IRB Study Number 22-1295
Status Recruiting
Institute Taussig Cancer Institute
Description
1.1 Primary Objectives
a. Safety run-in: To 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.
b. Phase II Component: 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).
c. Phase III component: To compare the overall survival (OS) between CC-486 + R-miniCHOP and R-miniCHOP alone.
1.2 Secondary Objectives
a. To assess the feasibility of delivering at least 4 cycles of CC-486 with R-miniCHOP in this population.
b. To assess toxicity for CC-486 + R-miniCHOP and for R-miniCHOP.
c. To compare complete response rates, as defined by Lugano 2014 classification, between CC-486 + R-miniCHOP and R-miniCHOP alone.
Inclusion Criteria
5.1 Disease Related Criteria
a. Participants must have histologically or cytologically confirmed DLBCL, Ann Arbor Stage IIX (bulky), III or IV. Participants with DLBCL transformed from FL or marginal zone lymphoma (MZL, including 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. See Section 4.0 for staging. Participants with DLBCL that arose from prior CLL (Richter's transformation) are not eligible.
b. As defined by the 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
c. Participants must have staging imaging performed within 28 days prior to registration, as follows. PET-CT baseline scans are strongly preferred; Diagnostic quality 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 (See Sections 7.5c, and 7.5d). 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.
d. 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.
e. 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.
f. 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.
g. Participants must not have known lymphomatous involvement of the CNS.
h. 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.
5.2 Prior/Concurrent Therapy Criteria
a. 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, as described in Section 7.1. 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.
b. Participants must not have received more than a cumulative of dose 250 mg/m2 of prior doxorubicin (or equivalent dose of another anthracycline, such as epirubicin) therapy (at any time prior to registration).
c. Participants must not currently be receiving any other investigational agents.
d. Participant must not have a history of allergic reactions attributed to azacitidine, mannitol, or other hypomethylating agents.
5.3 Clinical/Laboratory Criteria
a. Participants must be age ≥ 75.
b. Participants must have a Zubrod performance status of 0-2. See Section 10.3.
c. 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.
Calculated Creatinine Clearance = (140 - age) X (weight in kg) †
72 x serum creatinine *
Multiply this number by 0.85 if the participant is a female.
† The kilogram weight is the participant weight with an upper limit of 140% of the IBW.
* Actual lab serum creatinine value with a minimum of 0.8 mg/dL.
d. Participants must have adequate liver function within 28 days prior to registration, as evidenced by: AST≤ 2.5 x IULN, ALT ≤ 2.5 x IULN and Total Bilirubin ≤ 2 x IULN, unless due to Gilbert’s disease, hemolysis, or lymphomatous involvement of liver. 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.
e. Participants must have adequate bone marrow function within 28 days prior to registration, as evidenced by:
• ANC ≥ 1000/mcL and
• Platelets ≥ 75,000/ mcL.
• Hgb ≥ 8 g/ dL
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 and
• Platelets ≥ 50,000/ mcL.
• Hgb ≥ 8 g/dL
f. Participants must have a left ventricular ejection (LVEF) fraction ≥ 45% as measured by echocardiogram or radionuclide (MUGA) ventriculography within 56 days prior to registration.
g. 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).
h. 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).
i. Participants must not have active cardiac disease within 26 weeks prior to registration, including: symptomatic congestive heart failure (NYHA Class 4), unstable angina pectoris, hemodynamically unstable cardiac arrhythmia, or myocardial infarction. See Section 18.5: New York Heart Association Criteria
j. Participants must not have ≥ Grade 2 neuropathy, by CTCAE v. 5.0, within 28 days prior to registration.
k. 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.
5.4 Specimen Submission Criteria
Participants must be offered the opportunity to participate in specimen banking as outlined in Section 15.1.
5.5 Patient Reported Outcome Criteria
a. Participants who can complete the S1918 Comprehensive Geriatric Assessment – Participant Portion form in English or Spanish must complete the baseline assessment prior to registration. Participants who can complete the S1918 Comprehensive Geriatric Assessment – Participant Portion form in English or Spanish must also agree to participate in the patient reported outcome (PRO) study as outlined in Section 15.2.
Note: In event that the participant is not able to complete the Participant-Portion of the CGA in English or Spanish, then the S1918 Provider-Portion of the CGA assessment is not required to be completed.
b. For the participant to be eligible, the provider must administer the Italian Lymphoma Foundation (FIL) Tool, complete the S1918 Comprehensive Geriatric Assessment – Provider Portion form prior to participant registration, and be willing to complete the provider component of the S1918 Comprehensive Geriatric Assessment – Provider Portion form at the planned follow-up timepoints, as outlined in Section 15.3.
5.6 Regulatory Criteria
NOTE: As a part of the OPEN registration process (see Section 13.5 for OPEN access instructions) the treating institution's identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered in the system.
a. Participants must be informed of the investigational nature of this study and must sign and give informed consent in accordance with institutional and federal guidelines. For participants with impaired decision-making capabilities, legally authorized representatives may sign and give informed consent on behalf of study participants in accordance with applicable federal, local, and CIRB regulations.
Exclusion Criteria
Exclusion Criteria Not Available
