detect a lower limit of the 95% confidence interval (CI) exceeding the 5% threshold of ORR, based on the assumptions that the minimum required response ORR to a new drug for relapsed ATL is 5% and the expected ORR to KW-0761 is 30%. Results: Twenty-seven patients (12 males and 15 females) were enrolled and received KW-0761. The median age was 64 years (range: 49–83). The disease subtypes of ATL consisted of 14 acute-, 6 lymphoma-, and 7 chronic-types with unfavorable prognostic factors. Among the 27 patients enrolled, 14 patients (52%) completed the protocol treatment of 8 infusions. Eleven patients (41%) discontinued the protocol treatment because of progressive disease, and the remaining 2 discontinued because of skin rash or the concurrent colon tumor. The treatment-related grade (G) 2 or greater adverse events (AEs) were lymphopenia (96%), leukopenia (56%), skin rash (52%), neutropenia (33%), thrombocytopenia (26%), AST increase (26%), ALT increase (22%), hypoxemia (19%), anemia (15%), pruritus (15%), g-GTP increase (15%) and hypophosphatemia (15%). G2 or greater Infusion-related toxicities were observed in 22 of 27 patients (81%) including 1 G3, but immediately recovered after treatment with systemic steroids. Treatment-related severe AEs (SAEs) were observed in 5 patients, including a Stevens-Johnson syndrome (G3) and 4 skin rashes (each G3). All these AEs also improved by steroids. PK analysis demonstrated that Cmax and trough (C168h) after the 8th infusion was 38,853 ± 11,267 and 25,934 ± 10,193 ng/mL, respectively, and T1/2 after the 8th infusion were 457 ± 144 h. No anti-KW-0761 antibody has been detected. Among the 26 patients evaluable for efficacy, KW-0761 exhibited an ORR of 54% (14/26; 95% CI, 33 to 73) (acute: 6/14 patients, lymphoma: 3/6 patients, chronic: 5/6 patients) including 7 complete responses (CRs) (27%; 95% CI, 12 to 48) and 7 partial responses (PRs). These are remarkable results, considering that the ORR of relapsed or refractory patients with ATL to a single-agent chemotherapy has been reported to be low (7 to 39%). Response rates according to the affected disease lesion were 100% (13 patients, all CR), 71% (5 of 7 patients), and 38% (5 of 13 patients), respectively, for peripheral blood, skin, and lymph node disease. Conclusions: KW-0761 is a highly effective agent with acceptable toxicity profiles in relapsed patients with CCR4-positive ATL who have no standard therapies. A multicenter, randomized study for untreated ATL patients to compare mLSG15 (a dose-intensified multi-agent regimen, J Clin Oncol 2007;25:5458-64) + KW-0761 with mLSG15 alone has been initiated. Disclosures: Ogura: Kyowa Hakko Kirin Co Ltd: Consultancy. Akinaga:Kyowa Hakko Kirin Co Ltd: Employment.

Description: The long-term prognosis of indolent adult T-cell leukemia-lymphoma (ATL) is not clearly elucidated. From 1974 to 2003, newly diagnosed indolent ATL in 90 patients (65 chronic type and 25 smoldering type) was analyzed. The median survival time was 4.1 years; 12 patients remained alive for more than 10 years, 44 progressed to acute ATL, and 63 patients died. The estimated 5-, 10-, and 15-year survival rates were 47.2%, 25.4%, and 14.1%, respectively, with no plateau in the survival curve. Although most patients were treated with watchful waiting, 12 patients were treated with chemotherapy. Kaplan-Meier analyses showed that advanced performance status (PS), neutrophilia, high concentration of lactate dehydrogenase, more than 3 extranodal lesions, more than 4 total involved lesions, and receiving chemotherapy were unfavorable prognostic factors for survival. Multivariate Cox analysis showed that advanced PS was a borderline significant independent factor in poor survival (hazard ratio, 2.1, 95% confidence interval, 1.0-4.6; P = .06), but it was not a factor when analysis was limited to patients who had not received chemotherapy. The prognosis of indolent ATL in this study was poorer than expected. These findings suggest that even patients with indolent ATL should be carefully observed in clinical practice. Further studies are required to develop treatments for indolent ATL.

Description: Abstract 795 Background: Mogamulizumab (KW-0761) is a humanized anti-CCR4 antibody engineered to exert potent ADCC by defucosylation. In a phase I study for patients with CCR4-positive T-cell malignancies, once weekly administration for 4 weeks of mogamulizumab was well tolerated up to 1.0 mg/kg, and encouraging efficacy was observed (J Clin Oncol 2010;28:1591). In a subsequent phase II study in CCR4-positive relapsed adult T-cell leukemia-lymphoma (ATL) patients, mogamulizumab exhibited an overall response rate (ORR) of 50% (J Clin Oncol 2012;30:837), leading to its approval in Japan in 2012 for relapsed/refractory ATL. In addition, a phase I/IIa study for previously treated cutaneous T-cell lymphoma (CTCL) in the USA showed an ORR of 37% (14/38) (T-CELL LYMPHOMA FORUM 2012). Based on these findings, a phase II study of mogamulizumab for relapsed peripheral T-cell lymphoma (PTCL) and CTCL was conducted in Japan. Methods: A multicenter phase II study of mogamulizumab monotherapy for patients with relapsed CCR4-positive PTCL and CTCL was conducted to evaluate efficacy, pharmacokinetic profile, and safety. The primary endpoint was ORR and secondary endpoints included progression-free survival (PFS) and overall survival (OS). At least 35 patients were needed to detect a lower limit of the 95% confidence interval (CI) exceeding the 5% threshold, with an expected ORR for mogamulizumab of 25% with 90% statistical power. Patients received intravenous infusions of mogamulizumab once per week for 8 weeks at a dose of 1.0 mg/kg. Responses were assessed after the 4th and 8th infusions of mogamulizumab by an independent efficacy assessment committee. The histopathological subtypes of PTCL were confirmed by an independent pathology review committee according to the 2008 WHO classification. In addition, we examined blood T-cell subset distributions. Results: A total of 38 patients were enrolled, and 37 patients (male/female 23/14; median age 64 years, range 33–80) received mogamulizumab. One patient was withdrawn due to an infectious complication. Twenty-nine of the 37 assessable patients had PTCL [PTCL- not otherwise specified (NOS), n=16; angioimmunoblastic T-cell lymphoma (AITL), n=12; anaplastic large cell lymphoma (ALCL)-ALK negative, n=1] and 8 had CTCL [mycosis fungoides (MF), n=7; cutaneous ALCL, n=1]. Performance status at enrollment was 0 (n=24), 1 (n=12), and 2 (n=1). The median number of prior systemic chemotherapy regimens was 2 (range 1–6). Of the 37 patients, 25 completed the schedule of 8 planned infusions. Nine patients (24%) discontinued the treatment protocol due to progressive disease and 3 due to adverse events (AEs). The ORR in 37 patients was 35% (13/37, 95% CI, 20 to 53%) with 14% having a complete response (5/37) (Table 1). By PTCL subtype, the ORR was 34% (10/29) for PTCL (3/16 for PTCL-NOS, 6/12 for AITL, and 1/1 for ALCL-ALK negative) and 38% (3/8) for CTCL (2/7 for MF and 1/1 for cutaneous ALCL). AEs possibly, probably, or definitely related to mogamulizumab monotherapy were as follows. Lymphopenia of all grades and that of grades 3–4 were observed in 78% and 70% of the 37 patients, respectively. Leukopenia of all grades and that of grades 3–4 were observed in 43% and 14% of the 37 patients. For all grades and grades 3–4, neutropenia was observed in 35% and 16%, thrombocytopenia in 35% and 3%, ALT increases in 22% and 3%, and skin eruptions in 49% and 8% of patients, respectively. Infusion-related toxicities occurred in 22%, which were all within grade 2 or lower. Fourteen severe AEs were observed in 7 patients, including a grade 3 polymyositis in 1 and grade 2 cytomegalovirus retinitis in 2. All severe AEs were improved. No grade 5 AEs were observed. Pharmacokinetic analysis demonstrated that Cmax and trough (C168h) after the 8th infusion were 45.9 ± 9.3 and 29.0 ± 13.3 μg/mL, respectively. No anti-mogamulizumab antibody has been detected. Updated results of PFS, OS, and T-cell subset analysis are being analyzed for presentation. Conclusions: Mogamulizumab monotherapy showed promising antitumor activity with acceptable toxicity profiles in patients with relapsed PTCL and CTCL, warranting further investigation. Disclosures: Ishida: Kyowa Hakko Kirin Co., Ltd,: Honoraria, Research Funding, Speakers Bureau. Ogura:Kyowa Hakko Kirin Co., Ltd,: Consultancy. Suzumiya:Kyowa Hakko Kirin Co., Ltd,: Consultancy. Inagaki:Kyowa Hakko Kirin Co., Ltd,: Consultancy. Tamura:Kyowa Hakko Kirin Co., Ltd,: Consultancy. Akinaga:Kyowa Hakko Kirin Co., Ltd,: Employment. Tomonaga:Kyowa Hakko Kirin Co., Ltd,: Consultancy. Ueda:Kyowa Hakko Kirin Co., Ltd,: endowed chair Other.