This is an open-label, multicenter, Phase I/II study of the safety of escalating doses of single-agent PRO131921 in patients with relapsed or refractory CD20-positive indolent NHL. The trial will enroll in two phases: a Phase I dose-escalation portion for patients with indolent NHL and a Phase II portion with enrollment of additional patients with follicular NHL into two expanded treatment cohorts in order to expand the safety database and collect preliminary anti-lymphoma activity data.

• Signed informed consent
• Ability and willingness to comply with the requirements of the study protocol
• Age ≥ 18 years
• Documented history of histologically confirmed CD20-positive follicular NHL (Phases I and II); for Phase I, other CD20-positive indolent lymphomas (marginal zone lymphoma and small lymphocytic lymphoma) are also included. Patients with a history of a CD20-positive NHL of mixed (indolent/aggressive) histology may also be included in Phase I if the most recent relapse biopsy shows only indolent NHL
• Indolent lymphoma (Phase I) or follicular lymphoma (Phase II) that either has relapsed after a documented history of response (CR, CRu, or PR) of ≥6 months to a rituximab-containing regimen or was refractory to a previous rituximab-containing regimen
• Bi-dimensionally measurable disease, with at least one lesion >1.5 cm in its largest dimension
• Absolute B-cell count ≥LLN at screening (Phase I only)
• ECOG performance status of 0, 1, or 2
• For patients of reproductive potential (males and females), use of a reliable means of contraception during the study and for 1 year following the last dose of study treatment
• For females of childbearing potential, a negative serum pregnancy test within 14 days prior to enrollment

Exclusion Criteria:

• Prior use of anti-CD20 monoclonal antibody therapy (other than rituximab or radioimmunotherapy)
• Prior use of any non-CD20-targeted monoclonal antibody therapy within 6 months of enrollment
• Current or recent lymphoma treatment
• History of severe allergic or anaphylactic reactions to human, humanized, chimeric, or murine monoclonal antibodies
• Evidence of significant uncontrolled concomitant diseases, such as cardiovascular disease, nervous system, pulmonary, renal, hepatic, endocrine, or gastrointestinal disorders
• Evidence of myelodysplasia or myelodysplastic changes on bone marrow examination
• Untreated or persistent/recurrent malignancy (other than lymphoma)
• Known active bacterial, viral, fungal, mycobacterial, or other infection
• A major episode of infection requiring hospitalization or treatment with IV antimicrobials within 4 weeks of screening or oral antimicrobials within 2 weeks of screening
• History of recurrent significant infection or bacterial infections
• Positive hepatitis B or C serology
• Positive human immunodeficiency virus (HIV) serology
• Pregnancy or lactation
• Central nervous system lymphoma
• Recent major surgery within 4 weeks of screening, other than diagnostic surgery