Testing CC-486 (Oral Azacitidine) Plus the Standard Drug Therapy in Patients 75 Years or Older With Newly Diagnosed Diffuse Large B Cell Lymphoma
Purpose
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.
Conditions
- 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
Eligibility
- Eligible Ages
- Over 75 Years
- Eligible Genders
- All
- Accepts Healthy Volunteers
- No
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
Study Design
- Phase
- Phase 2/Phase 3
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel Assignment
- Primary Purpose
- Treatment
- Masking
- None (Open Label)
Arm Groups
Arm | Description | Assigned Intervention |
---|---|---|
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. |
|
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. |
|
Recruiting Locations
Little Rock, Arkansas 72205
Site Public Contact
501-686-8274
Anaheim, California 92806
Baldwin Park, California 91706
Bellflower, California 90706
Beverly Hills, California 90211
Costa Mesa, California 92627
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Los Angeles, California 90048
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310-423-8965
Ontario, California 91761
Orange, California 92868
Palo Alto, California 94304
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San Mateo, California 94402
Woodland Hills, California 91367
Newark, Delaware 19713
Newark, Delaware 19713
Newark, Delaware 19713
Miami, Florida 33136
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305-243-2647
Atlanta, Georgia 30322
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404-778-1868
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'Aiea, Hawaii 96701
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Honolulu, Hawaii 96813
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Chicago, Illinois 60637
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Glenview, Illinois 60026
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Lake Forest, Illinois 60045
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Orland Park, Illinois 60462
Urbana, Illinois 61801
Warrenville, Illinois 60555
Ames, Iowa 50010
Des Moines, Iowa 50309
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515-241-3305
Shreveport, Louisiana 71103
Boston, Massachusetts 02111
Ann Arbor, Michigan 48106
Brighton, Michigan 48114
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Canton, Michigan 48188
Canton, Michigan 48188
Chelsea, Michigan 48118
Chelsea, Michigan 48118
Livonia, Michigan 48154
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Ypsilanti, Michigan 48197
Deer River, Minnesota 56636
Duluth, Minnesota 55805
Hibbing, Minnesota 55746
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218-786-3308
Sandstone, Minnesota 55072
Virginia, Minnesota 55792
Southhaven, Mississippi 38671
Chesterfield, Missouri 63017
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Creve Coeur, Missouri 63141
Saint Louis, Missouri 63110
Saint Louis, Missouri 63129
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Saint Peters, Missouri 63376
Lincoln, Nebraska 68516
Lincoln, Nebraska 68516
Basking Ridge, New Jersey 07920
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Middletown, New Jersey 07748
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Montvale, New Jersey 07645
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New Brunswick, New Jersey 08903
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Buffalo, New York 14263
Commack, New York 11725
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Harrison, New York 10604
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Mineola, New York 11501
New York, New York 10016
New York, New York 10032
New York, New York 10065
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New York, New York 10065
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Oneida, New York 13421
Oswego, New York 13126
Syracuse, New York 13210
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315-464-5476
Uniondale, New York 11553
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Cleveland, Ohio 44111
Cleveland, Ohio 44195
Columbus, Ohio 43210
Independence, Ohio 44131
Mansfield, Ohio 44906
Mayfield Heights, Ohio 44124
Sandusky, Ohio 44870
Strongsville, Ohio 44136
Warrensville Heights, Ohio 44122
Wooster, Ohio 44691
Lawton, Oklahoma 73505
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877-231-4440
Oklahoma City, Oklahoma 73104
Portland, Oregon 97239
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800-949-1004
Charleston, South Carolina 29425
Greenville, South Carolina 29607
Memphis, Tennessee 38120
Salt Lake City, Utah 84112
Charlottesville, Virginia 22908
Fairfax, Virginia 22031
Bellevue, Washington 98004
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425-454-2148
Kirkland, Washington 98034
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425-899-6000
Seattle, Washington 98133
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206-606-5800
Charleston, West Virginia 25304
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304-388-9944
Ashland, Wisconsin 54806
Eau Claire, Wisconsin 54701
La Crosse, Wisconsin 54601
Marshfield, Wisconsin 54449
Minocqua, Wisconsin 54548
Rice Lake, Wisconsin 54868
Stevens Point, Wisconsin 54482
Weston, Wisconsin 54476
More Details
- NCT ID
- NCT04799275
- Status
- Recruiting
- Sponsor
- National Cancer Institute (NCI)
Detailed 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.