Testing CC-486 (Oral Azacitidine) Plus the Standard Drug Therapy in Patients 75 Years or Older With Newly Diagnosed Diffuse Large B Cell Lymphoma
Testing CC-486 (Oral Azacitidine) Plus the Standard Drug Therapy in Patients 75 Years or Older With Newly Diagnosed Diffuse Large B Cell Lymphoma
This phase II/III trial compares the side effects and activity of oral azacitidine in
 combination with the standard drug therapy (reduced dose rituximab-cyclophosphamide,
 doxorubicin, vincristine, and prednisone [R-miniCHOP]) versus R-miniCHOP alone in treating
 patients 75 years or older with newly diagnosed diffuse large B cell lymphoma. R-miniCHOP
 includes a monoclonal antibody (a type of protein), called rituximab, which attaches to the
 lymphoma cells and may help the immune system kill these cells. R-miniCHOP also includes
 prednisone which is an anti-inflammatory medication and a combination of 3 chemotherapy
 drugs, cyclophosphamide, doxorubicin, and vincristine. These 3 chemotherapy drugs, as well as
 oral azacitidine, work in different ways to stop the growth of cancer cells, either by
 killing the cells, by stopping them from dividing, or by stopping them from spreading.
 Combining oral azacitidine with R-miniCHOP may shrink the cancer or extend the time without
 disease symptoms coming back or extend patient's survival when compared to R-miniCHOP alone.
PRIMARY OBJECTIVES:

 I. To determine if the addition of CC-486 (oral azacitidine) to R-miniCHOP results in excess
 toxicity compared to R-miniCHOP alone that would preclude the combination from being studied
 further. (Safety run-in) II. To determine if the CC-486 + R-miniCHOP regimen should be tested
 further (Phase III) against the control R-miniCHOP alone based on progression-free survival
 (PFS). (Phase II component) III. To compare the overall survival (OS) between CC-486 +
 R-miniCHOP and R-miniCHOP alone. (Phase III component)

 SECONDARY OBJECTIVES:

 I. To assess the feasibility of delivering at least 4 cycles of CC-486 with R-miniCHOP in
 this population.

 II. To assess toxicity for CC-486 + R-miniCHOP and for R-miniCHOP. III. To compare complete
 response rates, as defined by Lugano 2014 classification, between CC-486 + R-miniCHOP and
 R-miniCHOP alone.

 INTEGRATED CORRELATIVE GERIATRIC ASSESSMENTS:

 I. To compare functioning as assessed by the S1918 Comprehensive Geriatric Assessment (S1918
 CGA) between participants treated with CC-486 + R-miniCHOP versus R-miniCHOP alone.

 II. To evaluate if frailty status (fit/unfit versus [vs] frail/superfrail) as assessed by the
 FIL tool is associated with OS.

 III. To evaluate if frailty as measured by the FIL tool correlates with the summary frailty
 index as measured using components of the S1918 CGA.

 BANKING OBJECTIVE:

 I. To bank specimens for future correlative studies.

 OUTLINE:

 Beginning 7 days prior to starting [protocol treatment, all patients receive vincristine
 sulfate intravenously (IV) on day 1, and prednisone orally (PO) daily on days 1-7.

 Patients are then randomized to 1 of 2 arms.

 ARM I: Patients receive CC-486 PO for 7 days prior to cycle 1. Patients then receive CC-486
 PO on days 8-21. Treatment repeats every 21 days for cycles 1-5 in the absence of disease
 progression or unacceptable toxicity. Patients also receive rituximab IV (or subcutaneously
 [SC] for cycles 2-6), cyclophosphamide IV, doxorubicin hydrochloride IV, and vincristine
 sulfate IV on day 1, and prednisone PO on days 1-5. Treatment repeats every 21 days for
 cycles 1-6 (6 cycles total) in the absence of disease progression or unacceptable toxicity.

 ARM II: Patients receive rituximab IV (or SC for cycles 2-6), cyclophosphamide IV,
 doxorubicin hydrochloride IV, and vincristine sulfate IV on day 1, and prednisone PO on days
 1-5. Treatment repeats every 21 days for up to 6 cycles in the absence of disease progression
 or unacceptable toxicity.

 After completion of study treatment, patients are followed up periodically until 5 years from
 the date of registration.
Inclusion Criteria:

 -  Participants must have histologically or cytologically confirmed diffuse large B-cell
 lymphoma (DLBCL), Ann Arbor stage IIX (bulky), III or IV. Participants with DLBCL
 transformed from follicular lymphoma (FL) or marginal zone lymphoma (MZL, including
 mucosa-associated lymphoid tissue [MALT] lymphomas), lymphoplasmacytic lymphoma (LPL),
 or nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) are eligible. Participants
 with grade IIIB follicular lymphoma (FL) and high-grade B-cell lymphomas with MYC and
 BCL2 and/or BCL6 rearrangements are also eligible. Participants with DLBCL that arose
 from prior chronic lymphocytic leukemia (CLL) (Richter's transformation) are not
 eligible

 -  As defined by the World Health Organization (WHO), eligible lymphoma subtypes include
 the following:

 -  DLBCL, not otherwise specified (NOS)

 -  DLBCL, germinal-center B-cell type (GCB)

 -  DLBCL, activated B-cell type (ABC)

 -  T-cell histiocyte-rich B-cell lymphomas (THRBCL)

 -  Primary cutaneous DLBCL, leg type

 -  Intravascular large B cell lymphoma

 -  EBV+ DLBCL, NOS

 -  DLBCL associated with chronic inflammation

 -  HHV8+ DLBCL, NOS

 -  High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements

 -  High grade B-cell lymphoma, NOS

 -  Follicular lymphoma grade 3b

 -  Staging imaging must have occurred within 28 days prior to registration. Positron
 emission tomography (PET)-computed tomography (CT) baseline scans are strongly
 preferred; diagnostic quality magnetic resonance imaging (MRI), contrast-enhanced CT,
 or contrast-enhanced MRI scans are also acceptable if PET-CT is not feasible at
 baseline. Note: PET-CT will be required at end of treatment (EOT) and progression for
 response assessment. All measurable lesions must be assessed within 28 days prior to
 registration. Tests to assess non-measurable disease must be performed within 42 days
 prior to registration

 -  Participants with known human immunodeficiency virus (HIV)-infection are eligible
 providing they are on effective anti-retroviral therapy and have undetectable viral
 load at their most recent viral load test (must be within 26 weeks prior to
 registration). Participants with known HIV must have a CD4 count checked within 28
 days before starting therapy, but may proceed with therapy regardless of CD4 count

 -  All participants must be screened for chronic hepatitis B virus (HBV) within 28 days
 prior to registration. Participants with known HBV infection (positive serology) must
 also have a HBV viral load performed within 28 days prior to registration, and
 participants must have an undetectable HBV viral load on suppressive therapy within 28
 days prior to registration. Participants found to be HBV carriers during screening are
 eligible and must receive standard of care prophylaxis. Participants with active
 hepatitis B (HBV viral load > 500 IU/mL) within 28 days prior to registration are not
 eligible

 -  Participants with a known history of hepatitis C virus (HCV) infection must have an
 undetectable HCV viral load within in 28 days prior to registration

 -  Participants must have a Zubrod performance status of 0-2

 -  Participants must have adequate renal function, as demonstrated by a creatinine
 clearance, calculated by the Cockcroft and Gault formula, of >= 30 ml/min that was
 obtained within 28 days prior to registration

 -  Aspartate aminotransferase (AST) =< 2.5 x institutional upper limit of normal (IULN),
 alanine aminotransferase (ALT) =< 2.5 x IULN (within 28 days prior to registration)

 -  Total bilirubin =< 2 x institutional upper limit of normal (IULN), unless due to
 Gilbert's disease, hemolysis, or lymphomatous involvement of liver (within 28 days
 prior to registration). Note: If total bilirubin is elevated, and direct bilirubin is
 subsequently performed (within 28 days prior to registration) and resulted to be =< 2
 x IULN, the participant will be considered eligible

 -  Absolute neutrophil count (ANC) >= 1000/mcL (within 28 days prior to registration)

 -  Platelets >= 75,000/mcL (within 28 days prior to registration)

 -  If there is a documented lymphomatous involvement of the bone marrow, bone marrow
 function within 28 days prior to registration, as evidenced by:

 -  ANC >= 500/mcL

 -  Platelets >= 50,000/mcL

 -  Participants must have a left ventricular ejection (LVEF) fraction >= 45% as measured
 by echocardiogram or radionuclide (multigated acquisition scan [MUGA])
 ventriculography within 56 days prior to registration

 -  For the duration of the study treatment period and for at least 4 months following the
 last dose of study drug, male participants must agree to use effective contraceptive
 methods during sexual contact with a female of childbearing potential (FCBP) and must
 agree to refrain from semen or sperm donation during the same timeframe. Effective
 contraceptive methods include a history of vasectomy, use of hormonal contraception or
 an intrauterine device (IUD) by the female partner, or use of condoms

 -  A FCBP is a sexually mature woman who: 1) has not undergone a hysterectomy or
 bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least
 24 consecutive months (i.e., has had menses at any time in the preceding 24
 consecutive months)

 Exclusion Criteria:

 -  Participants must not have known lymphomatous involvement of the central nervous
 system (CNS)

 -  Participants must not have active inflammatory bowel disease (such as, Crohn's
 disease, ulcerative colitis), celiac disease (i.e., sprue), prior gastrectomy or upper
 bowel removal, or any other gastrointestinal disorder or defect that would interfere
 with the absorption, distribution, metabolism, or excretion of the study drug and/or
 predispose the subject to an increased risk of gastrointestinal toxicity

 -  Participants must not have received any prior cytotoxic chemotherapy or rituximab for
 treatment of the newly diagnosed DLBCL. Participants who received a short course of
 glucocorticoids (=< 7 days) per the pre-phase are eligible. Inhaled, nasal, and
 topical steroid use is allowed. Prior cytotoxic chemotherapy and/or antibody therapy
 for an indolent lymphoma prior to transformation is allowed

 -  Participants must not have received more than a cumulative of 250 mg/m^2 of prior
 anthracycline therapy (at any time prior to registration)

 -  Participants must not currently be receiving any other investigational agents

 -  Participant must not have a history of allergic reactions attributed to azacitidine,
 mannitol, or other hypomethylating agents

 -  Participants must not have active infection (systemic fungal, bacterial, or viral
 infection) that is not controlled (defined as ongoing signs/symptoms related the
 infection without improvement despite appropriate antibiotics, antiviral therapy,
 and/or other treatment)

 -  Participants must not have active cardiac disease within 26 weeks prior to
 registration, including: symptomatic congestive heart failure (New York Heart
 Association [NYHA] class 4), unstable angina pectoris, hemodynamically unstable
 cardiac arrhythmia, or myocardial infarction

 -  Participants must not have >= grade 2 neuropathy, by Common Terminology Criteria for
 Adverse Events (CTCAE) version (v.) 5.0, within 28 days prior to registration

 -  Participants must not have any other known uncontrolled intercurrent illness
 including, but not limited to ongoing psychiatric illness/social situations that would
 limit compliance with study requirements