A Multi-Cohort Phase 1b Clinical Trial of Rituximab in Combination With Immunotherapy in Untreated and Previously Treated Follicular Lymphoma

• Patients must have histologically determined follicular lymphoma, grade 1-3A, with pathologic review at the participating institutions, that has either:

‣ Relapsed or primary refractory after at least one line of therapy including anti-CD-20 monoclonal antibody treatment (part A) or;

⁃ Has had no previous anti-lymphoma therapy other than corticosteroids or radiotherapy (part B).

• Patients with active histologic transformation are excluded. Relapsed/refractory patients with prior transformation may be included as long as there is no evidence of transformation at the time of study entry by pathology, imaging, or clinical status

• Patients in part B, without prior anti-lymphoma therapy, must be in need of treatment as defined by any of the following criteria:

‣ Symptomatic adenopathy

⁃ Organ function impairment due to disease involvement, including cytopenias due to marrow involvement (WBC \<1.5x109/L; absolute neutrophil count \[ANC\] \<1.0x109/L, Hgb \<10g/dL; platelets \<100x109/L)

⁃ Constitutional symptoms

⁃ Maximum diameter of disease \> 7cm

∙ -\>3 nodal sites of involvement

⁃ Risk of local compressive symptoms

⁃ Splenomegaly (craniocaudal diameter \> 16cm on CT imaging)

⁃ Clinically significant pleural or peritoneal effusion

⁃ Leukemic phase (\>5x109/L circulating malignant cells)

⁃ Rapid generalized disease progression

⁃ Renal infiltration

⁃ Bone lesions

• Patients may have had a prior autologous stem cell transplant and may have been treated with autologous chimeric antigen receptor T-cells (CAR T-cells).

• Not in need of urgent cytoreductive therapy in the opinion of the investigator

• Measurable disease that has not been previously irradiated on CT scans of at least 1.5 cm, OR if the patient has had previous radiation to the marker lesion(s), there must be evidence of progression since the radiation. Imaging must be completed no greater than 6 weeks prior to study enrollment.

• Eastern Cooperative Oncology Group (ECOG) performance status 0-2 (see Appendix A)

• Adequate hematologic and organ function:

‣ Absolute neutrophil count \> 1.0x109/L unless due to marrow involvement by lymphoma in which case ANC must be \>0.5x109/L

⁃ Platelets \> 75 x109/L, unless due to marrow involvement by lymphoma, in which case platelets must be \>50 x109/L

⁃ Creatinine \< 1.5 x ULN (upper limit of normal) or estimated GFR \> 40ml/min

⁃ Total bilirubin \< 1.5 X ULN, unless Gilbert syndrome, in which case direct bilirubin must be \< 3 x ULN

• AST/ALT \< 2.5 X ULN, unless documented liver involvement by lymphoma, in which case AST/ALT must be \<5 x ULN

• Age \>18 years

• Ability to understand and the willingness to sign a written informed consent document.

• Willingness to provide pre-treatment (or recent archival w/o intervening therapy), and on-treatment tumor samples by core needle or excisional surgical biopsy