Testing CC-486 (Oral Azacitidine) Plus the Standard Drug Therapy in Patients 75 Years or Older With Newly Diagnosed Diffuse Large B Cell Lymphoma
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|ClinicalTrials.gov Identifier: NCT04799275|
Recruitment Status : Recruiting
First Posted : March 16, 2021
Last Update Posted : May 25, 2023
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|Condition or disease||Intervention/treatment||Phase|
|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 Hodgkin 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||Drug: Cyclophosphamide Drug: Doxorubicin Hydrochloride Drug: Oral Azacitidine Drug: Prednisone Other: Questionnaire Administration Biological: Rituximab Drug: Vincristine Sulfate||Phase 2 Phase 3|
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||422 participants|
|Intervention Model:||Parallel Assignment|
|Masking:||None (Open Label)|
|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|
|Actual Study Start Date :||March 19, 2021|
|Estimated Primary Completion Date :||March 31, 2025|
|Estimated Study Completion Date :||March 31, 2025|
Experimental: Arm I (oral azacitidine, R-miniCHOP)
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: Doxorubicin Hydrochloride
Drug: Oral Azacitidine
Other Name: CC-486
Other: Questionnaire Administration
Given IV or SC
Drug: Vincristine Sulfate
Active Comparator: Arm II (R-miniCHOP)
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: Doxorubicin Hydrochloride
Other: Questionnaire Administration
Given IV or SC
Drug: Vincristine Sulfate
- 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) [ Time Frame: Up to completion of cycle 6 ]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.
- Progression-free survival (PFS) (Phase II) [ Time Frame: 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 ]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.
- Overall survival (Phase III) [ Time Frame: From date of registration to date of death due to any cause, assessed up to 2 years ]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.
- Metabolic complete response (CR) [ Time Frame: Up to end of cycle 6 or end of treatment ]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.
- Incidence of adverse events [ Time Frame: Until disease progression, assessed up to 5 years ]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.
- Overall survival (Phase III) [ Time Frame: From date of registration to date of death due to any cause, assessed up to 5 years ]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.
- Changes in function (Integrated Correlative Geriatric Assessments Substudy) [ Time Frame: From time of randomization up to 24 months after date of registration ]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.
- Frailty status (fit/unfit vs frail) (Integrated Correlative Geriatric Assessments Substudy) [ Time Frame: Baseline ]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.
- Frailty status (Integrated Correlative Geriatric Assessments Substudy) [ Time Frame: Up to 24 months after date of registration ]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.
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|Ages Eligible for Study:||75 Years and older (Older Adult)|
|Sexes Eligible for Study:||All|
|Accepts Healthy Volunteers:||No|
- 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)
- 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
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04799275
|Principal Investigator:||Elizabeth A Brem||SWOG Cancer Research Network|
|Responsible Party:||National Cancer Institute (NCI)|
|Other Study ID Numbers:||
NCI-2020-01256 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
S1918 ( Other Identifier: SWOG )
S1918 ( Other Identifier: CTEP )
U10CA180888 ( U.S. NIH Grant/Contract )
|First Posted:||March 16, 2021 Key Record Dates|
|Last Update Posted:||May 25, 2023|
|Last Verified:||April 2023|
|Individual Participant Data (IPD) Sharing Statement:|
|Plan to Share IPD:||Yes|
|Plan Description:||NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page.|
|Studies a U.S. FDA-regulated Drug Product:||Yes|
|Studies a U.S. FDA-regulated Device Product:||No|
Lymphoma, Large B-Cell, Diffuse
Neoplasms by Histologic Type
Immune System Diseases
Neoplasms, Plasma Cell
Blood Protein Disorders