Testing CC-486 (Oral Azacitidine) Plus the Standard Drug Therapy in Patients 75 Years or Older With Newly Diagnosed Diffuse Large B Cell Lymphoma

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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A Phase II/III Randomized Study of R-MiniCHOP With or Without CC-486 (Oral Azacitidine) in Participants Age 75 Years or Older With Newly Diagnosed Diffuse Large B Cell Lymphoma, Grade IIIB Follicular Lymphoma, Transformed Lymphoma, and High-Grade B-Cell Lymphomas With MYC AND BCL2 and/or BCL6 Rearrangements

Conditions
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Ann Arbor Stage III Diffuse Large B-Cell Lymphoma, Ann Arbor Stage IIX (Bulky) Diffuse Large B-Cell Lymphoma, Ann Arbor Stage IV Diffuse Large B-Cell Lymphoma, Diffuse Large B-Cell Lymphoma Activated B-Cell Type, Diffuse Large B-Cell Lymphoma Associated With Chronic Inflammation, Diffuse Large B-Cell Lymphoma Germinal Center B-Cell Type, Diffuse Large B-Cell Lymphoma, Not Otherwise Specified, EBV-Positive Diffuse Large B-Cell Lymphoma, Not Otherwise Specified, Grade 3b Follicular Lymphoma, HHV8-Positive Diffuse Large B-Cell Lymphoma, Not Otherwise Specified, High Grade B-Cell Lymphoma With MYC and BCL2 and/or BCL6 Rearrangements, High Grade B-Cell Lymphoma With MYC and BCL2 or BCL6 Rearrangements, High Grade B-Cell Lymphoma With MYC, BCL2, and BCL6 Rearrangements, High Grade B-Cell Lymphoma, Not Otherwise Specified, Intravascular Large B-Cell Lymphoma, Lymphoplasmacytic Lymphoma, Nodular Lymphocyte Predominant B-Cell Lymphoma, Primary Cutaneous Diffuse Large B-Cell Lymphoma, Leg Type, T-Cell/Histiocyte-Rich Large B-Cell Lymphoma, Transformed Follicular Lymphoma to Diffuse Large B-Cell Lymphoma, Transformed Marginal Zone Lymphoma to Diffuse Large B-Cell Lymphoma

Intervention / Treatment
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* Drug: Cyclophosphamide
* Drug: Doxorubicin Hydrochloride
* Drug: Oral Azacitidine
* Drug: Prednisone
* Other: Questionnaire Administration
* Biological: Rituximab
* Drug: Vincristine Sulfate


Participation Criteria
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Eligibility Criteria
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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) or high-grade B-cell lymphomas with MYC and BCL2 and/or BCL6 rearrangements are also eligible. Participants with DLBCL that arose from prior 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 Participants must have staging imaging performed within 28 days prior to registration, as follows. 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 (longest diameter >= 1.5 cm) 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 prior to registration, 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) Hemoglobin (Hgb) >= 8 g/ dL (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 Hemoglobin (Hgb) >= 8 g/ dL 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 except for the pre-phase treatment (within specified dose range) that may have either started before or may start after registration to S1918. Inhaled, nasal, and topical steroid use is allowed. Prior cytotoxic chemotherapy and/or antibody therapy for an indolent lymphoma prior to transformation is allowed. Up to 4 doses of intrathecal (IT) chemotherapy administered for central nervous system (CNS) prophylaxis is allowed in addition to protocol therapy. High-dose intravenous methotrexate is not allowed. Participants must not have received more than a cumulative of dose 250 mg/m^2 of prior doxorubicin (or equivalent dose of another anthracycline, such as epirubicin) 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

Ages Eligible for Study
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Minimum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I (oral azacitidine, R-miniCHOP)<br>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 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. | Drug: Cyclophosphamide<br>* Given IV<br>* Other names: WR-138719;Drug: Doxorubicin Hydrochloride<br>* Given IV<br>* Other names: Rubex;Drug: Oral Azacitidine<br>* Given PO<br>* Other names: Onureg;Drug: Prednisone<br>* Given PO<br>* Other names: SK-Prednisone;Other: Questionnaire Administration<br>* Ancillary studies<br>Biological: Rituximab<br>* Given IV or SC<br>* Other names: Truxima;Drug: Vincristine Sulfate<br>* Given IV<br>* Other names: Vincristine, sulfate;|
| Active Comparator: Arm II (R-miniCHOP)<br>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. | Drug: Cyclophosphamide<br>* Given IV<br>* Other names: WR-138719;Drug: Doxorubicin Hydrochloride<br>* Given IV<br>* Other names: Rubex;Drug: Prednisone<br>* Given PO<br>* Other names: SK-Prednisone;Other: Questionnaire Administration<br>* Ancillary studies<br>Biological: Rituximab<br>* Given IV or SC<br>* Other names: Truxima;Drug: Vincristine Sulfate<br>* Given IV<br>* Other names: Vincristine, sulfate;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Excess toxicity as a result of adding oral azacitidine (CC-486) to reduced dose rituximab-cyclophosphamide, doxorubicin, vincristine, and prednisone (R-miniCHOP) (Safety run-in) | Will determine if the addition of CC-486 to R-miniCHOP results in excess toxicity compared to R-miniCHOP alone that would preclude the combination from being studied further. | Up to completion of cycle 6 | 
| Progression-free survival (PFS) (Phase II) | Will determine if the CC-486 + R-miniCHOP regimen should be tested further (Phase III) against the control R-miniCHOP alone based on PFS. After accruing 130 patients (65 per arm, 21 months of accrual and potentially pausing accrual for 6 months follow-up to reach a target 63 events across arms), a one-sided stratified .10 log-rank test will inform a go/no-go decision based on sufficient evidence of efficacy to continue to the Phase III portion of the study. | From date of registration to date of first observation of progressive disease according to the 2014 Lugano classification, or death due to any cause, assessed up to 1 year | 
| Overall survival (Phase III) | Will compare overall survival in the control arm of R-miniCHOP to the experimental arm of CC-486 (oral azacitidine) + R-miniCHOP. Will be evaluated using a 1-sided .025 level stratified logrank test. | From date of registration to date of death due to any cause, assessed up to 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Metabolic complete response (CR) | Will be defined using 2014 Lugano classification. Fisher's exact test will be used to compare CR rates between the experimental arm of CC-486 + R-miniCHOP and the control arm of R-miniCHOP alone. | Up to end of cycle 6 or end of treatment | 
| Incidence of adverse events | Will be assessed using Common Terminology Criteria for Adverse Events version 5. The maximum Grade for each toxicity will be recorded for each patient, and frequency tables will be reviewed to determine toxicity patterns. Treatment-related toxicities between arms will be compared using Fisher's exact test. | Until disease progression, assessed up to 5 years | 
| Overall survival (Phase III) | An additional secondary analysis of overall survival of the Phase III comparison will adjust for patients with identified double-hit phenotype in addition to the pre-specified stratification factors. Will also prospectively collect the number of days between diagnostic biopsy and cycle 1 day 1 of therapy for a pre-planned secondary analysis. | From date of registration to date of death due to any cause, assessed up to 5 years |