Golcadomide With Pemetrexed, Rituximab, and Dexamethasone for Relapsed and Refractory CNS Lymphomas

Inclusion Criteria:

* Participants or their legally acceptable representative must have signed and dated an IRB approved written ICF in accordance with regulatory, local, and institutional guidelines.
* Participants ≥ 18 years of age.
* Confirmed histopathological diagnosis of aggressive malignant B-cell lymphoma based upon a representative histology specimen according to the WHO classification. For participants with secondary CNS lymphoma, this can be confirmed by prior systemic biopsy. If a CNS lesion was not amenable for biopsy, imaging (e.g. MRI Brain ± MRI Full Spine) with CSF analysis for cytology may be used to confirm diagnosis, in lieu of a biopsy. Required. Acceptable histologies include:

  * Large B-cell lymphoma NOS
  * Diffuse large B-cell lymphoma (including GCB and ABC types)
  * High-grade B-cell lymphoma with MYC and BCL2 rearrangements (double hit lymphomas)
  * High-grade B-cell lymphoma NOS
  * T-cell/histiocyte/rich large B-cell lymphoma (THRLBCL)
  * EBV + DLBCL
  * PMBCL
  * Follicular Large B-Cell (previously referred to as Follicular Lymphoma, Grade 3B)
* Participants must have active CNS lymphoma for which this trial is planned. Confirmation of the histology in relapsed setting is not required but participants must have measurable disease per the International PCSNL Collaboration Group Criteria (Section 11.1), as evidenced by at least one of the following:

  * CNS disease on MRI (brain or spine including parenchymal and leptomeningeal)
  * Detectable in the CSF
  * Detectable on ophthalmologic exam
* Participants must have received ≥ 1 prior systemic therapy for treatment of their CNS lymphoma. Participants who had systemic lymphoma and then relapsed with secondary CNS lymphoma must have received at least one prior line of therapy to specifically treat the CNS lymphoma.
* Participants must have received prior high dose methotrexate as a line of therapy OR have been ineligible for methotrexate therapy based on the investigator's discretion.

  * Participants who have received methotrexate as their first line of therapy but are no longer eligible for ongoing methotrexate and have persistent disease are eligible
* ECOG performance status ≤ 0-3. PS 3 is allowed if it is disease related and not due to comorbidities or frailty and PS 4 is allowed if it is from CNS causing motor weakness and not due to comorbidities or frailty. (see Appendix I)
* Adequate bone marrow function, defined by the following laboratory parameters:

  * Absolute neutrophil ≥ 1.5 x 109/L
* Platelet count ≥ 100 x 109/L

  * Hemoglobin ≥ 8 g/dL
* Adequate organ function, defined by the following laboratory parameters:

  * Adequate hepatic function, with transaminases (alanine aminotransferase \[ALT\], aspartate aminotransferase \[AST\], and gamma glutamyl transferase \[GGT\]) ≤ 2.5 times the upper limit of normal
* Bilirubin ≤1.5 x ULN (unless bilirubin rise is due to Gilbert's syndrome or of non-hepatic origin)
* Calculated creatinine clearance \> 45 mL/min by the Cockcroft-Gault equation.
* Treating investigator must specify at screening:

  * If the intent of therapy is a bridge to cellular therapy or to complete all six cycles of therapy. If bridge to cellular therapy is planned, the type of cellular therapy should also be specified at this time.
  * If the r/r CNS lymphoma is primary or secondary
* For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use two methods of contraception simultaneously from signing the ICF, at least 28 days before starting golcadomide, throughout the study, for up to 28 days following the last dose of golcadomide, and for 12 months after the last dose of rituximab, whichever is longer.. Two methods of contraception must include one highly effective method and one additional effective (barrier method).

  * A woman is considered to be of childbearing potential if she is postmenarcheal, has not reached a postmenopausal state (\< 12 continuous months of amenorrhea with no identified cause other than menopause), and has not undergone surgical sterilization (removal of ovaries, fallopian tubes, and/or uterus).

    * Examples of contraceptive methods include highly effective methods such as oral, injectable, or implantable hormonal contraceptive; tubal ligation; intrauterine device; vasectomized partner and barrier methods with spermicide.
    * The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception.
    * Must agree to pregnancy testing per protocol. This applies even if the participant practices true abstinence from heterosexual contact.
    * Agree to abstain from breastfeeding or providing breast milk while on golcadomide and 28 days after discontinuation of golcadomide and according to the approved
  * For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures, and agreement to refrain from donating sperm, as defined below:
  * With female partners of childbearing potential, men must remain abstinent or use a condom plus an additional contraceptive method that together result in a failure rate of \< 1% per year during the treatment period and for at least 28 days after the last dose of study intervention or 90 days for rituximab, whichever is longer. Men must refrain from donating sperm during this same period.
  * With pregnant female partners, men must remain abstinent or use a condom during the treatment period and for at least 28 days after the last dose of study intervention or 90 days for rituximab, whichever is longer.
  * The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception.

Exclusion Criteria:

* Prior treatment toxicities not resolved to grade \< 2 according to NCI CTCAE 6.0 (with the exception of alopecia or grade 2 sensory peripheral neuropathy).
* Participants receiving any other investigational agents.
* History of anaphylactic reactions or severe allergic reactions prohibiting further administration attributed to compounds of similar chemical or biologic composition to rituximab or other agents used in this study.
* Autologous stem cell transplant within 30 days of start of study drug (C1D1).
* CAR T-cell therapy within 90 days of start of study drug (C1D1).
* Previous allogeneic stem cell transplant
* Women who are pregnant or breastfeeding.
* Clinically significant autoimmune disease.
* Known seropositive and requiring anti-viral therapy for human immunodeficiency (HIV) virus.
* Malabsorption syndrome or other conditions that precludes enteral route of administration.
* Chemotherapy or radiation within 2 weeks of the first scheduled study treatment
* Participant is currently receiving warfarin. Participants may begin screening if the plan is to change to an alternative anticoagulant such as a DOAC prior to enrollment.
* Participant has current treatment with strong cytochrome P450 3A4/5 (CYP3A4/5) modulators. The washout period for strong CYP3A4/5 modulators is 7 days or 5 half-lives (whichever is longer) before initiation of golcadomide.
* Evidence of other clinically significant uncontrolled condition(s) including, but not limited to:

  * Uncontrolled and/or active systemic infection (viral, bacterial or fungal)
  * Chronic hepatitis B virus (HBV) or hepatitis C (HCV) requiring treatment. Note: participants with serologic evidence of prior vaccination to HBV (i.e. hepatitis B surface (HBs) antigen negative-, anti-HBs antibody positive and anti-hepatitis B core (HBc) antibody negative) or positive anti-HBc antibody from intravenous immunoglobulins (IVIG) may participate.
  * Other uncontrolled conditions including uncontrolled cardiovascular disease or arrhythmia, decompensated diabetes or COPD.