Golcadomide and Rituximab as Bridging Therapy for Relapsed or Refractory Aggressive B-cell Non-Hodgkin Lymphoma Before CAR T-cell Therapy

Inclusion Criteria:

• Age ≥ 18 years

• Confirmed pathology diagnosis according to 2016 World Health Organization (WHO)classification including patients with diseases listed below with relapsed,progressive and/or refractory disease (Cheson et al. 2014) following treatment withone or two prior lines of standard therapy, no more than two lines of therapy arepermitted:

• Diffuse large B-cell lymphoma not otherwise specified (NOS) including:

• Transformed lymphoma

• Germinal center B-cell type

• Activated B-cell type

• High-grade B-cell lymphoma (HGBCL), NOS

• High grade B-cell lymphoma with MYC and BCL2 translocation

• Primary mediastinal (thymic) large B-cell lymphoma

• Grade 3B follicular lymphoma

• T-cell/histiocyte-rich large B-cell lymphoma

• Large B-cell lymphoma with IRF4 rearrangement

• Primary cutaneous diffuse large B-cell lymphoma (DLBCL), leg type

• Epstein-Barr virus (EBV) positive DLBCL, NOS

• DLBCL associated with chronic inflammation

• Intravascular large B-cell lymphoma

• ALK positive large B-cell lymphoma

• NOTE: Richters transformation patients are excluded

• Measurable disease by PET-CT with at least one lymph node or other type of lesionthat has a size > 1.5 cm in the transverse diameter, as defined by Luganoclassification

• NOTE: Tumor lesions in a previously irradiated area are not consideredmeasurable disease; Disease that is measurable by physical examination only isnot eligible

• Patient is potentially eligible for CAR-T therapy as determined by treatingphysician

• Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1, or 2

• Hemoglobin > 7.0 g/dL (obtained ≤ 14 days prior to registration)

• Absolute neutrophil count (ANC) ≥ 1000/mcL (obtained ≤ 14 days prior toregistration); growth factor support allowed at physician discretion

• Platelet count ≥ 75,000/mcL (obtained ≤ 14 days prior to registration)

• Total bilirubin ≤ 1.5 x upper limit of normal (ULN) (obtained ≤ 14 days prior toregistration); if total bilirubin is > 1.5 ULN, direct bilirubin must be normal

• Alanine aminotransferase (ALT) and aspartate transaminase (AST) ≤ 2.5 x ULN (≤ 5 xULN if there is evidence of parenchymal liver involvement with lymphoma) (obtained ≤ 14 days prior to registration)

• Calculated creatinine clearance ≥ 45 ml/min using the Cockcroft-Gault formula (obtained ≤ 14 days prior to registration)

• Have 2 negative pregnancy tests as verified by the investigator prior to startingCC-99282:

• A negative serum pregnancy test (sensitivity of at least 25 mIU/mL) atscreening (between 10 to 14 days prior to cycle 1 day 1)

• A negative serum or urine pregnancy test (investigator's discretion) within 24hours prior to cycle 1 day 1 of study treatment

• Provide written informed consent

• Willing to return to enrolling institution for follow-up (during the activemonitoring phase of the study)

• Subjects must agree not to donate blood while receiving golcadomide, during doseinterruptions and for ≥ 28 days following the last dose of golcadomide

Exclusion Criteria:

• Any of the following because this study involves an investigational agent that hasknown genotoxic, mutagenic, and teratogenic effects:

• Pregnant persons

• Nursing persons

• Persons of childbearing potential (and persons able to father a child) who areunwilling to employ adequate contraception

• Persons of childbearing potential (PCBP) unwilling to use two reliable forms ofcontraception simultaneously or to practice complete abstinence (trueabstinence is acceptable when this is in line with the preferred and usuallifestyle of the subject. Periodic abstinence [e.g., calendar, ovulation,symptothermal or postovulation methods] and withdrawal are not acceptablemethods of contraception) from heterosexual contact during the following timeperiods related to this study:

• For ≥ 28 days before starting treatment, during treatment and doseinterruptions, and for ≥ 28 days after the last dose of golcadomide

• Examples of highly effective methods of contraception:

• Intrauterine device (IUD)

• Hormonal (birth control pills, injections, implants,levonorgestrel-releasing intrauterine system [IUS], medroxyprogesteroneacetate depot injections, ovulation inhibitory

• Progesterone-only pills [e.g., desogestrel])

• Tubal ligation

• Partner's vasectomy

• Examples of additional effective methods:

• Male condom

• Diaphragm

• Cervical cap

• Persons who can father a child unwilling to practice complete abstinence (trueabstinence is acceptable when this is in line with the preferred and usuallifestyle of the subject. Periodic abstinence [e.g., calendar, ovulation,symptothermal or post-ovulation methods] and withdrawal are not acceptablemethods of contraception.) or unwilling to use a condom during sexual contactwith a pregnant person or a PCBP during treatment and dose interruptions, andfor > 28 days following the last dose of golcadomide, even if they haveundergone a successful vasectomy

• Persons who can father a child and are unwilling to refrain from donating semenor sperm while receiving golcadomide, during dose interruptions, or for ≥ 28days following the last dose of golcadomide

• Life expectancy < 3 months

• Any of the following prior therapies:

• Any prior CAR-T or other T-cell targeting treatment (approved orinvestigational) ≤ 4 weeks prior to registration

• Any prior systemic anti-cancer treatment (approved or investigational) ≤ 5half-lives or 4 weeks prior to registration, whichever is shorter

• Exception: Monoclonal and bispecific antibodies is acceptable

• Prior therapy with golcadomide ≤ 4 weeks prior to registration

• Prior autologous stem cell transplantation (SCT) ≤ 3 months prior toregistration. If subject had autologous SCT > 3 months prior to the start ofregistration, any treatment-related toxicity is unresolved (grade > 1)

• Major surgery ≤ 3 weeks prior to registration

• Chemotherapy ≤ 2 weeks prior to registration

• Concomitant radiation therapy; local palliative radiotherapy is permitted

• Co-morbid systemic illnesses or other severe concurrent disease or cancer which, inthe judgment of the investigator, would make the patient inappropriate for entryinto this study or interfere significantly with the proper assessment of safety andtoxicity of the prescribed regimens

• Impaired cardiac function or clinically significant cardiac diseases including, butnot limited to:

• Symptomatic congestive heart failure

• History of myocardial infarction ≤ 6 months, or congestive heart failurerequiring use of ongoing maintenance therapy for life-threatening ventriculararrhythmias

• Unstable angina pectoris

• Cardiac arrhythmia

• Uncontrolled intercurrent non-cardiac illness including, but not limited to:

• Ongoing or active infection

• Psychiatric illness/social situations

• Dyspnea at rest due to complications of advanced malignancy or other diseasethat requires continuous oxygen therapy (such as interstitial lung disease orchronic obstructive pulmonary disease [COPD])

• Any other conditions that would limit compliance with study requirements

• Subject had prior allogeneic SCT with either standard or reduced intensityconditioning ≤ 6 months prior to registration. If subject had prior allogeneic SCT > 6 months prior to registration, any treatment-related toxicity is unresolved (grade >1)

• Immunocompromised patients and patients known to be HIV positive and currentlyreceiving antiretroviral therapy, as there is currently no safety data in HIVpositive patients

• Subject has known chronic active hepatitis B or C virus (HBV/HCV) infection

• Exception: Patients with HBV and an undetectable viral load who are onsuppressive therapy and/or those with HCV and an undetectable viral load areallowed

• Concurrent administration of strong or moderate CYP3A4/5 inhibitors and inducerswithin 14 days or 5 half-lives, whichever is longer before the study treatmentadministration

• Receiving any other investigational agent which would be considered as a treatmentfor lymphoma.

• Exception: Corticosteroids are allowed

• Active second malignancy requiring treatment that would interfere with theassessment of the response of the primary cancer or interpretation of the safety ofthis protocol therapy

• History of deep venous thrombosis/embolism, threatening thromboembolism or knownthrombophilia. Patients with a history of deep vein thrombosis (DVT)/pulmonaryembolism (PE) or thrombophilia may still participate if they are willing to be onfull anticoagulation during treatment. Full anticoagulation is defined as Warfarin,factor X inhibitors, or low molecular weight heparin at therapeutic doses. Therationale for this requirement is that golcadomide therapy is associated with anincreased risk of thrombosis. Patients with no history of DVT/PE or thrombophiliaare not required to take anticoagulation and/or anti-platelet prophylaxis

• NOTE: If a patient develops a thrombotic event, they must be able and willingto receive anticoagulation therapy with aspirin 81-325 mg daily prophylaxis,low molecular weight heparin, factor X inhibitors or Warfarin. This is due toan increased risk of thrombosis in patients treated with golcadomide withoutprophylaxis

• Live COVID-19 vaccine administered ≤ 28 days prior to registration