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Temozolomide, etoposide, doxil, dexamethasone, and rituximab without ibrutinib (TEDD-R) or TEDD-R with ibrutinib (TEDDI-R), concurrent with cytarabine and isavuconazole, based upon response to 14-day ibrutinib window

Temozolomide, etoposide, doxil, dexamethasone, and rituximab without ibrutinib (TEDD-R) or TEDD-R with ibrutinib Days 1-10 (TEDDI-R), concurrent with cytarabine and isavuconazole, based upon response to 14-day ibrutinib window

Temozolomide, etoposide, doxil, dexamthasone, and rituximab (TEDD-R) given every 21 days for cycles 1-4

TEDD-R

Temozolomide, etoposide, doxil, dexamthasone, ibrutinib and rituximab (TEDDI-R) given every 21 days for cycles 1-4

TEDDI-R

For Arm 1:Ibrutinib given on days -14 to day -1 prior to cycle 1;then given every 21 days for cycles 1-4 For Arm 2: Ibrutinib given on days -14 to day -1 prior to cycle 1; then on days 1-10 for cycles 1-4

Cytarabine on days 1 and day 5 of cycles 2-5 (all arms), as applicable

Isavuconazole to begin at least 3 days prior to ibrutinib and continue throughout chemotherapy unless ibrutinib discontinued permanently

Methotrexate on days 1 and day 5 of cycles 2-5 (all arms), as applicable

Mark J Roschewski, M.D.

Background:

Secondary central nervous system lymphoma (sCNSL) is cancer that has spread to the central nervous system. Most drugs used to treat it do not cross the blood-brain barrier. This makes it hard to treat. Researchers hope that a new combination of drugs may be able to help.

Objective:

To find a better way to treat sCNSL.

Eligibility:

People ages 18 and older with sCNSL

Design:

Participants will be screened with:

* Medical history
* Physical exam
* Blood, urine, and heart tests
* Eye exam
* Tissue or tumor biopsy
* Collection of cerebrospinal fluid
* CT, PET, and MRI scans: Participants will like in a machine that takes pictures of the body.
* Bone marrow aspirations or biopsies: A needle will be inserted into the participant s hipbone. The needle will remove a small amount of marrow.

Participants will take the study drugs in 21-day cycles. They will take some drugs by mouth. They will take others through a catheter: A small tube will be inserted into a vein in the arm, neck, or chest. They may have drugs given through a catheter placed through the brain or injected into the spinal canal.

Participants will have regular visits during the study. These will include repeats of the screening test. They may also provide a saliva sample or have a cheek swab.

Participants will have up to 4 treatment cycles.

Participants will have a follow-up visit 30 days after their last treatment dose. Then they will have visits every 3-6 months for 3 years and then yearly....

Background:

* Aggressive B-cell lymphomas with secondary involvement of the CNS (sCNSL) have a grave prognosis
* No standard of care exists for sCNSL; treatment approaches include combination chemotherapy regimens effective in primary CNS lymphoma (PCNSL)
* Ibrutinib is an inhibitor of Bruton s tyrosine kinase (BTK) and has demonstrated a high response rate in PCNSL and sCNSL but with short response duration
* We developed a novel regimen that combines ibrutinib with a chemoimmunotherapy platform maximized for CNS penetrance that includes temozolomide, etoposide, Doxil, dexamethasone, and rituximab (TEDDI-R) for aggressive B-cell lymphomas in the CNS
* A phase 1 study of TEDDI-R demonstrated durable remissions in refractory PCNSL
* We propose a small phase 2 to study the safety and efficacy of TEDDI-R in sCNSL

Objective:

-To estimate the progression-free survival (PFS) after TEDDI-R or TEDD-R in secondary CNS lymphoma (sCNSL)

Eligibility:

* Aggressive B-cell lymphomas with secondary involvement of the CNS (sCNSL)
* Relapsed/refractory from prior therapy or untreated with CNS involvement
* Age greater than or equal to 18 years
* No pregnant or breast-feeding women.
* Adequate organ function (defined in protocol)

Design:

* Phase II study of 58 evaluable participants with untreated and relapsed/refractory sCNSL (accrual ceiling will be set at 65 to allow for a few possible inevaluable participants and screen fails)
* Participants will first be treated with a 14-day "window" of ibrutinib monotherapy in combination with isavuconazole to establish efficacy of ibrutinib. Participants who are known refractory to BTK inhibitors will skip the 14-day and proceed on to chemotherapy.
* Following the 14-day ibrutinib window, participants with at least a 20% reduction in bidimensional masses on imaging scans or those without measurable disease will receive ibrutinib with TEDD-R (TEDDI-R) chemotherapy for 4 cycles. Participants who are previously known to be refractory to BTK inhibitors and those who have less than a 20% reduction during the ibrutinib window will receive TEDD-R (without ibrutinib) for 4 cycles.

Temozolomide, Etoposide, Doxil, Dexamethasone, Ibrutinib, and Rituximab (TEDDI-R) in Aggressive B-cell Lymphomas With Secondary Involvement of the Central Nervous System (CNS)

A Study of Temozolomide, Etoposide, Doxil, Dexamethasone, Ibrutinib, and Rituximab (TEDDI-R) in Aggressive B-cell Lymphomas With Secondary Involvement of the Central Nervous System (CNS)

.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.

time from study enrollment until disease progression or death from any cause by arm

the proportion of patients with adverse events leading to discontinuation of therapy

proportion of patients who achieve at least a partial response (PR) to therapy

time from first documentation of tumor response to disease progression

time from study enrollment until disease progression or death from any cause

time from study enrollment until death from any cause

the proportion of patients with adverse events leading to discontinuation of therapy between arms

National Cancer Institute (NCI)

Antineoplastic Agents, Immunological

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.

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

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Temozolomide, Etoposide, Doxil, Dexamethasone, Ibrutinib, and Rituximab (TEDDI-R) in Aggressive B-cell Lymphomas With Secondary Involvement of the Central Nervous System (CNS)	NCT03964090	Central Nervous... Secondary Centr...	TEDD-R TEDDI-R Ibrutinib Cytarabine Isavuconazole Methotrexate	18 Years -	National Institutes of Health Clinical Center (CC)
Phase 1 Study of Ibrutinib and Immuno-Chemotherapy Using Temozolomide, Etoposide, Doxil, Dexamethasone, Ibrutinib,Rituximab (TEDDI-R) in Primary CNS Lymphoma	NCT02203526	Primary Central...	Isavuconazole TEDDI Rituximab Cytarabine TEDD Ibrutinib (Arms... Methotrexate Ibrutinib (Arm ... Ibrutinib (Arm ...	18 Years -	National Institutes of Health Clinical Center (CC)
Temozolomide, Etoposide, Doxil, Dexamethasone, Ibrutinib, and Rituximab (TEDDI-R) in Aggressive B-cell Lymphomas With Secondary Involvement of the Central Nervous System (CNS)	NCT03964090	Central Nervous... Secondary Centr...	TEDD-R TEDDI-R Ibrutinib Cytarabine Isavuconazole Methotrexate	18 Years -	National Institutes of Health Clinical Center (CC)

Spots Global Cancer Trial Database for lymphoma in brain and cns