An open-label, multi-centre, dose escalating, phase I/randomized phase II study to investigate the safety and tolerability of RO5072759 given as monotherapy in patients with CD20+ malignant disease

INTERVENTION: Product Name: RO5072759 Product Code: RO5072759/F01 Pharmaceutical Form: Powder for solution for infusion CAS Number: 949142‐50‐1 Current Sponsor code: RO5072759 Other descriptive name: GA101 Concentration unit: mg/ml milligram(s)/millilitre Concentration type: equal Concentration number: 10‐ Trade Name: MabThera 100mg concentrate for solution for infusion Product Name: MabThera (Rituximab) Pharmaceutical Form: Concentrate for solution for infusion INN or Proposed INN: Rituximab Current Sponsor code: RO 045‐2294/V01 Concentration unit: mg/ml milligram(s)/millilitre Concentration type: equal Concentration number: 100‐10 Trade Name: MabThera 500mg concentrate for solution for infusion Product Name: MabThera (Rituximab) Pharmaceutical Form: Concentrate for solution for infusion INN or Proposed INN: Rituximab Current Sponsor code: RO45‐2294/V02 Concentration unit: mg/ml milligram(s)/millilitre Concentration type: equal Concentration number: 500‐50 CONDITION: Patients with relapsed CD20+ indolent NHL will be enrolled (Relapsed defined as; relapsed indolent lymphoma with documented history of response [CR, CRu, or PR) of=6 months in duration from the completion of last rituximab containing regimen at some point in a patients treatment history). ; MedDRA version: 9.1 Level: LLT Classification code 10029547 Term: Non‐Hodgkin's lymphoma PRIMARY OUTCOME: Main Objective: To investigate the overall response rate and safety data of RO5072759 (1000mg flat dose) given as monotherapy in patients with relapsed CD20+ indolent NHL compared with rituximab (375mg/m2) monotherapy. Primary end point(s): The primary endpoint for the phase II part of the study will be overall response rate. Overall response rate will be analyzed in frequency tables including 95% Pearson Clopper confidence intervals by dose group for the phase I part of the study and by treatment group for the phase II part of the study. (This is a secondary endpoint for the phase I part of the study.); For the phase II part of the study, the hypothesis of no difference in overall response rate versus a larger overall response rate in RO5072759 over rituximab will be tested in the two randomized treatment arms using a one sided y2‐test at an alpha level of 0.2 restricted to follicular NHL patients only.; Secondary Objective: The secondary objectives of the study are:; • To characterize the pharmacokinetics of RO5072759.; • To investigate if a shorter RO5072759 duration of infusion schedule is feasible (Phase II part of the study only).; • To investigate peripheral blood B‐cell depletion and repletion with increasing doses of RO5072759.; • To obtain preliminary data on the anti‐tumor efficacy of RO5072759 monotherapy compared with rituximab (375mg/m2) monotherapy (including the maintenance extended treatment regimen period) in patients with relapsed CD20+ indolent NHL by evaluating:; – overall response rate (ORR); – progression‐ free survival (PFS); – event‐free survival (EFS); • To investigate pharmacogenetic parameters (FcyRIIa and FcyRIIIa polymorphisms at baseline) and pharmacodynamic parameters (including but not limited to bcl‐2 rearrangements, at baseline, during and after treatment) in relation to efficacy.; • To evaluate the feasibility of extended therapy with RO5072759.; INCLUSION CRITERIA: Patients in the phase II (including those in the SDI) part of the study must meet the following criteria: 1. Have history of histologically confirmed CD20+, indolent B‐cell NHL (any grade). This includes small lymphocytic lymphoma and marginal zone lymphoma but exclude B‐CLL. For each patient, a prior biopsy demonstrating CD20 positivity of tumor cells must be available locally at the investigator site (review performed according to local standard procedures), prior to dosing, and will be further confirmed following central pathology review after dosing. A biopsy must be performed if transformation is suspected. 2. Have a clinical indication for treatment as determined by the investigator. 3. Relapsed disease with documented history of response (CR, CRu, or PR) of =6 months in duration from completion of last rituximab containing regimen. A rituximab‐containing regimen is defined as rituximab as a single agent during induction and/or maintenance, or in