Ublituximab Followed by Response-driven Addition of Umbralisib for Treatment-naive Follicular or Marginal Zone Lymphoma

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.

What this study is about