A Study of GA101 (RO5072759) in Combination With Chemotherapy in Patients With Previously Untreated Chronic Lymphocytic Leukemia (GALTON)

• Clinical laboratory abnormalities [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]
• Incidence of adverse events [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]
• Incidence of human anti-human antibodies (HAHAs) [ Time Frame: Up to 6 months after end of treatment ] [ Designated as safety issue: No ]
• Nature of adverse events [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]
• Severity of adverse events [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]

• Pharmacokinetic parameters derived from plasma concentration-time profiles of GA101 following administration [ Time Frame: Up to Day 141 ] [ Designated as safety issue: No ]
• Objective response rate [ Time Frame: Up to 3 months after end of treatment ] [ Designated as safety issue: No ]
• Duration of response [ Time Frame: Up to 3 years after end of treatment ] [ Designated as safety issue: No ]
• Progression free survival [ Time Frame: Up to 3 years after end of treatment ] [ Designated as safety issue: No ]
• Overall survival, defined as the time from randomization until death from any cause [ Time Frame: up to 3.5 years ] [ Designated as safety issue: No ]
• Pharmacodynamics: Peripheral blood B-cell depletion and recovery [ Time Frame: Up to Day 141 ] [ Designated as safety issue: No ]

• Pharmacokinetic parameters derived from plasma concentration-time profiles of GA101 following administration [ Time Frame: Up to Day 141 ] [ Designated as safety issue: No ]
• Objective response rate [ Time Frame: Up to 3 months after end of treatment ] [ Designated as safety issue: No ]
• Duration of response [ Time Frame: Up to 3 years after end of treatment ] [ Designated as safety issue: No ]
• Progression free survival [ Time Frame: Up to 3 years after end of treatment ] [ Designated as safety issue: No ]

This open-label, 2-arm, nonrandomized, multicenter, Phase Ib study will investigate the safety and efficacy of RO5072759 (GA101) administered in combination with chemotherapy (bendamustine or FC regimens) in patients with previously untreated CD20-positive B-CLL. Patients will be enrolled to receive a maximum of 6 cycles of GA101 (1000mg iv infusion, on days 1, 8 and 15 of cycle 1 and day 1 of cycles 2 - 6) plus bendamustine (90 mg/m2 IV, on days 2 and 3 of cycle 1 and days 1 and 2 of cycles 2 - 6) on 28 day cycles or a maximum of 6 cycles of GA101 (1000mg iv infusion, on days 1, 8 and 15 of cycle 1 and day 1 of cycles 2 - 6) plus FC (fludarabine 25 mg/m2 IV on days 2, 3 and 4 of cycle 1 and days 1, 2 and 3 of cycles 2 - 6; cyclophosphamide 250 mg/m2 IV on days 2, 3 and 4 of cycle 1 and days 1, 2 and 3 of cycles 2 - 6) on 28 day cycles.

• Drug: bendamustine
  Intravenous repeating dose
• Drug: cyclophosphamide
  Intravenous repeating dose
• Drug: Fludarabine
  Intravenous repeating dose
• Drug: RO5072759
  Intravenous repeating dose

• Experimental: A
  Interventions:

  • Drug: bendamustine
  • Drug: RO5072759
• Experimental: B
  Interventions:

  • Drug: cyclophosphamide
  • Drug: Fludarabine
  • Drug: RO5072759

Inclusion Criteria:

• Confirmed diagnosis of CD20-positive B-CLL
• Rai Stage III/IV or Binet Stage C disease
• Rai Stage I/II or Binet Stage B disease that requires treatment
• Adequate baseline bone marrow function, unless there is clear evidence of extensive bone marrow involvement with tumor infiltration, myelodysplasia, or hypocellularity
• No previous treatment for CLL by chemotherapy, radiotherapy, or immunotherapy
• ECOG performance status of 0, 1, or 2
• Life expectancy of > 6 months

Exclusion Criteria:

• Treatment with any other investigational agent or participation in another clinical trial within 28 days prior to the start of Cycle 1
• Transformation of CLL to aggressive B-cell malignancy
• Creatinine clearance =< 60 mL/min, calculated according to the formula of Cockroft and Gault
• Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 2.5 times the upper limit of normal (ULN)
• Total bilirubin >= 3 x ULN
• History of severe allergic or anaphylactic reactions to monoclonal antibody therapy
• History of sensitivity to mannitol (if bendamustine is to be administered)
• History of other malignancy that could affect compliance with the protocol or interpretation of results
• Evidence of significant, uncontrolled concomitant diseases that could affect compliance with the protocol or interpretation of results, including significant cardiovascular disease or pulmonary disease
• Known active bacterial, viral, fungal, mycobacterial, or other infection (excluding fungal infections of nail beds) or any major episode of infection requiring treatment with IV antibiotics or hospitalization (related to the completion of the course of antibiotics) within 4 weeks before the start of Cycle 1
• Recent major surgery (within 4 weeks prior to the start of Cycle 1), other than for diagnosis
• Known infection with human immunodeficiency virus (HIV) seropositive status
• Presence of positive test results for hepatitis B (hepatitis B virus [HBV] surface antigen [HBsAg] and/or total hepatitis B core antibody [anti-HBc]) or hepatitis C (hepatitis C virus [HCV] antibody serology testing). Patients with chronic HBV infection, occult HBV infection, or past HBV infection will be excluded. Patients who have received IVIG within 3 months of enrollment and who are anti-HBc positive but HBV DNA negative will be considered for inclusion on the study by the Medical Monitor on a case-by-case basis. Patients positive for HCV antibody are eligible only if PCR is negative for HCV RNA.
• Women who are pregnant or lactating
• Fertile men or women of childbearing potential unless 1) surgically sterile or 2) using an adequate measure of contraception such as oral contraceptives, intrauterine device, or barrier method of contraception in conjunction with spermicidal jelly
• Concurrent (or within 7 days prior to the first dose of study treatment) systemic corticosteroid use except low-dose corticosteroid therapy used to treat an illness other than lymphoma