Ublituximab and Umbralisib for the Treatment of Treatment-Naive Follicular or Marginal Zone Lymphoma

Inclusion Criteria

• 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
• Ann Arbor stage II (Non-contiguous), III or IV disease
• 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 National Comprehensive Cancer Network (NCCN) guidelines unless patient has borderline renal function or allergic to contrast dye
• Patients must have bone marrow biopsy performed within 6 months prior to registration
• Measurable node must have an longest transverse diameter (LDi) greater than 1.5 cms. In the absence of nodal lesions, measurable extranodal disease should have an LDi greater than 1 cm. In patients with splenic marginal zone lymphoma, in the absence of nodal lesions, spleen size should be over 14 cms with evidence of lymphoma in the bone marrow biopsy
• For low tumor burden lymphomas (as determined by Groupe d'Etude des Lymphomes Folliculaires [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
• Patients must be untreated advanced stage disease (stage III or stage IV) or stage II (non-contiguous). (Exception: Involved field or involved site radiation given for localized diagnosis is not considered a line of therapy)
• Patients must be >= 18 years of age and be able to swallow and retain oral medication
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
• Absolute neutrophil count (ANC) >= 1000/uL (within 28 days prior to registration unsupported by growth factors)
• Platelets >= 50,000uL (within 28 days prior to registration unsupported by growth factors)
• Hemoglobin (Hb) >= 8 g/dl (within 28 days prior to registration unsupported by growth factors)
• Serum creatinine < 2.0 mg/dL or calculated creatinine clearance (CrCl) > 45 mL/min
• Total bilirubin =< 1.5 x institutional upper limit of the normal (IULN) (=< 5 x IULN if secondary to lymphoma, Gilbert’s syndrome, or medication related) (within 28 days prior to registration)
• Direct bilirubin =< 1.5 x IULN (=< 5 x IULN if secondary to lymphoma) within 28 days prior to registration
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x IULN (=< 5 x IULN secondary to lymphoma) (within 28 days prior to registration)
• 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)
• Patients must have a complete history and physical examination within 28 days prior to registration
• 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 * Lactate dehydrogenase (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
• 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
• 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
• 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

• Transformed lymphoma; if clinical evidence of transformed lymphoma is present, transformation should be ruled out by biopsy of the suspicious lymph node/lesion
• Prior treatment for follicular lymphoma or marginal zone lymphoma (Except: involved field or site radiation therapy is allowed)
• Medically apparent central nervous system lymphoma or leptomeningeal disease
• Tumor burden where administration of other Food and Drug Administration (FDA) approved anti-CD20 antibodies like single-agent rituximab would be inappropriate
• Patients in need of immediate cytoreduction with chemotherapy based regimen
• Evidence of chronic active hepatitis B (hepatitis b virus [HBV], not including patients with prior hepatitis B vaccination; or positive serum hepatitis B antibody) or chronic active hepatitis C infection (hepatitis C virus [HCV]), active cytomegalovirus (CMV), or known history of human immunodeficiency virus (HIV) (or positive HIV test during screening). If hepatitis B core (HBc) antibody is positive, the subject must be evaluated for the presence of HBV deoxyribonucleic acid (DNA) by polymerase chain reaction (PCR). If HCV antibody is positive, the subject must be evaluated for the presence of HCV ribonucleic acid (RNA) by PCR. If the subject is CMV immunoglobulin (Ig)G 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)
• For subjects with a prior known history of hepatitis B and for those with a positive anti-HBc with negative hepatitis B surface antigen (HBsAg) at screening, contraindication or intolerance to antiviral agents effective against hepatitis B.
• Ongoing drug-induced liver injury, alcoholic liver disease, non-alcoholic steatohepatitis, primary biliary cirrhosis, extrahepatic obstruction caused by stones, or cirrhosis of the liver
• Inflammatory bowel disease (such as Crohn’s disease or ulcerative colitis)
• Irritable bowel syndrome with greater than 3 loose stools per day as a baseline
• 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 hypoglycemic agents for diabetes mellitus
• 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 * Significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure (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
• Women who are pregnant or lactating
• Live virus vaccines within 4 weeks prior to ublituximab therapy, or planned administration of live virus vaccines during ublituximab therapy
• 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 prostate specific antigen (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