Background:~Primary CNS lymphoma (PCNSL) is a rare subtype of diffuse large B-cell lymphoma~The outcome for patients with this diagnosis is significantly worse than for that of systemic DLBCL.~Most treatment approaches in the past have included high dose methotrexate and radiation treatment.~Most PCNSLs appear to be of activated B-cell (ABC) origin~Ibrutinib is an inhibitor of Bruton s tyrosine kinase (BTK) and effective for systemic DLBCL of ABC origin.~We propose doing a study in which ibrutinib is combined with a novel chemotherapy platform called temozolomide, etoposide, doxil, dexamethasone, ibrutinib, rituximab (TEDDI-R).~Objective:~To identify the dose of ibrutinib (not to exceed 840 mg per dose) with voriconazole anti-fungal prophylaxis that can be safely administered to achieve an ibrutinib median CSF CMAX of 1.98 nM (Range 0.69 to 11.1)~Revised in Amendment M (version date: 11/03/2020): To assess the safety, feasibility, and complete response (CR) rate of the TEDDI-R in untreated PCNSL (DLBCL type) patients.~Eligibility:~Relapsed/refractory PCNSL~Age >= 18 years.~No pregnant or breast-feeding women.~Adequate organ function (defined in protocol).~Study Design:~This is a phase 1 study of 93 patients.~The study will have three components.~Phase 1: MTD of ibrutinib will be identified or the dose at which ibrutinib achieves a concentration of >= 100 nM in the CSF, when given in combination with TEDDI-R immuno-chemotherapy, whichever comes first.~Expansion cohort: Safety and tolerability of the regimen in relapsed/refractory PCNSL (DLBCL type) will be assessed at the final ibrutinib dose with TEDDI-R in 10 patients. Secondary objectives will be PFS and OS.~Cohorts Revised Study DesignA, B and C: Effective with Amendment G (version date: 7/31/2017), 3 new cohorts ibrutinib dose levels (A, B and C) are being added to provide together with anti-fungal prophylaxis and to determine the dose of ibrutinib that will be given with voriconazole at steady-state concentrationsmay be safely given with the chemotherapy platform.~Effective with Amendment M (version date: 11/03/2020), a second expansion cohort of untreated PCNSL (DLBCL type) will be added: Safety, feasibility, and complete response rate of the regimen in untreated PCNSL (DLBCL type) will be assessed at the final ibrutinib dose with TEDDI-R in 15 patients. Secondary objectives will be PFS and OS.~Effective with Amendment 06/04/2021, a new dosing schedule will be tested in up to 10 relapsed or refractory patients and 15 patients with untreated PCNSL. Secondary objectives will be PFS and OS.
BACKGROUND:~Primary CNS lymphoma (PCNSL) is a rare subtype of diffuse large B-cell lymphoma.~The outcome for patients with this diagnosis is significantly worse than for that of systemic DLBCL. Most treatment approaches in the past have included high dose methotrexate and radiation treatment.~Most PCNSLs appear to be of activated B-cell (ABC) origin.~Ibrutinib is an inhibitor of Bruton s tyrosine kinase (BTK) and effective for systemic DLBCL of ABC origin.~We propose doing a study in which ibrutinib is combined with a novel chemotherapy platform called dose adjusted temozolomide, etoposide, doxil, dexamethasone, ibrutinib, rituximab (TEDDI-R).~OBJECTIVE:~- Identify the maximum tolerated dose (MTD) of ibrutinib or the dose that achieves adequate CSF concentrations, whichever comes first, when ibrutinib is given with TEDDI-R.~ELIGIBILITY:~Relapsed/refractory PCNSL.~Age greater than or equal to 18 years.~No pregnant or breast-feeding women.~Adequate organ function (defined in protocol).~STUDY DESIGN:~This is a phase 1 study of 40 patients.~The study will have two components.~Phase 1: MTD of ibrutinib will be identified or the dose at which ibrutinib achieves a concentration of less than or equal to 100 nM in the CSF, when given in combination with TEDDI-R immuno-chemotherapy, whichever comes first.~Expansion cohort: Safety and tolerability of the regimen in relapsed/refractory or previously untreated PCNSL (DLBCL type) will be assessed at the final ibrutinib dose with TEDDI-R in 10 patients. Secondary objectives will be PFS and OS.