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

  • STATUS
    Recruiting
  • End date
    Jun 15, 2023
  • participants needed
    93
  • sponsor
    National Cancer Institute (NCI)
Updated on 20 January 2022
platelet count
cancer
methotrexate
cytarabine
rituximab
ejection fraction
serum pregnancy test
anticoagulants
growth factor
oophorectomy
etoposide
dexamethasone
neutrophil count
aptt
diffuse large b-cell lymphoma
b-cell lymphoma
temozolomide
nervous
ibrutinib
isavuconazole

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.

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 (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.

Details
Condition Primary Central Nervous System Lymphoma
Treatment Rituximab, methotrexate, cytarabine, Ibrutinib, Isavuconazole, TEDDI, TEDD, Rituximab (R), Ibrutinib - (Arm 1 - Closed with Amendment G), Ibrutinib (Arms 2 and 3), Ibrutinib (Arm 1 - Closed with Amendment G), Ibrutinib (Arm 4)
Clinical Study IdentifierNCT02203526
SponsorNational Cancer Institute (NCI)
Last Modified on20 January 2022

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