A Phase I Study of GA101 (RO5072759) Monotherapy Followed by Maintenance in Patients with Multiply Relapsed/Refractory CD20+ Malignant Disease.

Abstract Abstract 934 Background: GA101 (RO5072759) is the first humanized glycoengineered type II anti-CD20 monoclonal antibody to enter clinical trials. Preclinical studies have shown superior efficacy compared to rituximab and an initial phase I trial with 3-weekly dosing (Salles, ASH 2008) has demonstrated promising activity. The current phase I study has investigated the pharmacokinetics, safety and tolerability of escalating doses of GA101 administered on a weekly x 4 schedule followed by maintenance therapy. Methods: Patients with relapsed/refractory CD20+ malignant disease for whom no therapy of higher priority was available were treated with GA101 monotherapy administered as a flat dose on days 1, 8,15 and 22 (with first infusion administered at 50% of cohort dose). Cohort doses were escalated based on safety in a 3+3 design. Tumor response was assessed at 3 months. Patients achieving a CR or PR were eligible to receive 3-monthly maintenance GA101 × 2 years. Select patients with stable disease (SD) and major clinical benefit were also permitted to receive maintenance therapy. Results: Since January 2008, 22 patients at 5 Canadian sites have been treated with GA101 at doses ranging from 100 mg to 2000 mg. Safety data is available on all patients, 20 of whom are evaluable for response following induction. The median age was 59 yrs (47-77). Histologies included follicular lymphoma (10), CLL (5), DLBCL (3), SLL (2), MCL (1) and MZL with high-grade transformation (1). Patients were highly pretreated, receiving a median of 4 (1-7) prior therapies: 19/22 (86%) had been treated with rituximab at least once, median was twice (1-4). 11/22 patients (50%) were refractory to rituximab. GA101 was well tolerated with no dose limiting toxicities observed across the escalating dose cohorts. The most common adverse events were grade 1/2 infusion-related reactions (IRRs), characterized by fever, chills, hypo/hypertension, nausea and vomiting. IRRs were mainly associated with the first infusion (16 events), with decreased frequency in subsequent infusions (only 8 events for all subsequent infusions). There were 4 grade 3 IRRs (one associated with tumour lysis syndrome) and one grade 4 IRR (with hypoxia) on day 1, the grade 4 event leading to the only permanent discontinuation from the protocol. During the induction period, a total of 6 minor infections and one episode of febrile neutropenia were reported in 4 patients. Five cases of grade 3/4 neutropenia (1 febrile) were reported in 4 patients and 1 case of grade 3 thrombocytopenia. To date, 8 serious adverse events have been reported in 7 patients (two of which were IRRs). Two patients have died, one with DLBCL who completed induction but progressed and died prior to efficacy assessment and one with follicular lymphoma who progressed and died on day 133. Measurement of plasma cytokines during and immediately after the first infusion showed an increase in IL6 and IL8 with a smaller increase in IL10 and TNF , a pattern of change that is broadly similar to other anti-CD20 antibodies. Minimal change in complement fractions was observed, which is in keeping with the known pre-clinical profile of GA101. GA101 pharmacokinetics in this study was characterized by two clearance components, one linear and one saturable, consistent with target-mediated disposition. Peak serum concentration levels were achieved by the third dose with significant inter-patient variability in peak levels noted. The overall response rate was 25% (5 pts, all PRs) with 13 patients having SD and 2 progressing. Of those patients with SD, 6/13 had objective evidence of tumour shrinkage, with one consolidating to a PR with maintenance treatment. Clinical benefit was seen across all dosing cohorts, including rituximab-refractory patients. The overall (best) response rate in patients with lymphoma was 38% (6 PRs). In all, 8 patients have continued on to maintenance treatment following induction, 3 of whom have subsequently progressed (2 aggressive lymphoma, 1 CLL). 5 patients remain on maintenance therapy; 4 in remission with durations ranging from 73 to 258 days and one patient with SD. Conclusion: GA101 is a novel type II anti-CD20 monoclonal antibody that appears to have a safety profile similar to rituximab with promising efficacy in a clinically heterogeneous, heavily pretreated, end-stage patient population. Following review of pharmacokinetic and efficacy data, a dose of 1000 mg has been selected for ongoing phase II trials. Disclosures: Sehn: Roche, Inc: Consultancy, Honoraria, Research Funding. Stewart:Roche, Inc: Honoraria, Research Funding. Pisa:F Hoffman La Roche: Employment. Kothari:Roche Products Limited : Employment. Crump:Roche, Inc: Honoraria.

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