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TEDD-R (cycle 1) with ibrutinib; TEDDI-R with cytarabine (cycles 2-6)

TEDDI-R with cytarabine, and isavuconazole

TEDDI-R with cytarabine and isavuconazole

TEDDI-R, cytarabine or methotrexate, isavuconazole, ibrutinib for 10 days

Isavuconazole to begin at least 3 days prior to ibrutinib and continue throughout chemotherapy (cycles 1-6)

Temozolomide, etoposide, doxil, dexamthasone, ibrutinib (TEDDI) given every 21 days for cycles 2-6 (Arm 1-A); given every 21 days for cycles 1-6 (Arms 1-B, 2, 3 and 4)

TEDDI

Rituximab (R) given with TEDD and TEDDI every 3 weeks for cycles 1-6 (all arms)

Cytarabine given via Ommaya reservoir (IT therapy) on days 1 and day 5 of cycles 2-6 (all arms)

Temozolomide, etoposide, doxil, dexamthasone, (TEDD) given on first cycle (Arm 1-A)

TEDD

Ibrutinib given on day -3 to day -1 on cycle 1 (Arms 2, 3 and 4)

Ibrutinib (Arms 2, 3 and 4)

Methotrexate on days 1 and day 5 of cycles 2-6 (Arm 4)

Ibrutinib given on day -14 to day -1 on cycle 1 (Arm 1)

Ibrutinib (Arm 1 - Closed with Amendment G)

Ibrutinib given on days 1-10 for cycles 1-6 (Arm 4)

Ibrutinib (Arm 4)

Kimberly A Johnson, R.N.

Mark J Roschewski, M.D.

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.

  1. 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.
  2. 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.

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 with 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 or untreated 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.
  * Revised Study Design: Effective with Amendment G (version date: 7/31/2017), new ibrutinib dose levels are being added together with anti-fungal prophylaxis to determine the dose of ibrutinib that may 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.

Phase 1 Study of Ibrutinib and Immuno-Chemotherapy Using Temozolomide, Etoposide, Doxil, Dexamethasone, Ibrutinib,Rituximab (TEDDI-R) in Primary CNS Lymphoma

Phase 1 Study of Ibrutinib and Immuno-Chemotherapy Using Temozolomide, Etoposide, Doxil, Dexamethasone, Ibrutinib, Rituximab (TEDDI-R) in Primary CNS Lymphoma

.All IPD recorded in the medical record will be shared with intramural investigators upon request. @@@@@@In addition, all large scale genomic sequencing data will be shared with subscribers to dbGaP. @@@@@@All collected IPD will be shared with collaborators under the terms of collaborative agreements.

Incidence of adverse events (i.e., grade and frequency)

The response rate will be determined and reported along with a 95% confidence interval

Spots Global Cancer Trial Database for ibrutinib (arms 2, 3 and 4)