ME-401 and R-CHOP in Newly Diagnosed Diffuse Large B-Cell Lymphoma

Inclusion Criteria: * Participants must have histologically confirmed diffuse large B-cell lymphoma (DLBCL). Participants with previously diagnosed indolent lymphoma (follicular and marginal zone lymphoma but not small lymphocytic lymphoma) who have transformed to DLBCL are eligible only if they have not previously been treated for indolent lymphoma. --If participants received single rituximab (maximum 4-8 doses with no maintenance) for their low grade lymphoma ≥12 months prior to starting study drug are eligible to participate * Participants must have radiographically measurable disease. At least one bi-dimensionally measurable nodal lesion ≥1.5 cm in its longest diameter by CT scan or MRI, as defined by the Lugano Classification * Patients participating in the phase II part are allowed to receive brief (\<15 days) treatment with glucocorticoids (max dose of prednisone 40 mg) and/or 1 cycle of chemotherapy such as R-CHOP \[or some component(s) thereof\] for the diagnosis of B-cell lymphoma provided they had all necessary staging tests performed prior to R-CHOPor steroids including CT and/or PET/CTscans, and bone marrow biopsy. Treatment must occur within 30 days prior to enrollment. * No prior therapy with PI3K inhibitors or Bruton tyrosine kinase (BTK) inhibitors * ECOG Performance status ≤2. Performance Status of 3 will be accepted if impairment is caused by DLBCL complications and improvement is expected once therapy is initiated. * Participants must have adequate hematologic, hepatic, and renal function as defined below: * Hemoglobin ≥9.0g/dl unless the anemia is clearly due to DLBCL. If there is BM involvement, this criteria can be waived after discussion with the Sponsor Investigator (per investigators discretion). * Absolute neutrophil count≥1,000/mcL, unless the neutropenia is clearly due to DLBCL. If there is BM involvement, this criteria can be waived after discussion with the Sponsor Investigator(per investigator discretion) * Platelet count ≥75,000/mcl unless thrombocytopenia is clearly due to DLBCL. If there is BM involvement, this criteria can be waived after discussion with the Sponsor Investigator(per investigator discretion) * Bilirubin ≤ 2.0 x ULN unless considered secondary to Gilbert's syndrome, in which case ≤ 3 x ULN * AST (SGOT) \< 2.0 x institutional upper limit of normal * ALT (SGPT) \< 2.0 x institutional upper limit of normal * Creatinine clearance ≥45 mL/min calculated by Cockcroft-Gault or 24 hour collection * Adequate cardiac function left ventricular ejection fraction (LVEF) ≥50% as assessed by echocardiogram or MUGA (Multi Gated Acquisition Scan). * QT-interval corrected according to Fridericia's formula (QTcF) ≤450 milliseconds (ms); participants with QTc \< 480 msec may be enrolled provided the QTc prolongation is due to a right bundle branch block and stable . * Negative pregnancy test in women of child-bearing age. The effects of ME-401 on the developing human fetus are unknown. For this reason and because chemotherapeutic agents used in this study are known to be teratogenic, women of child-bearing potential and men must agree to use adequate contraception (double barrier method of birth control or abstinence) 2 weeks prior to initiation of treatment, for the duration of study participation and for 3 months after completing treatment. Should a woman become pregnant or suspect that she is pregnant while she or her partner is participating in this study, she should inform the treating physician immediately. Men must agree to refrain from sperm donation for at least 90 days after the last dose of ME-401 * Participants must have the ability to understand and the willingness to sign a written informed consent document. * International Prognostic Index must be documented: * ECOG performance status ≥2 * Age ≥60 years * extranodal sites ≥ 2 * LDH \>upper limit of normal * Ann Arbor Stage III or IV * Is there evidence of transformation from indolent lymphoma? Exclusion Criteria: * Participants receiving any other investigational agents. * Known CNS involvement by lymphoma. Participants at high risk for secondary CNS involvement but without neurologic symptoms suspected to be due to lymphoma are allowed to be enrolled and receive prophylactic intrathecal chemotherapy including but not limited to methotrexate, cytarabine and glucocorticoids. Participants who are enrolled and subsequently identified to have pathologic confirmation of CNS involvement by lymphoma may be continued on study at the discretion of the principal investigator. * History of allergic reactions attributed to compounds of similar chemical or biologic composition to R-CHOP. * Participants with ongoing uncontrolled illness including, but not limited to ongoing significantly active infections requiring intravenous antibiotics, hypertension, angina, arrhythmias, pulmonary disease, or autoimmune dysfunction. * Uncontrolled autoimmune hemolytic anemia or immune thrombocytopenia. * Ongoing drug-induced pneumonitis. * History of clinically significant gastrointestinal (GI) conditions, particularly: * Known GI condition that would interfere with swallowing or the oral absorption or tolerance of study drug * Pre-existing malabsorption syndrome or other clinical situation that would * Active congestive heart failure (New York Heart Association \[NYHA\] Class\>2), symptomatic ischemia, or conduction abnormalities uncontrolled by conventional intervention or myocardial infarction within six months prior to enrollment. * Participants who have tested positive for hepatitis B surface antigen and/or hepatitis B core antibody PLUS have detectable viral load on hepatitis B polymerase chain reaction (PCR) assay (participants with a negative PCR assay are permitted with appropriate anti-viral prophylaxis) * Positive hepatitis C virus antibody (HCV Ab) participants with positive hepatitis C antibody are eligible if they are negative for hepatitis C virus by PCR * HIV-positive participants on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with ME-401 * Pregnant or breastfeeding women are excluded from this study because there are no studies assessing the reproductive and developmental toxicity or excretion into breast milk of ME-401. Because there is an unknown, but potential risk for adverse events in nursing infants secondary to treatment of the mother with ME-401, breastfeeding should be discontinued if the mother is treated with ME-401. These potential risks may also apply to other drugs used in this study. * Other malignancies within the past 3 years except for adequately treated carcinoma of the cervix or basal or squamous cell carcinomas of the skin, or low-risk prostate cancer after curative therapy. * Participants who have had major surgical procedures or significant traumatic injury within 28 days prior to study treatment. * Psychiatric illness/social situations that would interfere with study compliance