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

Lymphoplasmacytic Lymphoma Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04799275
• Other study ID #: NCI-2020-01256
• Secondary ID: NCI-2020-01256S1
• Status: Recruiting
• Phase: Phase 2/Phase 3
• Start date: May 20, 2021
• Est. completion date: March 1, 2026

Study information

• Verified date: April 2024
• Source: National Cancer Institute (NCI)
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 422
• Est. completion date: March 1, 2026
• Est. primary completion date: March 1, 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 75 Years and older

Eligibility

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

Related Conditions & MeSH terms

• 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
• Inflammation
• Intravascular Large B-Cell Lymphoma
• Lymphoma
• Lymphoma, B-Cell
• Lymphoma, Follicular
• Lymphoma, Large B-Cell, Diffuse
• Lymphoplasmacytic 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
• Waldenstrom Macroglobulinemia

Intervention

Drug:
• Cyclophosphamide
Given IV
• Doxorubicin Hydrochloride
Given IV
• Oral Azacitidine
Given PO
• Prednisone
Given PO

Other:
• Questionnaire Administration
Ancillary studies

Biological:
• Rituximab
Given IV or SC

Drug:
• Vincristine Sulfate
Given IV

Locations

Country	Name	City	State
United States	Hawaii Cancer Care - Westridge	'Aiea	Hawaii
United States	Pali Momi Medical Center	'Aiea	Hawaii
United States	McFarland Clinic - Ames	Ames	Iowa
United States	Kaiser Permanente-Anaheim	Anaheim	California
United States	Saint Joseph Mercy Hospital	Ann Arbor	Michigan
United States	Duluth Clinic Ashland	Ashland	Wisconsin
United States	Emory Saint Joseph's Hospital	Atlanta	Georgia
United States	Emory University Hospital Midtown	Atlanta	Georgia
United States	Emory University Hospital/Winship Cancer Institute	Atlanta	Georgia
United States	Augusta University Medical Center	Augusta	Georgia
United States	Kaiser Permanente-Baldwin Park	Baldwin Park	California
United States	Memorial Sloan Kettering Basking Ridge	Basking Ridge	New Jersey
United States	FHCC Overlake	Bellevue	Washington
United States	Kaiser Permanente-Bellflower	Bellflower	California
United States	Tower Cancer Research Foundation	Beverly Hills	California
United States	Tufts Medical Center	Boston	Massachusetts
United States	Saint Joseph Mercy Brighton	Brighton	Michigan
United States	Trinity Health IHA Medical Group Hematology Oncology - Brighton	Brighton	Michigan
United States	Roswell Park Cancer Institute	Buffalo	New York
United States	Saint Joseph Mercy Canton	Canton	Michigan
United States	Trinity Health IHA Medical Group Hematology Oncology - Canton	Canton	Michigan
United States	Saint Francis Medical Center	Cape Girardeau	Missouri
United States	UNC Lineberger Comprehensive Cancer Center	Chapel Hill	North Carolina
United States	Medical University of South Carolina	Charleston	South Carolina
United States	West Virginia University Charleston Division	Charleston	West Virginia
United States	University of Virginia Cancer Center	Charlottesville	Virginia
United States	Saint Joseph Mercy Chelsea	Chelsea	Michigan
United States	Trinity Health IHA Medical Group Hematology Oncology - Chelsea Hospital	Chelsea	Michigan
United States	Saint Luke's Hospital	Chesterfield	Missouri
United States	Northwestern University	Chicago	Illinois
United States	University of Chicago Comprehensive Cancer Center	Chicago	Illinois
United States	University of Illinois	Chicago	Illinois
United States	Cleveland Clinic Cancer Center/Fairview Hospital	Cleveland	Ohio
United States	Cleveland Clinic Foundation	Cleveland	Ohio
United States	Ohio State University Comprehensive Cancer Center	Columbus	Ohio
United States	Memorial Sloan Kettering Commack	Commack	New York
United States	UC Irvine Health Cancer Center-Newport	Costa Mesa	California
United States	Siteman Cancer Center at West County Hospital	Creve Coeur	Missouri
United States	Carle at The Riverfront	Danville	Illinois
United States	Cancer Care Specialists of Illinois - Decatur	Decatur	Illinois
United States	Decatur Memorial Hospital	Decatur	Illinois
United States	Essentia Health - Deer River Clinic	Deer River	Minnesota
United States	Northwestern Medicine Cancer Center Kishwaukee	DeKalb	Illinois
United States	Iowa Methodist Medical Center	Des Moines	Iowa
United States	Medical Oncology and Hematology Associates-Des Moines	Des Moines	Iowa
United States	City of Hope Comprehensive Cancer Center	Duarte	California
United States	Essentia Health Cancer Center	Duluth	Minnesota
United States	Marshfield Medical Center-EC Cancer Center	Eau Claire	Wisconsin
United States	Crossroads Cancer Center	Effingham	Illinois
United States	Englewood Hospital and Medical Center	Englewood	New Jersey
United States	NorthShore University HealthSystem-Evanston Hospital	Evanston	Illinois
United States	Inova Schar Cancer Institute	Fairfax	Virginia
United States	Kaiser Permanente-Fontana	Fontana	California
United States	Northwestern Medicine Cancer Center Delnor	Geneva	Illinois
United States	Glens Falls Hospital	Glens Falls	New York
United States	NorthShore University HealthSystem-Glenbrook Hospital	Glenview	Illinois
United States	SCL Health Cancer Centers of Colorado - Lutheran Medical Center	Golden	Colorado
United States	Saint Francis Cancer Center	Greenville	South Carolina
United States	Saint Francis Hospital	Greenville	South Carolina
United States	Kaiser Permanente - Harbor City	Harbor City	California
United States	Memorial Sloan Kettering Westchester	Harrison	New York
United States	Essentia Health Hibbing Clinic	Hibbing	Minnesota
United States	NorthShore University HealthSystem-Highland Park Hospital	Highland Park	Illinois
United States	Hawaii Cancer Care Inc - Waterfront Plaza	Honolulu	Hawaii
United States	Queen's Cancer Cenrer - POB I	Honolulu	Hawaii
United States	Queen's Cancer Center - Kuakini	Honolulu	Hawaii
United States	Queen's Medical Center	Honolulu	Hawaii
United States	Straub Clinic and Hospital	Honolulu	Hawaii
United States	City of Hope at Huntington Beach	Huntington Beach	California
United States	Cleveland Clinic Cancer Center Independence	Independence	Ohio
United States	City of Hope at Irvine Lennar	Irvine	California
United States	Kaiser Permanente-Irvine	Irvine	California
United States	Seattle Cancer Care Alliance at EvergreenHealth	Kirkland	Washington
United States	Gundersen Lutheran Medical Center	La Crosse	Wisconsin
United States	Northwestern Medicine Lake Forest Hospital	Lake Forest	Illinois
United States	Monmouth Medical Center Southern Campus	Lakewood	New Jersey
United States	City of Hope Antelope Valley	Lancaster	California
United States	Cancer Centers of Southwest Oklahoma Research	Lawton	Oklahoma
United States	Cancer Partners of Nebraska - Pine Lake	Lincoln	Nebraska
United States	Southeast Nebraska Cancer Center - 68th Street Place	Lincoln	Nebraska
United States	University of Arkansas for Medical Sciences	Little Rock	Arkansas
United States	Hope Cancer Clinic	Livonia	Michigan
United States	Trinity Health Saint Mary Mercy Livonia Hospital	Livonia	Michigan
United States	City of Hope at Long Beach Elm	Long Beach	California
United States	Tibor Rubin VA Medical Center	Long Beach	California
United States	Monmouth Medical Center	Long Branch	New Jersey
United States	Cedars Sinai Medical Center	Los Angeles	California
United States	Kaiser Permanente Los Angeles Medical Center	Los Angeles	California
United States	Kaiser Permanente West Los Angeles	Los Angeles	California
United States	Cleveland Clinic Cancer Center Mansfield	Mansfield	Ohio
United States	Marshfield Medical Center-Marshfield	Marshfield	Wisconsin
United States	Hillcrest Hospital Cancer Center	Mayfield Heights	Ohio
United States	Baptist Memorial Hospital and Cancer Center-Memphis	Memphis	Tennessee
United States	University of Miami Miller School of Medicine-Sylvester Cancer Center	Miami	Florida
United States	Memorial Sloan Kettering Monmouth	Middletown	New Jersey
United States	NYU Winthrop Hospital	Mineola	New York
United States	Marshfield Clinic-Minocqua Center	Minocqua	Wisconsin
United States	Ochsner LSU Health Monroe Medical Center	Monroe	Louisiana
United States	Memorial Sloan Kettering Bergen	Montvale	New Jersey
United States	Rutgers Cancer Institute of New Jersey	New Brunswick	New Jersey
United States	UC Comprehensive Cancer Center at Silver Cross	New Lenox	Illinois
United States	Laura and Isaac Perlmutter Cancer Center at NYU Langone	New York	New York
United States	Memorial Sloan Kettering Cancer Center	New York	New York
United States	NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center	New York	New York
United States	NYP/Weill Cornell Medical Center	New York	New York
United States	Delaware Clinical and Laboratory Physicians PA	Newark	Delaware
United States	Helen F Graham Cancer Center	Newark	Delaware
United States	Medical Oncology Hematology Consultants PA	Newark	Delaware
United States	Newark Beth Israel Medical Center	Newark	New Jersey
United States	City of Hope Newport Beach	Newport Beach	California
United States	Cancer Care Center of O'Fallon	O'Fallon	Illinois
United States	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma
United States	Kaiser Permanente-Ontario	Ontario	California
United States	UC Irvine Health/Chao Family Comprehensive Cancer Center	Orange	California
United States	University of Chicago Medicine-Orland Park	Orland Park	Illinois
United States	Upstate Cancer Center at Oswego	Oswego	New York
United States	Baptist Memorial Hospital and Cancer Center-Oxford	Oxford	Mississippi
United States	Stanford Cancer Institute Palo Alto	Palo Alto	California
United States	Kaiser Permanente - Panorama City	Panorama City	California
United States	Illinois CancerCare-Peoria	Peoria	Illinois
United States	Portland VA Medical Center	Portland	Oregon
United States	Providence Saint Vincent Medical Center	Portland	Oregon
United States	Marshfield Medical Center-Rice Lake	Rice Lake	Wisconsin
United States	Kaiser Permanente-Riverside	Riverside	California
United States	Siteman Cancer Center at Christian Hospital	Saint Louis	Missouri
United States	Siteman Cancer Center-South County	Saint Louis	Missouri
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	Siteman Cancer Center at Saint Peters Hospital	Saint Peters	Missouri
United States	Huntsman Cancer Institute/University of Utah	Salt Lake City	Utah
United States	Kaiser Permanente-San Diego Zion	San Diego	California
United States	Kaiser Permanente-San Marcos	San Marcos	California
United States	UCSF Cancer Center - San Mateo	San Mateo	California
United States	Essentia Health Sandstone	Sandstone	Minnesota
United States	North Coast Cancer Care	Sandusky	Ohio
United States	FHCC at Northwest Hospital	Seattle	Washington
United States	Memorial Hospital East	Shiloh	Illinois
United States	LSU Health Sciences Center at Shreveport	Shreveport	Louisiana
United States	City of Hope South Pasadena	South Pasadena	California
United States	Baptist Memorial Hospital and Cancer Center-Desoto	Southhaven	Mississippi
United States	Marshfield Medical Center-River Region at Stevens Point	Stevens Point	Wisconsin
United States	Cleveland Clinic Cancer Center Strongsville	Strongsville	Ohio
United States	State University of New York Upstate Medical University	Syracuse	New York
United States	Community Medical Center	Toms River	New Jersey
United States	City of Hope South Bay	Torrance	California
United States	Banner University Medical Center - Tucson	Tucson	Arizona
United States	University of Arizona Cancer Center-North Campus	Tucson	Arizona
United States	Memorial Sloan Kettering Nassau	Uniondale	New York
United States	City of Hope Upland	Upland	California
United States	Carle Cancer Center	Urbana	Illinois
United States	Upstate Cancer Center at Verona	Verona	New York
United States	Essentia Health Virginia Clinic	Virginia	Minnesota
United States	South Pointe Hospital	Warrensville Heights	Ohio
United States	Northwestern Medicine Cancer Center Warrenville	Warrenville	Illinois
United States	Marshfield Medical Center - Weston	Weston	Wisconsin
United States	Kaiser Permanente-Woodland Hills	Woodland Hills	California
United States	Cleveland Clinic Wooster Family Health and Surgery Center	Wooster	Ohio
United States	Huron Gastroenterology PC	Ypsilanti	Michigan
United States	Trinity Health IHA Medical Group Hematology Oncology Ann Arbor Campus	Ypsilanti	Michigan

Sponsors (1)

Lead Sponsor	Collaborator
National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Changes in function (Integrated Correlative Geriatric Assessments Substudy)	Will be assessed by a Comprehensive Geriatric Assessment (Carolina Frailty Index [CFI] Score) between patients treated with CC-486 + R-miniCHOP and those treated with R-miniCHOP alone. Linear regression will be used for each examination, adjusting for the stratification factors from the clinical study and the baseline score (for the examination of change from 12 to 24 months, the 12-month score will be considered the baseline score). Although the number of timepoints is limited to 3, longitudinal assessments of the CFI Score over time will also be conducted using linear mixed models, adjusting for the stratification factors and the baseline score, with patient considered a random effect.	From time of randomization up to 24 months after date of registration
Other	Frailty status (fit/unfit vs frail) (Integrated Correlative Geriatric Assessments Substudy)	Will evaluate if frailty status (fit/unfit versus frail) as assessed by the Italian Lymphoma Foundation (FIL) tool is associated with overall survival. Multivariable Cox regression will be conducted, adjusting for the stratification variables and the randomized treatment arm as covariates. Will also examine whether randomization to CC-486 + R-miniCHOP is associated with better overall survival compared to treatment with R-miniCHOP alone in the subset of fit and unfit patients. Multivariable Cox regression will be conducted, adjusting for the stratification variables as covariates.	Baseline
Other	Frailty status (Integrated Correlative Geriatric Assessments Substudy)	Will evaluate if frailty status (fit/unfit versus frail) as assessed by the FIL tool correlates with the summary frailty indexed as measured by the S1918 Comprehensive Geriatric Assessment (CGA). In particular, agreement between the FIL and CGA will measured using an unweighted Kappa statistic; moderate or better agreement is defined as a Kappa coefficient of >= 0.41.	Up to 24 months after date of registration
Primary	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
Primary	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
Primary	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	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
Secondary	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
Secondary	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