Clinical Trial of Ublituximab and Umbralisib With CHOP (U2-CHOP) Followed by U2 Maintenance (U2-CHOP-U2) in Previously Untreated Mantle Cell Lymphoma (MCL)

Inclusion Criteria:

* Males or female patients \>18 years of age
* Diagnosis of MCL (Ann Arbor Stage II, III, IV) as supported by histology and over expression of cyclin D1 (in association with CD20 and CD5) or evidence of t(11;14) by FISH (fluorescent in situ hybridization) with indication of initiation of therapy.
* At least one LN of \>1.5 cm size as index/measurable site of disease
* No prior anti-cancer therapy for MCL
* Not eligible for bone marrow transplantation/ASCT (assessed by treating physician due to comorbidities) or not interested in bone marrow transplant/ASCT (clear documentation of patient's unwillingness to pursue transplant)
* Eastern cooperative Oncology Group (ECOG) performance status: 0,1 or 2
* Absolute neutrophil count (ANC) \>1500/microL (\>1000 if bone marrow involvement with MCL) within 28 days prior to initiation of therapy. Growth factors are not permitted for the purpose of meeting eligibility criteria.
* Platelets \>100000 cells/uL (\>75000 cells/uL if bone marrow involvement with MCL) within 28 days prior to initiation of therapy. Growth factors are not permitted for the purpose of meeting eligibility criteria.
* Hemoglobin \>9.0 gm/dL (\>8.0 gm/dL if bone marrow involvement with MCL) within 28 days prior to initiation of therapy. Growth factors are not permitted for the purpose of meeting eligibility criteria.
* Alanine transaminase (ALT)/Aspartate Transaminase (AST) \<2.5 X Upper limit of Normal (ULN) if no liver involvement or ≤ 5 x the ULN if known liver involvement within 28 days prior to initiation of therapy
* Total Bilirubin \<1.5X ULN within 28 days prior to initiation of therapy (Except in Gilbert's disase \<3XULN is allowed)
* Calculated Creatinine Clearance \>35 mL/min by Cockcroft-Gault Equation
* Male patients must agree to use an acceptable method of contraception for the entire duration of study and for 4 months after the last dose of either study drug.
* All patients (or their legal representative) must have signed an informed consent indicating that they are willing to participate in the study and are willing to follow the procedure required by the study in accordance with federal, local and institutional guidelines.
* Female patients who are not of child-bearing potential, and female patients of child-bearing potential who have a negative serum pregnancy test within 3 days prior to initial trial treatment Female patients of child-bearing potential and all male partners must consent to use a medically acceptable method of contraception throughout the study period and for 4 months after the last dose of either study drug.

Exclusion Criteria:

* Any prior anti-neoplastic therapy for MCL
* CNS involvement by MCL
* Malignancy within the past 3 years with the exception of a) adequately treated basal cell carcinoma, squamous cell skin cancer, non-melanomatous skin cancer or localized thyroid cancer; b) carcinoma in situ of the cervix or breast; c) prostate cancer of Gleason Grade 6 or less with stable prostate-specific antigen levels; or d) cancer considered cured by surgical resection/radiation or unlikely to impact survival during the duration of the study, such as localized transitional cell carcinoma of the bladder or benign tumors of the adrenal or pancreas.
* If patient has received prior anthracycline therapy, the cumulative anthracycline dose should be \<150mg/m2 of doxorubicin equivalent
* H/O prior Allogeneic transplantation or autologous stem cell transplantation for any other reason.
* Use of immunosuppressive therapy (e.g. cyclosporine A, tacrolimus or high dose steroids). Patients receiving steroids must be at a dose of \<10mg/day prednisone (or equivalent) within 7 days of the first day of the study treatment administration. Patients are allowed to use topical or inhaled corticosteroids.
* Concurrent any systemic anticancer therapy for any other cancer (chemotherapy, radiation, surgery, immunotherapy, biologic therapy, hormonal therapy, investigational therapy or tumor embolization).
* Uncontrolled Diabetes Mellitus, Hyperglycemia (patients with endocrine consultation and proper plan with reasonable control of blood sugars are allowed)
* Any uncontrolled auto-immune condition like hepatitis, colitis, pneumonitis etc which in view of investigator is high risk to be treated on this combination
* History of stroke or intracranial hemorrhage within 6 months of the date of study treatment administration (unless complete and full recovery)
* Chronic or current active infections requiring intravenous antibiotics, antifungal or antiviral treatment or exposure to live vaccines within 30 days of study treatment.
* Known HIV infection or history of HIV.
* Evidence of Hepatitis B or Hepatitis C infection or risk of reactivation. HBV DNA or HCV RNA 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. If HBc antibody is positive, the subject must be evaluated for the presence of HBV DNA by PCR. If CMV IgG or IgM is reactive, the subject must be evaluated for the presence of CMV 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. 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.
* Known history of drug-induced liver injury, alcoholic liver disease, non-alcoholic steatohepatitis, primary biliary cirrhosis, ongoing extrahepatic obstruction caused by stones, cirrhosis of the liver
* 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 (New York Heart Association functional classification II-IV)\[see Appendix: NYHA Classifications\]
* 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.
* Cardiac ejection fraction (EF) \<45%.
* Current NY heart association Class II to IV congestive heart failure or uncontrolled arrhythmia
* Presence of an abnormal ECG that is clinically meaningful. Patients with QTc interval \>450 for males and \>470 milliseconds for females are excluded (corrected by Fridericia).
* Currently pregnant or breast feeding.
* Unable to swallow and retain oral medication, malabsorption syndrome, disease significantly affecting GI function, total resection of stomach or small bowel, ulcerative colitis, symptomatic IBD or complete or partial obstruction.
* Anaphylaxis, excluding infusion related reactions, to monoclonal antibody/Rituximab in past.
* Any condition that would, in investigator's judgment, interfere with full participation in the study, including administration of study medication/chemotherapy, attending study visits, pose a risk to the patient or interfere with interpretation of study data.
* Inability to comprehend or unwilling to sign the ICF.
* Subjects with pleural effusions requiring thoracentesis or ascites requiring paracentesis within 21 days prior to registration
* Contraindication or intolerance to required supportive care medications (pegfilgrastim, acyclovir or bactrim/dapsone/pentamidine/atovaquone)