Phase 1 Study of Ibrutinib and Immuno-Chemotherapy Using Temozolomide, Etoposide, Doxil, Dexamethasone, Ibrutinib,Rituximab (TEDDI-R) in Primary CNS Lymphoma
- Conditions
- Primary Central Nervous System Lymphoma
- Interventions
- Registration Number
- NCT02203526
- Lead Sponsor
- National Cancer Institute (NCI)
- Brief 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.
- Detailed 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.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 93
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description Arm 1-A (original study design - prior to Amendment G) Ibrutinib (Arm 4) TEDD-R (cycle 1) with ibrutinib; TEDDI-R with cytarabine (cycles 2-6) Arm 1-A (original study design - prior to Amendment G) Ibrutinib (Arms 2, 3 and 4) TEDD-R (cycle 1) with ibrutinib; TEDDI-R with cytarabine (cycles 2-6) Arm 1-A (original study design - prior to Amendment G) Ibrutinib (Arm 1 - Closed with Amendment G) TEDD-R (cycle 1) with ibrutinib; TEDDI-R with cytarabine (cycles 2-6) Arm 4 (Dose Expansion; Amendment 06/04/21) Methotrexate TEDDI-R, cytarabine or methotrexate, isavuconazole, ibrutinib for 10 days Arm 1-A (original study design - prior to Amendment G) Cytarabine TEDD-R (cycle 1) with ibrutinib; TEDDI-R with cytarabine (cycles 2-6) Arm 1-A (original study design - prior to Amendment G) TEDD TEDD-R (cycle 1) with ibrutinib; TEDDI-R with cytarabine (cycles 2-6) Arm 4 (Dose Expansion; Amendment 06/04/21) TEDDI TEDDI-R, cytarabine or methotrexate, isavuconazole, ibrutinib for 10 days Arm 1-A (original study design - prior to Amendment G) TEDDI TEDD-R (cycle 1) with ibrutinib; TEDDI-R with cytarabine (cycles 2-6) Arm 1-B (original study design-prior to Amendment G) TEDDI TEDDI-R with cytarabine Arm 3 (Dose Expansion; prior to Amendment 06/04/2021) TEDDI TEDDI-R with cytarabine and isavuconazole Arm 4 (Dose Expansion; Amendment 06/04/21) Ibrutinib (Arm 4) TEDDI-R, cytarabine or methotrexate, isavuconazole, ibrutinib for 10 days Arm 2 (Dose Escalation; prior to Amendment 06/04/2021) TEDDI TEDDI-R with cytarabine, and isavuconazole Arm 1-A (original study design - prior to Amendment G) Rituximab TEDD-R (cycle 1) with ibrutinib; TEDDI-R with cytarabine (cycles 2-6) Arm 1-B (original study design-prior to Amendment G) Rituximab TEDDI-R with cytarabine Arm 2 (Dose Escalation; prior to Amendment 06/04/2021) Isavuconazole TEDDI-R with cytarabine, and isavuconazole Arm 1-B (original study design-prior to Amendment G) Cytarabine TEDDI-R with cytarabine Arm 2 (Dose Escalation; prior to Amendment 06/04/2021) Rituximab TEDDI-R with cytarabine, and isavuconazole Arm 2 (Dose Escalation; prior to Amendment 06/04/2021) Cytarabine TEDDI-R with cytarabine, and isavuconazole Arm 4 (Dose Expansion; Amendment 06/04/21) Cytarabine TEDDI-R, cytarabine or methotrexate, isavuconazole, ibrutinib for 10 days Arm 3 (Dose Expansion; prior to Amendment 06/04/2021) Isavuconazole TEDDI-R with cytarabine and isavuconazole Arm 3 (Dose Expansion; prior to Amendment 06/04/2021) Rituximab TEDDI-R with cytarabine and isavuconazole Arm 3 (Dose Expansion; prior to Amendment 06/04/2021) Cytarabine TEDDI-R with cytarabine and isavuconazole Arm 4 (Dose Expansion; Amendment 06/04/21) Isavuconazole TEDDI-R, cytarabine or methotrexate, isavuconazole, ibrutinib for 10 days Arm 4 (Dose Expansion; Amendment 06/04/21) Rituximab TEDDI-R, cytarabine or methotrexate, isavuconazole, ibrutinib for 10 days
- Primary Outcome Measures
Name Time Method safety and feasibility in untreated PCNSL patients Initiation of ibrutinib until 30 days after treatment Incidence of adverse events (i.e., grade and frequency)
MTD of ibrutinib with anti-fungal prophylaxis when given with TEDD-R after one cycle AEs will be tabulated and reported
MTD of ibrutinib when given with TEDD-R after one cycle AEs will be tabulated and reported
Complete Response rate in untreated PCNSL patients every 3 months for 1 year, every 4 months year 2, every 6 months year 3 then yearly The response rate will be determined and reported along with a 95% confidence interval
- Secondary Outcome Measures
Name Time Method Safety and Tolerability Initiation of ibrutinib until 30 days after treatment Incidence of adverse events (i.e., grade and frequency)
Progression-free survival every 3 months for 1 year, every 4 months year 2, every 6 months year 3 then yearly The response rate will be determined and reported along with a 95% confidence interval
Overall survival every 3 months for 1 year, every 4 months year 2, every 6 months year 3 then yearly The response rate will be determined and reported along with a 95% confidence interval
Trial Locations
- Locations (1)
National Institutes of Health Clinical Center
🇺🇸Bethesda, Maryland, United States