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

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.

Conditions

• Primary Central Nervous System Lymphoma

Interventions

DRUG

Isavuconazole

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

DRUG

TEDDI

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)

BIOLOGICAL

Rituximab

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

DRUG

Cytarabine

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

DRUG

TEDD

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

DRUG

Ibrutinib (Arms 2, 3 and 4)

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

DRUG

Methotrexate

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

DRUG

Ibrutinib (Arm 1 - Closed with Amendment G)

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

DRUG

Ibrutinib (Arm 4)

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

Sponsors & Collaborators

• National Cancer Institute (NCI)

  lead NIH

Principal Investigators

• Rahul Lakhotia, M.D. · National Cancer Institute (NCI)

Study Design

Allocation

NA

Purpose

TREATMENT

Masking

NONE

Model

SEQUENTIAL

Eligibility

Min Age

18 Years

Max Age

120 Years

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2014-08-14

Primary Completion

2026-09-01

Completion

2027-12-01

FDA Drug

Yes

Countries

• United States

Study Locations