Obinutuzumab With or Without Umbralisib, Lenalidomide, or Combination Chemotherapy in Treating Patients With Relapsed or Refractory Grade I-IIIa Follicular Lymphoma

Inclusion Criteria:

• Patients must have follicular lymphoma (grade I, II or IIIa) confirmed at initialdiagnosis and at relapse with identifiable fludeoxyglucose F-18 (FDG) avid diseaseon PET/CT; patients that have involvement with large cell lymphoma are not eligible

• Patients must have a whole body or limited whole body PET/CT scan performed within 42 days prior to registration

• Patients must have bone marrow biopsy performed within 42 days prior to registration

• Patients must have an indication for therapy as determined by the treatinginvestigator

• All disease must be assessed and documented on the S1608 FDG-PET/CT assessment form

• The intent is to enroll patients with follicular lymphoma (FL) relapsed within 2years of completing their first course of chemotherapy (CHOP or bendamustine basedtherapy) + anti-CD20 therapy. Patient is still eligible if he/she received radiationtherapy or anti-CD20 therapy prior to chemoimmunotherapy or if maintenance anti-CD20therapy was administered after chemoimmunotherapy

• Patients must have either failed to achieve a complete remission, or must haverelapsed within 2 years after completing CHOP or bendamustine-containingchemoimmunotherapy (including an anti-CD20 monoclonal antibody), as measuredfrom the last dose of CHOP or bendamustine; relapsed patients must not havereceived any intervening chemotherapy

• Patients must have received only 1 course of chemotherapy, containing at least 3 cycles of CHOP or bendamustine; (note that no minimum dose of bendamustine isrequired)

• Patients who received any anti-CD20 antibody therapy prior to CHOP orbendamustine are eligible

• Patients who additionally received any maintenance anti-CD-20 antibody therapyor consolidative radioimmunotherapy within 2 years of the last dose of the CHOPor bendamustine therapy are eligible

• Involved field or involved site radiation is not considered a line of therapy;examples of eligible prior treatment regimens (note this list is not allinclusive):

• 1st line rituximab treatment followed years later by bendamustinerituximab

• Bendamustine rituximab x 4 cycles

• 1st line rituximab treatment, 2nd line ibritumomab tiuxetan, followed bybendamustine bortezomib rituximab x 6 cycles followed by rituximabmaintenance

• Bendamustine obinutuzumab x 3 cycles

• CHOP rituximab x 6 cycles followed by rituximab maintenance

• For all forms of systemic therapy, patients must have completed therapy at least 21days prior to registration; patients must have completed any radioimmunotherapy atleast 84 days prior to registration; patients prior treatment related toxicities (except alopecia) must have resolved to grade 1 or less prior to registration

• Patients must have tissue specimens collected prior to registration; patients mustbe offered participation in biobanking of residual specimens; with patient consent,residuals from the mandatory submission(s) will be banked for future research

• Patients must be >= 18 years of age

• All patients must have a Zubrod performance status of 0, 1 or 2

• Absolute neutrophil count (ANC) >= 1,500/mcL within 28 days prior to registration

• Platelets >= 75,000/mcL within 28 days prior to registration

• Patients must have adequate renal function as documented by a calculated creatinineclearance >= 60 mL/min, within 28 days prior to registration

• Total bilirubin =< 1.5 x institutional upper limit of normal (IULN) (=< 5 x IULN ifsecondary to lymphoma, Gilbert's syndrome, or medication related [e.g., indinavir,tenofovir, atazanavir]) within 28 days prior to registration

• Direct bilirubin =< 1.5 x IULN (=< 5 x IULN if secondary to lymphoma) within 28 daysprior 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 have an echocardiogram (ECHO) or multigated acquisition (MUGA) scanwithin 42 days prior to registration with a cardiac ejection fraction >= 45%

• Patients with hepatitis B virus infection must have undetectable hepatitis B virus (HBV) on suppressive therapy and no evidence of HBV-related hepatic damage; patientswith hepatitis C virus infection are eligible if complete eradication therapy hasbeen successfully completed, and there is no detectable hepatitis C virus (HVC) orrelated hepatic damage; patients with known human immunodeficiency virus (HIV)infection are eligible if they meet all of the following criteria in addition to theother protocol eligibility criteria:

• Patient must have no history of acquired immune deficiency syndrome (AIDS)-related complications, other than a history of low CD4+ T-cell count (< 200/mm^3) prior to initiation of combination antiretroviral therapy; on studyCD4+ T-cell count may not be informative due to leukemia and should not be usedas an exclusion criterion if low

• Patient must be healthy on the basis of HIV disease with high likelihood ofnear normal life span were it not for the leukemia

• Patient must have serum HIV viral load of < 200 copies/mm^3

• Patient must be on combination antiretroviral therapy with minimalpharmacokinetic interactions with study therapy and minimal overlappingclinical toxicity with protocol therapy; (recommend a regimen of the integraseinhibitor dolutegravir combined with either disoproxil fumarate/emtricitabineor dolutegravir combined with tenofovir alafenamide/emtricitabine)

• Protease inhibitors and once daily formulations containing cobicistat are NOTallowed due to potential pharmacokinetic interactions with leukemia therapy

• Stavudine and zidovudine (AZT) are NOT allowed because of overlapping toxicitywith protocol therapy

• Patients must be able and willing to receive prophylaxis with daily aspirin, lowmolecular weight heparin, factor X inhibitors or warfarin if randomized tolenalidomide; patients unable or unwilling to take any listed prophylaxis are NOTeligible

• No second prior malignancy is allowed except for adequately treated basal (orsquamous cell) skin cancer, in situ cervical cancer or other cancer for which thepatient has been disease free for three years

• Patients must have a complete history and physical examination within 28 days priorto registration

• Females of childbearing potential (FCBP) must have a negative serum or urinepregnancy test with a sensitivity of at least 25 mIU/mL within 10-14 days and againwithin 24 hours prior to starting cycle 1 of lenalidomide; further, they must eithercommit to complete abstinence (true abstinence is acceptable when this is in linewith the preferred and usual lifestyle of the subject; periodic abstinence [e.g.,calendar, ovulation, symptothermal or post ovulation methods] and withdrawal are notacceptable methods of contraception) from heterosexual intercourse or begin TWOacceptable methods of birth control: one highly effective method and one additionaleffective method AT THE SAME TIME, at least 28 days before starting lenalidomide;while taking lenalidomide, during dose interruptions, and for at least 28 days afterthe last dose of lenalidomide; FCBP must also agree to ongoing pregnancy testing;men must agree to use a latex condom during sexual contact with a FCBP, even if theyhave had a successful vasectomy; a FCBP is a female who: 1) has achieved menarche atsome point; 2) has not undergone a hysterectomy or bilateral oophorectomy; or 3) hasnot been naturally postmenopausal (amenorrhea following cancer therapy does not ruleout childbearing potential) for at least 24 consecutive months (i.e., has had mensesat any time in the preceding 24 consecutive months); all patients must be counseledby a trained counselor every 28 days about pregnancy precautions and risks of fetalexposure; NOTE: patients not randomized to receive lenalidomide will not be requiredto undergo serial pregnancy testing or lenalidomide counseling after registration

• Patients must have lactate dehydrogenase (LDH) and beta-2-microglobulin collectedwithin 28 days prior to registration

• Patients must be informed of the investigational nature of this study and must signand give written informed consent in accordance with institutional and federalguidelines

• As a part of the Oncology Patient Enrollment Network (OPEN) registration process thetreating institution's identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study hasbeen entered in the system

Exclusion Criteria:

• Patients must not have clinical evidence of central nervous system involvement bylymphoma since the proposed treatment strategies are not designed to address centralnervous system (CNS) involvement adequately; if performed, any laboratory orradiographic tests performed to assess CNS involvement must be negative

• Patients must not have any prior treatment with any PI3K inhibitor, or lenalidomide