A Study of RO5072759 (GA101) in Combination With CHOP Chemotherapy in Patients With Previously Untreated Advanced Diffuse Large B-Cell Lymphoma (GATHER)

• Complete response (CR), tumor assessments according to the Revised Response Criteria for Malignant Lymphoma (Cheson et al., 2007) [ Time Frame: approximately 5 years ] [ Designated as safety issue: No ]
• Overall response rate (ORR: complete response + partial response) [ Time Frame: approximately 5 years ] [ Designated as safety issue: No ]

• Safety: Incidence of adverse events [ Time Frame: approximately 5 years ] [ Designated as safety issue: No ]
• Safety: Incidence of Grade 3 or 4 infusion-related adverse events in patients receiving shorter duration infusion (SDI) [ Time Frame: approximately 5 years ] [ Designated as safety issue: No ]
• Progression-free survival: time from first RO5072759 dose to first occurrence of disease progression or relapse or death of any cause [ Time Frame: approximately 5 years ] [ Designated as safety issue: No ]
• Duration of response (CR and OR), defined as first occurrence of CR or OR until first occurrence of relapse or progression or death of any cause [ Time Frame: approximately 5 years ] [ Designated as safety issue: No ]
• Pharmacokinetics: area under the concentration-time curve (AUC) [ Time Frame: up to approximately 9 months ] [ Designated as safety issue: No ]
• Pharmacodynamics: Peripheral blood CD19-positive B-cell count [ Time Frame: up to approximately 24 months ] [ Designated as safety issue: No ]

This open-label, multicenter study will evaluate the efficacy and safety of RO5072759 (GA101) in combination with CHOP chemotherapy in patients with advanced diffuse large B-cell lymphoma. Patients will receive 8 cycles of RO5072759 (1000 mg intravenously on Day 1 of each 21-day cycle, during Cycle 1 RO5072759 will also be infused on Days 8 and 15) in combination with CHOP (Cyclophosphamide, Doxorubicin, Vincristine, Prednisone) chemotherapy during cycles 1 to 6. A substudy will investigate the drug-drug interaction of RO5072759 (GA101) with CHOP chemotherapy agents. For the substudy, an additional cohort of 15 patients will be enrolled at a subset of investigational sites.

• Drug: RO5072759
  1000 mg intravenously on Day 1 of each 21-day cycle, 8 cycles; during Cycle 1 administration also on Days 8 and 15
  Other Name: GA101
• Drug: cyclophosphamide
  750 mg/m2 iv, Day 1 of each 21-day cycle, 6 cycles
• Drug: doxorubicin
  50 mg/m2 iv, Day 1 of each 21-cycle, 6 cycles
• Drug: vincristine
  1.4 mg/m2 iv, Day 1 of each 21-day cycle, 6 cycles
• Drug: prednisone
  100 mg/day, Days 1 through 5 of each 21-day cycle, 6 cycles

Inclusion Criteria:

• Adult patients, >/= 18 years of age
• Previously untreated CD20-positive diffuse large B-cell lymphoma
• Ann Arbour Stage III/IV and bulky II (mass >10 cm)
• At least one bi-dimensionally measurable lesion defined as >1.5 cm in its largest dimension by CT scan
• Eastern Cooperative Oncology Group (ECOG) performance status 0, 1 or 2
• Left ventricular ejection fraction >/= 50%
• Adequate hematologic function

Exclusion Criteria:

• Transformed lymphoma (follicular IIIB) if previously treated with chemotherapy or immunotherapy
• Prior therapy for diffuse large B-cell lymphoma except for nodal biopsy or local irradiation
• CNS lymphoma, primary mediastinal large cell lymphoma, primary cutaneous lymphoma, primary effusion lymphoma
• Patients who received cytotoxic drugs or rituximab as part of their treatment for another condition (e.g. rheumatoid arthritis) or prior use of an anti-CD20 antibody
• Chemotherapy or other investigational therapy within 28 days prior to the start of Cycle 1
• Contraindication to any of the individual components of CHOP, including prior receipt of anthracyclines
• History of severe allergic or anaphylactic reactions to monoclonal antibody therapy
• History of other malignancy, except for curatively treated basal or squamous cell carcinoma or melanoma of the skin or in situ carcinoma of the cervix, or malignancy treated with or without curative intent and in remission without treatment for >/=2 years prior to enrolment
• Positive for hepatitis B, hepatitis C, HIV or HTLV-1 infection
• Pregnant or lactating women