This is an open-label, Phase II interventional study in order to assess efficacy and safety of single agent ublituximab as initial therapy for FL (Follicular lymphoma) and MZL (Marginal zone lymphoma ) with response driven addition of umbralisib for suboptimal response.

Based on overall reporting in low tumor burden FL and MZL, CR rate of at least 30% was achieved when single agent rituximab was used in these subsets. The investigators assume that by administering ublituximab (both as a single agent and in combination with umbralisib for individuals who fail to achieve a CR [Complete response] with the single agent), the CR rate will increase to 50%. Efficacy will be assessed using the proportion of patients treated with ublituximab alone or with ublituximab administered in combination who have a complete response. Thus, the investigators will test the efficacy of ublituximab using a difference in proportions design by comparing an expected study population control rate of 50% to the comparison proportion being determined by the historical control CR rate of 30%. In other words, the null hypothesis is that the true response rate is 30%, and it will be formally tested against a one-sided alternative that the response rate is 50%.

Inclusion Criteria:

Disease Related

1. Subjects with histologically documented Follicular lymphoma CD20+ (Grade 1, 2 or 3a) OR Marginal zone lymphoma CD20+ (nodal, extranodal or splenic) according to World Health Organization (WHO) criteria.
2. Ann Arbor Stage II (Non-contiguous), III or IV disease
3. Patients must have a whole body or limited whole body PET/CT scan performed within 42 days prior to registration. CT portion of PET/CT will be done with contrast based on current NCCN guidelines unless patient has borderline renal function or allergic to contrast dye.
4. Patients must have bone marrow biopsy performed within 6 months prior to registration
5. Measurable node must have an LDi greater than 1.5 cms. In the absence of nodal lesions, measurable extranodal disease should have an LDi greated than 1 cm. In patients with Splenic Marginal Zone lymphoma, in the absence of nodal lesions, spleen size should should be over 14 cms with evidence of lymphoma in the bone marrow biopsy.
6. For low tumor burden lymphomas (as determined by GELF criteria) : Include patients diagnosed within 2 years of diagnosis. Low tumor burden patients diagnosed more than 2 years from study entry will be allowed provided patients have documented progression.

Prior Therapy Criteria

1. Patients must be untreated advanced stage disease (Stage III or Stage IV) or Stage II (noncontiguous). (Exception: Involved field or involved site radiation given for localized diagnosis is not considered a line of therapy).

Clinical/Laboratory Criteria

1. Patients must be ≥ 18 years of age and be able to swallow and retain oral medication

2. ECOG performance status of 0-2

3. Patients must have adequate bone marrow function as evidenced by ANC ≥ 1000/µL and platelets ≥ 50,000µL and Hb >= 8g/dl within 28 days prior to registration unsupported by growth factors.

4. Serum creatinine < 2.0 mg/dL or calculated creatinine clearance (CrCl) > 45 mL/min

5. Patients must have adequate hepatic function obtained within 28 days prior to registration and documented by all of the following:

   • Total bilirubin ≤ 1.5 x IULN (≤ 5 x IULN if secondary to lymphoma, Gilbert's syndrome, or medication related)
   • Direct bilirubin ≤ 1.5 x IULN (≤ 5 x IULN if secondary to lymphoma)
   • AST and ALT ≤ 2.5 x IULN (≤ 5 x IULN secondary to lymphoma)

6. Patients must be willing to receive Pneumocystis jirovecii prophylaxis with sulfamethoxazole/trimethoprim, dapsone, and atovaquone or inhaled pentamadine, if they initiate combination umbralisib plus ublituximab (not for single agent ublituximab)

7. Patients must have a complete history and physical examination within 28 days prior to registration

8. Patients with follicular lymphoma must have the following components of Follicular Lymphoma International Prognostic Index (FLIPI) available from diagnosis, and collected again at time of registration:

   • Age
   • LDH
   • Number of nodal groups involved
   • Serum or plasma hemoglobin
   • Ann Arbor Stage Additionally, patients must have beta2-microglobulin collected at time of registration and response assessment.

9. Female subjects of reproductive potential must have a negative serum pregnancy test within 3 days prior to treatment start date. Female subjects who are of non-reproductive potential (i.e., post-menopausal by history - no menses for ≥1 year; OR history of hysterectomy; OR history of bilateral tubal ligation; OR history of bilateral oophorectomy at least six weeks ago) are exempt from pregnancy testing. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of child bearing potential.

10. Male and female subjects of reproductive potential who agree to use both a highly effective method of birth control (e.g., implants, injectables, combined oral contraceptives, some intrauterine devices [IUDs], complete abstinence, or sterilized partner) and a barrier method (e.g., condoms, cervical ring, sponge, etc.) during the period of therapy.

The following are UNACCEPTABLE forms of contraception for females of childbearing potential:

• natural family planning (rhythm method)
• breastfeeding
• fertility awareness
• withdrawal For subjects, these birth control requirements must be adhered to for 4 months after the last dose of umbralisib and 12 months after the last dose of ublituximab, whichever is later.

Regulatory Criteria

1. Patients must be informed of the investigational nature of this study and must sign and give written informed consent in accordance with institutional and federal guidelines.

Exclusion Criteria:

Disease-Related

1. Transformed lymphoma; if clinical evidence of transformed lymphoma is present, transformation should be ruled out by biopsy of the suspicious lymph node/lesion
2. Prior treatment for follicular lymphoma or marginal zone lymphoma (Except: involved field or site radiation therapy is allowed)
3. Medically apparent central nervous system lymphoma or leptomeningeal disease
4. Tumor burden where administration of other FDA approved anti-CD20 antibodies like singleagent rituximab would be inappropriate.
5. Patients in need of immediate cytoreduction with chemotherapy based regimen.

Concurrent Conditions

1. Evidence of chronic active Hepatitis B (HBV, not including patients with prior hepatitis B vaccination; or positive serum Hepatitis B antibody) or chronic active Hepatitis C infection (HCV), active cytomegalovirus (CMV), or known history of HIV (or positive HIV test during screening). If HBc antibody is positive, the subject must be evaluated for the presence of HBV DNA by PCR. If HCV antibody is positive, the subject must be evaluated for the presence of HCV RNA by PCR. See Appendix: HEPATITIS B SEROLOGIC TEST RESULTS. If the subject is CMV IgG or CMV IgM positive, the subject must be evaluated for the presence of CMV DNA by PCR. Subjects with positive HBc antibody and negative HBV DNA by PCR are eligible. Subjects with positive HCV antibody and negative HCV RNA by PCR are eligible (subjects who are CMV IgG or CMV IgM positive but who are CMV DNA negative by PCR are eligible).

2. Ongoing drug-induced liver injury, alcoholic liver disease, non-alcoholic steatohepatitis, primary biliary cirrhosis, extrahepatic obstruction caused by stones, or cirrhosis of the liver

3. Inflammatory bowel disease (such as Crohn's disease or ulcerative colitis)

4. Irritable bowel syndrome with greater than 3 loose stools per day as a baseline

5. Active autoimmune disease requiring ongoing immunosuppressive therapy including systemic corticosteroids (prednisone or equivalent ≤10 mg daily allowed as clinically warranted) within 12 months prior to enrollment. Patients are allowed to use topical or inhaled corticosteroids or levothyroxine for hypothyroidism or hypogylcemic agents for diabetes mellitis.

6. Any severe and/or uncontrolled medical conditions or other conditions that could affect participation in the study such as:

   • Symptomatic, or history of documented congestive heart failure NYHA (New York Heart Association) functional classification III-IV [see Appendix: New York Heart Association Classifications]
   • Significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, CHF, or myocardial infarction within 6 months of enrollment.
   • Concomitant use of medication known to cause QT prolongation or torsades de pointes should be used with caution and at investigator discretion.
   • Poorly controlled or clinically significant atherosclerotic vascular disease including cerebrovascular accident (CVA), transient ischemic attack (TIA), angioplasty, cardiac or vascular stenting within 6 months of enrollment.

7. Women who are pregnant or lactating

8. History of other malignancies (including myelodysplastic syndromes) except:

   • malignancy treated with curative intent and with no known active disease present for >2 years before the first dose of study drug and felt to be at low risk for recurrence by treating physician
   • adequately treated non-melanoma skin cancer without evidence of disease
   • adequately treated carcinoma in situ without evidence of disease
   • localized prostate cancer and PSA <1.0 mg/dL on 2 consecutive measurements at least 3 months apart with the most recent one being within 4 weeks of study entry

15 months, 9 days