Pharmacokinetics of RO5072759 (GA101) In Patients with Relapsed/Refractory CD20+ Malignant Disease (Phase I/II Study BO20999)

Abstract 1833 Background and Objective: GA101 is the first type II glycoengineered and humanized monoclonal anti-CD20 antibody to enter clinical trials. BO20999 is an open label multicenter, phase I/II study evaluating GA101 safety, tolerability and pharmacokinetics in patients with relapsed/refractory CD20+ NHL/CLL. Phase I results showed an end of treatment response rate (EOR) of 33% in NHL patients (Salles G. et al, Blood [ASH Annual Meeting Abstracts], Nov 2009; 114: 1704). Phase II results recently reported for indolent NHL showed an EOR of 55% and 17% for GA101 monotherapy given at a high dose (HD) and a low dose (LD), respectively supporting a possible dose-response relationship (Salles G. et al, Haematologica 2010; 95[suppl.2]:229, abs. 0558). Here within, we describe the results of analyses exploring GA101 exposure and response in indolent NHL patients. Study Population and Assessments: Phase I Study: 21 patients with CD20+B-lymphoproliferative disorders including [follicular lymphoma (fNHL), mantle cell lymphoma (MCL), diffused large B cell lymphoma (DLBCL), Waldenstrom9s macroglobulinemia (WM), small lymphocytic lymphoma (SLL) and lymphoplasmacytoid lymphoma received intravenous GA101 as a flat dose in a safety driven dose escalation 3+3 design (from 50 mg to 2000 mg). Phase II Study: 40 indolent NHL patients were randomized to receive low dose (LD) GA101 (n=18) or a high dose (HD) (n=22). GA101 was given on d1, d8, d22 and q21 days for a total of 9 infusions as a flat dose. In the LD cohort, GA101 was 400 mg; in the HD cohort, d1 and d8 were 1600 mg and subsequently 800 mg thereafter. Pharmacokinetic Assessments: GA101 serum samples were taken prior to and immediately after each infusion, for all eight cycles. Additional serum samples were taken between days 1–21 during cycle 1 and between days 1–25 during cycle 8. Serum levels of GA101 were measured by ELISA. Results: Phase I GA101 PK data: Although a high degree of variability was observed in the GA101 plasma concentrations, due in part to inter-individual differences, mean GA101 plasma concentration increased with dose. Phase II GA101 PK data: As anticipated, higher GA101 plasma concentrations were observed in the HD group compared to the LD group (Figure 1). In the HD group after cycle 2 mean Cmax and Cmin values plateaued whereas in the LD group both mean Cmax and Cmin values continued to increase between cycles 2 and 8. Given there were some responses (n=3) in the LD group, a dose of 400 mg has some biological effects; however target saturation appears incomplete, whereas the HD group indicates sustained target saturation. Responding patients from both dose groups appeared to have higher plasma concentrations compared to non-responding patients (Figure 2). Interestingly, responding patients showed increased plasma concentrations over time whereas there was a decrease in plasma concentrations in the non-responding patients. Moreover, further analysis in the HD group demonstrated that non-responding patients have the highest peak to trough concentration ratios indicating a higher rate of GA101 elimination compared to the responding patients (Figure 3). Overall, these data indicate that responding patients appear to eliminate GA101 slower compared to non-responding patients. Conclusions: Overall, GA101 plasma concentrations appeared to increase with dose in both Phase I (dose escalation) and Phase II parts of BO20999. Accumulation of GA101 levels in plasma was observed from 400/800 mg to 1200/2000 mg dose group which was consistent with target saturation. GA101 plasma profiles indicated that responding iNHL patients appeared to eliminate GA101 slower compared to non-responding iNHL patients. Disclosures: Wenger:Roche: Employment. Cartron:Roche: Consultancy, Honoraria; GSK: Honoraria. Morschhauser:Roche: Consultancy, Honoraria. Salles:Roche: Consultancy, Honoraria.