Inclusion Criteria:

• Subject is ≥ 18 years of age the time of signing the informed consent form (ICF).
• Subject must understand and voluntarily sign an ICF prior to any study-related assessments/procedures being conducted.
• Subject is willing and able to adhere to the study visit schedule and other protocol requirements.
• Subject is willing to undergo core needle or incisional/ excisional biopsy unless sufficient tissue is available from diagnostic tumor/ lymph node biopsy (from within 6 months prior to ICF signature) for translational research purposes.
• Subject has histologically confirmed (per local evaluation) diagnosis of de novo, previously untreated, a-BCL according to 2016 WHO classification including:
  • DLBCL, NOS (including GCB and ABC types);
  • High-grade B-cell lymphoma, with MYC and BCL2 and/or BCL6 rearrangements;
  • Primary mediastinal (thymic) large B-cell lymphoma (PMBCL);
  • Primary cutaneous DLBCL-leg type;
  • EBV+ DLBCL, NOS;
  • Grade 3b FL.
• Chemo- and immunotherapy-naïve FL transformed to a-BCL. Patient must not have received any previous therapy for the FL component.
• Subject is considered an appropriate candidate (per investigator assessment) for induction therapy with 6 cycles of R-CHOP-21 or polatuzumab-R-CHP immunochemotherapy.
• Subject has IPI score 0 to 5 in Part 1 and IPI 2 to 5 in Part 2. For the CELMoD and polatuzumab-R-CHP cohort, the subject must also have IPI score 0 to 5 in Part 2A and IPI 2 to 5 in Part 2B.
• Subjects must have measurable disease defined by at least one FDG-avid lesion for FDG-avid subtype and one bi-dimensionally measurable (> 1.5 cm in longest diameter) disease by computed tomography (CT) or magnetic resonance imaging (MRI), as defined by the Lugano classification (Cheson, 2014).
• Subject has an ECOG performance status of 0, 1, or 2.
• Subjects must have the following laboratory values:
  • ANC ≥ 1.5 × 10^9 /L or ≥ 1.0 × 10^9 /L in case of documented bone marrow involvement (> 50% or tumor cells), without growth factor support for 7 days (14 days if peg-G-CSF);
  • Hemoglobin (Hb) ≥ 8 g/dL;
  • Platelets (PLT) ≥ 75 × 10^9 /L or ≥ 50 × 10^9 /L in case of documented bone marrow involvement (> 50% or tumor cells), without transfusion for 7 days;
  • AST/SGOT and alanine aminotransferase )ALT)/ serum glutamate pyruvic transaminase (SGPT) ≤ 2.5 × ULN. In the case of documented liver involvement by lymphoma, ALT/SGPT and AST/SGOT must be ≤ 5.0 × ULN;
  • Serum total bilirubin ≤ 2.0 mg/dL (34 μmol/L) except in cases of Gilbert’s syndrome, then ≤ 5.0 mg/dL (86 μmol/L);
  • Subjects receiving polatuzumab vedotin must have serum total bilirubin ≤ 1.5 × ULN (26 μmol/L) (corresponding to mild degree as per National Cancer Institute Organ Dysfunction Working Group [NCI ODWG] criteria) except in cases of Gilbert’s syndrome, then ≤ 3.0 mg/dL (51 μmol/L);
  • Estimated serum creatinine clearance (CrCl) of ≥ 50 mL/min using the modification of diet in renal disease (MDRD) formula.
• All subjects must:
  • Have an understanding that the study drug could have a potential teratogenic risk.
  • Agree to refrain from donating blood while on study treatment, during dose interruptions and for at least 28 days following the last dose of study treatment;
  • Agree not to share study medication with another person;
  • Agree to follow all requirements defined in the Pregnancy Prevention Program (see APPENDIX D) for CC-220 or CC-99282 Pregnancy Prevention Plan for Subjects in Clinical trials.
• Females must agree to abstain from breastfeeding during study participation and for at least 28 days after last dose of CC-220 or CC-99282 discontinuation and according to the approved rituximab product/prescribing information.
• Females of childbearing potential (FCBP^)* must:
  • Have two negative pregnancy tests as verified by the investigator prior to starting study therapy. She must agree to ongoing pregnancy testing during the course of the study, and after end of study therapy. This applies even if the subject practices true abstinence* from heterosexual contact;
  • Either commit to true abstinence* from heterosexual contact (which must be reviewed on a monthly basis and source documented) or agree to use, and be able to comply with two forms of contraception: one highly effective, and one additional effective (barrier) measure of contraception without interruption 28 days prior to starting IP, during the study treatment (including dose interruptions), and for at least 28 days after the last dose of CC-220 or CC-99282 and for 12 months after the last dose of rituximab or polatuzumab vedotin, whichever is longer. Contraception requirements are detailed in APPENDIX D.
• Male subjects must:
  • Practice true abstinence* (which must be reviewed on a monthly basis and source documented) or agree to use a condom (APPENDIX D) during sexual contact with a pregnant female or an FCBP while participating in the study, during dose interruptions and for at least 28 days after the last dose of CC-220, or CC-99282, 6 months after the last dose of polatuzumab vedotin, or 90 days for rituximab, whichever is longer, even if he has undergone a successful vasectomy.
  • Must agree to refrain from donating sperm while on study treatment, during dose interruptions, and for at least 28 days following last dose of CC-220, CC-99282 6 months after the last dose of polatuzumab vedotin, or 90 days following last dose for rituximab, whichever is longer.
  • ^A FCBP is a female who: 1) has achieved menarche at some point, 2) has not undergone a hysterectomy or bilateral oophorectomy, or 3) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (ie, has had menses at any time in the preceding 24 consecutive months).
  • *True abstinence is acceptable when this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception.

Exclusion Criteria:

• Subject has any significant medical condition, active infection (including SARS-CoV-2 suspected or confirmed), laboratory abnormality, or psychiatric illness that would prevent the subject from participating in the study
  • A patient who is excluded for SARS-CoV-2 infection could be rescreened;
  • In the case of prior SARS-CoV-2 infection, symptoms must have completely resolved and based on investigator assessment in consultation with the clinical trial physician, there are no sequelae that would place the participant at a higher risk receiving investigational treatment;
  • Additionally, a patient who is currently in another interventional trial for COVID-19 may not participate in the clinical trial until the protocol-specific washout period is achieved;
  • Testing to exclude asymptomatic SARS-CoV-2 prior to enrollment should follow local standard practice.
• Subject has any condition including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study.
• Subject has any condition that confounds the ability to interpret data from the study.
• Subject has any other subtype of lymphoma.
• Subject has documented or suspected CNS involvement by lymphoma.
• Subject has persistent diarrhea or malabsorption ≥ Grade 2 (NCI CTCAE v5.0), despite medical management.
• Subject has peripheral neuropathy ≥ Grade 2 (NCI CTCAE v5.0).
• Subjects with a history of progressive multifocal leukoencephalopathy.
• Subject is on chronic systemic immunosuppressive therapy or corticosteroids (e.g., prednisone or equivalent not to exceed 10 mg per day within the last 14 days); stable use of inhaled or topical corticosteroids is allowed.
• Subject has impaired cardiac function or clinically significant cardiac disease, including any of the following:
  • Left ventricular ejection fraction (LVEF) < 45% as determined by multigated acquisition (MUGA) scan or echocardiogram (ECHO);
  • Heart failure (New York Heart Association Class III or IV);
  • Clinically significant abnormal electrocardiogram (ECG) finding at screening;
  • Unstable angina or myocardial infarction ≤ 6 months prior to starting;
  • Persistent or uncontrolled ventricular arrhythmias or atrial fibrillation or cardiac conduction abnormalities not mitigated by a pacemaker.
• Subject had major surgery ≤ 2 weeks prior to starting CC-220 or CC-99282; subject must have recovered from any clinically significant effects of recent surgery.
• Subject has any condition causing inability to swallow tablets.
• Subject has known seropositivity for or active viral infection with human immunodeficiency virus (HIV).
• Subject has known chronic active hepatitis B (hepatitis B virus surface antigen [HBsAg] positive and/or hepatitis B core antibody [anti-HBc] positive with viral DNA positive) or C (positive serology requiring treatment and/or with evidence of liver damage) infection.
• Subject has history of other malignancy, unless being free of the disease for ≥ 3 years; exceptions to the ≥ 3-year time limit include history of the following:
  • Localized nonmelanoma skin cancer;
  • Carcinoma in situ of the cervix;
  • Carcinoma in situ of the breast;
  • Incidental histologic finding of prostate cancer (T1a or T1b as per Tumor Node Metastasis [TNM] staging system) or prostate cancer that has been treated with curative intent.
•  Subject has current treatment with strong CYP3A4/5 modulators.
• Subject has hypersensitivity to the active substance or to murine proteins, or to any of the other excipients of rituximab or polatuzumab vedotin.
• Subject has known hypersensitivity to any component of CHOP/CHP regimen.
• Subject has known allergy to thalidomide, pomalidomide, or lenalidomide.
• Subject received live attenuated vaccines or live COVID-19 vaccines within 30 days prior to initiation of study treatment.

Note: Other protocol defined Inclusion/Exclusion Criteria may apply.

Eligibility last updated 12/13/23. Questions regarding updates should be directed to the study team contact.