Phase I Study of a New Humanized Anti-CD20 Monoclonal Antibody (LY2469298) in Japanese Patients (pts) with Relapsed or Refractory Follicular Lymphoma (FL) Pretreated with Rituximab-Containing Regimen

Abstract 3942 Background: Pts with FL in whom position 158 on the FcγRIIIa (CD16) gene is heterozygous for valine/phenylalanine (V/F) or homozygous for phenylalanine (F/F) (F-carriers) have natural killer cells with lower binding affinity to IgG than valine homozygote (V/V) pts. These pts showed a lower response rate and shorter time to progression compared with V/V genotype pts after initial rituximab treatment. A humanized IgG1 anti-CD20 monoclonal antibody, LY2469298, was optimized through protein engineering in the Fc region to increase affinity with FcγIIIa and is expected to increase effector function in F-carriers. This phase I study was conducted to evaluate the safety, clinical activity, and pharmacokinetics (PK) of LY2469298 in Japanese pts with relapsed or refractory FL. Methods: Japanese pts with FL who relapsed or progressed after prior treatment, but not within 120 days of prior rituximab, received four infusions of LY2469298 at weekly intervals. The dose was assessed for safety, tolerability, and immunogenicity (HAHA) in 2 cohorts of 100 and 375 mg/m2. Dose-limiting toxicity (DLT) was evaluated from the day of the first infusion until two weeks after the last infusion. Response was evaluated according to the International Workshop Response Criteria (IWRC) at 9 and 21 weeks after the last dose. The PK of LY2469298 were assessed after the first and fourth dose by means of a non-compartmental analysis. Results: Ten pts (male/female: 5/5), median age 60.4 yrs (range: 39–75), were enrolled and treated in 2 cohorts: 3 pts at 100 mg/m2 and 7 pts at 375 mg/m2. The number of pts with stage I/II/III/IV at enrollment was 1/4/1/4, respectively. All pts received 1 or more treatment of prior rituximab alone or rituximab-containing regimen; 3/10 pts were refractory to the regimen. The median number of prior regimens was 2 (range: 1–9). Follicular Lymphoma International Prognostic Index (FLIPI) identified 4 pts at low risk, 2 at intermediate risk, and 4 at high risk. There was one V/V patient in the 375 mg/m2 cohort; all other pts were F-carriers. No DLT was observed in either cohort; therefore, the recommended phase II dose was determined to be 375 mg/m2. The most common adverse events (≥40% of pts) included hematological toxicities and infusion-related reactions: lymphopenia (n=10), pyrexia (8), leukopenia (7), chills (7), and neutropenia (5). Grade 3 or 4 hematological toxicities were lymphopenia (n=7) and neutropenia (2; no G-CSF required). There were no grade 3 or 4 infusion-related reactions; most reactions were limited to the first infusion. B-cell (CD19+) depletion in peripheral blood was rapid and sustained in all pts. B-cell recovery began in the 21-week observation period. LY2469298 was eliminated in a biphasic manner from pts' blood with a elimination half-life of 10 to 14 days. Clearance, elimination half-life, and volume of distribution were similar between the 2 doses. AUC and Cmax increased with dose. Of 10 evaluable pts, responses were observed in 5 pts (3 CR, 1 CRu, and 1 PR). Conclusions: Weekly doses of LY2469298 at 100 and 375 mg/m2 were well tolerated and resulted in evidence of clinical activity in pts with relapsed or refractory FL after prior rituximab alone or rituximab-containing regimens, although 9 of 10 pts were F-carriers. The PK characteristics of clearance, elimination half-life, and volume of distribution of the 2 LY2469298 doses were similar, both of which were eliminated in a biphasic manner. The promising results of this phase I study warrant further investigation of LY2469298 in pts with FL. Disclosures: Off Label Use: LY2469298 is an investigational agent. Matsue:Eli Lilly Japan KK: Employment. Cronier:Lilly UK: Employment. Wooldridge:Eli Lilly & Company: Employment. Koshiji:Eli Lilly Japan KK: Employment.