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 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
Eligibility
- Eligible Ages
- Over 75 Years
- Eligible Genders
- All
- Accepts Healthy Volunteers
- No
Criteria
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. Participants must
have measurable disease (at least one lesion with longest diameter ≥ 1.5 cm). 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 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 a history of acute leukemia having been treated with
intensive induction therapy. Patients with a prior or concurrent malignancy whose
natural history or treatment does not have the potential to interfere with the
safety or efficacy assessment of the investigational regimen are eligible for this
trial
- 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 be age ≥ 75
- 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 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
- Participants must not have a concurrent primary malignancy undergoing active
therapy. Exceptions: participants may have non-melanomatous skin cancers requiring
only surgical intervention. Participants may have a history of early stage breast
cancer or prostate cancer in remission after surgical and/or radiation therapy on
adjuvant hormonal therapy only
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. Patients undergo blood sample collection throughout the study. |
|
|
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. Patients undergo blood sample collection throughout the study. |
|
Recruiting Locations
More Details
- NCT ID
- NCT04799275
- Status
- Suspended
- 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. Patients undergo blood sample collection throughout the study. 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. Patients undergo blood sample collection throughout the study. After completion of study treatment, patients are followed up periodically until 5 years from the date of registration.