A Study of Obinutuzumab (RO5072759) Induction in Patients With Relapsed/ Refractory Waldenström Macroglobulinemia, OBI-1

Inclusion Criteria:

1. Signed written informed consent prior to beginning study-related procedures.

2. Male and female subjects aged ≥ 18 years.

3. Able to comply with the study protocol, in the investigator's judgment.

4. Confirmed clinicopathological diagnosis of WM with detectable CD20 positive of thetumor cells

5. Measurable disease defined as serum monoclonal IgM >0.5 g/dL

6. Active disease and indication for treatment based on the Seventh IWWM recommendations (Dimopoulos et al., 2014) defined by presence of at least any one of the followingconditions:

• Recurrent fever, night sweats, weight loss, fatigue

• Hyperviscosity

• Lymphadenopathy which is either symptomatic or bulky (≥5 cm in maximum diameter)

• Symptomatic hepatomegaly and/or splenomegaly

• Symptomatic organomegaly and/or organ or tissue infiltration

• Peripheral neuropathy due to WM

• Symptomatic cryoglobulinemia

• Cold agglutinin anemia

• Immune hemolytic anemia and/or thrombocytopenia

• Nephropathy related to WM

• Amyloidosis related to WM

• Hemoglobin ≤10 g/dL

• Platelet count <100 × 109/L

7. Subjects must have received prior therapies for their WM and have relapsed orrefractory WM requiring therapy. Any number of prior therapies is acceptable. RelapsedWM: defined as a subject who has received at least one prior WM therapy and previouslyachieved a complete or partial remission/response lasting at least 6 months RefractoryWM: is defined as progression on treatment; disease progression < 6 months of the lastanti-WM therapy

8. Subjects must have adequate organ and marrow function as defined below:

• Absolute neutrophil count ≥ 1.5 x 109/l (unless decreased due to WM involvementof the bone marrow)

• Platelets ≥ 75 x 109/l (unless decreased due to WM involvement of the bonemarrow)

• Hemoglobin ≥ 9 g/dL

• Total bilirubin ≤ 1.5 x ULN or < 2 x ULN if attributable to hepatic infiltrationby neoplastic disease

• AST and ALT < 2.5 x ULN

• Calculated creatinine clearance by Cockcroft-Gault formula >40 mL/min

• INR ≤ 1.5

9. Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2.

10. Fertile men or women of childbearing potential, unless ≥ 2 years after the onset ofmenopause (for women), must be willing to use a highly effective contraceptive method (Pearl Index < 1) such as oral contraceptives, intrauterine device, sexual abstinenceor barrier method of contraception in conjunction with spermicidal jelly, during studytreatment and for 18 months after end of obinutuzumab treatment.

Exclusion Criteria:

1. Lactating women, women with a positive pregnancy test at Visit 1 or women (ofchildbearing potential) as well as men with partners of childbearing potential, whoare not willing to use adequate contraception from study start through 18 months afterend of obinutuzumab treatment.

2. Known involvement of the central nervous system by WM.

3. Vaccination with a live vaccine a minimum of 28 days prior to study enrolment (vaccination day considered as Day 0).

4. History of stroke or intracranial hemorrhage within 12 months prior to studyenrollment.

5. Currently active, clinically significant cardiovascular disease.

6. Any active systemic infection. Caution should be exercised when considering the use ofobinutuzumab in patients with a history of recurring or chronic infections.

7. Positive for hepatitis C antibody at screening.

8. Positive test result for chronic hepatitis B virus (HBV) infection (defined as apositive HBsAg serology). Patients with occult or prior HBV infection (defined asnegative hepatitis B surface antigen [HBsAg] and positive total hepatitis B coreantibody [HBcAb]) may be included if HBV DNA is undetectable, provided that they arewilling to undergo monthly DNA testing during treatment and follow-up until 12 monthsafter the last dose of obinutuzumab.

9. Known HIV infection at screening.

10. Any serious illness, medical condition, organ system dysfunction or abnormality inclinical laboratory test that, in the investigator's opinion, could compromise thesubject's safety or put the study outcomes at undue risk.

11. Concurrent use of other anti-cancer agents or treatments.

12. Prior use of any investigational monoclonal antibody therapy within 6 months of studystart.

13. History of severe allergic or anaphylactic reactions to monoclonal antibody therapy,known hypersensitivity to any of the study drugs or sensitivity to murine products.

14. Treatment with any known non-marketed drug substance or experimental therapy within 5terminal half-lives or 4 Weeks prior to first study treatment dose, whichever islonger, or participation in any other interventional clinical study.

15. Prior use of radiation therapy within 4 weeks of enrollment.

16. History of other malignancy within 5 years prior to screening, except forappropriately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, orStage I uterine cancer.

17. History of illicit drug or alcohol abuse within 12 months prior to screening, in theinvestigator's judgment.