Temozolomide, Etoposide, Doxil, Dexamethasone, Ibrutinib, and Rituximab (TEDDI-R) in Aggressive B-cell Lymphomas With Secondary Involvement of the Central Nervous System (CNS)

Background: Secondary central nervous system lymphoma (sCNSL) is cancer that has spread to the central nervous system. Most drugs used to treat it do not cross the blood-brain barrier. This makes it hard to treat. Researchers hope that a new combination of drugs may be able to help. Objective: To find a better way to treat sCNSL. Eligibility: People ages 18 and older with sCNSL Design: Participants will be screened with: * Medical history * Physical exam * Blood, urine, and heart tests * Eye exam * Tissue or tumor biopsy * Collection of cerebrospinal fluid * CT, PET, and MRI scans: Participants will like in a machine that takes pictures of the body. * Bone marrow aspirations or biopsies: A needle will be inserted into the participant s hipbone. The needle will remove a small amount of marrow. Participants will take the study drugs in 21-day cycles. They will take some drugs by mouth. They will take others through a catheter: A small tube will be inserted into a vein in the arm, neck, or chest. They may have drugs given through a catheter placed through the brain or injected into the spinal canal. Participants will have regular visits during the study. These will include repeats of the screening test. They may also provide a saliva sample or have a cheek swab. Participants will have up to 4 treatment cycles. Participants will have a follow-up visit 30 days after their last treatment dose. Then they will have visits every 3-6 months for 3 years and then yearly....

Background: * Aggressive B-cell lymphomas with secondary involvement of the CNS (sCNSL) have a grave prognosis * No standard of care exists for sCNSL; treatment approaches include combination chemotherapy regimens effective in primary CNS lymphoma (PCNSL) * Ibrutinib is an inhibitor of Bruton s tyrosine kinase (BTK) and has demonstrated a high response rate in PCNSL and sCNSL but with short response duration * We developed a novel regimen that combines ibrutinib with a chemoimmunotherapy platform maximized for CNS penetrance that includes temozolomide, etoposide, Doxil, dexamethasone, and rituximab (TEDDI-R) for aggressive B-cell lymphomas in the CNS * A phase 1 study of TEDDI-R demonstrated durable remissions in refractory PCNSL * We propose a small phase 2 to study the safety and efficacy of TEDDI-R in sCNSL Objective: -To estimate the progression-free survival (PFS) after TEDDI-R or TEDD-R in secondary CNS lymphoma (sCNSL) Eligibility: * Aggressive B-cell lymphomas with secondary involvement of the CNS (sCNSL) * Relapsed/refractory from prior therapy or untreated with CNS involvement * Age greater than or equal to 18 years * No pregnant or nursing women * Adequate organ function (defined in protocol) Design: * Phase II study of 58 evaluable participants with untreated and relapsed/refractory sCNSL (accrual ceiling will be set at 61 to allow for a few possible inevaluable participants) * Participants will first be treated with a 14-day "window" of ibrutinib monotherapy in combination with isavuconazole to establish efficacy of ibrutinib. Participants who are known refractory to BTK inhibitors will skip the 14-day and proceed on to chemotherapy. * Following the 14-day ibrutinib window, participants with at least a 20% reduction in bidimensional masses on imaging scans or those without measurable disease will receive ibrutinib with TEDD-R (TEDDI-R) chemotherapy for 4 cycles. Participants who are previously known to be refractory to BTK inhibitors and those who have less than a 20% reduction during the ibrutinib window will receive TEDD-R (without ibrutinib) for 4 cycles.