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

Primary Central Nervous System Lymphoma Clinical Trial

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

Status Recruiting

Clinical Trial Summary

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.

Clinical Trial Description

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. ;

Related Conditions & MeSH terms

• Lymphoma
• Primary Central Nervous System Lymphoma

• NCT number: NCT02203526
• Study type: Interventional
• Source: National Institutes of Health Clinical Center (CC)
• Contact: Kimberly A Johnson, R.N.
• Phone: (240) 271-8477
• Email: kim.johnson@nih.gov
• Status: Recruiting
• Phase: Phase 1
• Start date: August 14, 2014
• Completion date: June 15, 2027