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

NCT03964090 | Active Not Recruiting Phase 2 FDA Drug

• 2 other identifiers: 19010319-C-0103
• Study Type: interventional
• Target: 48
• Locations: 1 country
• Sites: 1

Brief Summary

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....

Conditions

Central Nervous System Lymphoma; Secondary Central Nervous System Lymphoma

Keywords

Tyrosine Kinase Inhibitor; Lymphoma in Brain and CNS; ABC DLBCL; Diffuse Large B-Cell Lymphomas in CNS

Outcome Measures

Primary Outcomes (1)

• Progression-free survival (PFS)

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

  every 3-6 months

Secondary Outcomes (7)

• Safety and tolerability of TEDDI-R and TEDD-R in sCNSL

  ongoing

• Best overall response after 14 days of ibrutinib monotherapy in sCNSL; after up to 4 cycles of TEDDI-R; and, after up to 4 cycles of TEDD-R (no ibrutinib)

  after 14 days and 4 cycles

• Duration of response (DOR)

  every 2 cycles during treatment; every 3-6 months in follow-up

• Assessment of pharmacokinetics (PK) and safety of TEDDI-R with concomitant anti-fungal prophylaxis

  at least each cycle, up to cycle 4

• Overall survival (OS) to TEDDI-R and TEDD-R in sCNSL

  every 3-6 months

Study Arms (2)

1

EXPERIMENTAL

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

Drug: TEDD-R; Drug: TEDDI-R; Drug: Ibrutinib; Drug: Cytarabine; Drug: Isavuconazole

2

EXPERIMENTAL

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

Drug: TEDD-R; Drug: TEDDI-R; Drug: Ibrutinib; Drug: Cytarabine; Drug: Isavuconazole; Drug: Methotrexate

Interventions

TEDD-R DRUG

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

1; 2

TEDDI-R DRUG

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

1; 2

Ibrutinib DRUG

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

1; 2

Isavuconazole DRUG

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

1; 2

Methotrexate DRUG

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

2

Cytarabine DRUG

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

1; 2

Eligibility Criteria

• Age: 18 Years - 120 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Participants must have histologically or cytologically confirmed secondary involvement of an aggressive B-cell lymphoma in the CNS (eye, CSF, and/or brain parenchyma).
• NOTE: B-cell lymphomas that were previously indolent but now involve the CNS (i.e. transformed from previous follicular lymphoma or chronic lymphocytic leukemia and mantle cell lymphoma) are eligible.
• Participants must have disease that is relapsed or refractory after initial systemic treatment or participants without prior therapy for systemic DLBCL must have concomitant involvement of the eyes, CSF or brain parenchyma.
• Age greater than or equal to18 years. NOTE: Because no dosing or adverse event data are currently available on the use of ibrutinib and TEDDI-R in participants \<18 years of age, children are excluded from this study, but may be eligible for future pediatric trials.
• ECOG performance status less than or equal to 2 (Karnofsky greater than or equal to 60%) unless due to disease
• Participants must have adequate organ function as defined below, independent of growth factor or platelet transfusion support:
• Absolute neutrophil count (ANC): greater than or equal to 750 cells/mcL (0.75 (SqrRoot) 10\^9/L)
• Platelets: greater than or equal to 50,000 cells/mcL (50 (SqrRoot) 10\^9/L)
• Hemoglobin: greater than or equal to 8 g/dL (transfusions permitted)
• Serum total bilirubin: less than or equal to 1.5 X ULN unless Gilbert s syndrome or disease infiltration of the liver is present)
• AST (SGOT) and ALT (SGPT): less than or equal to 3.0 (SqrRoot) institutional ULN (less than or equal to 5 x ULN for participants with liver involvement by lymphoma)
• Serum creatinine: less than or equal to 1.5 mg/dL OR
• Creatinine clearance: greater than or equal to 40 ml/min/1.73m\^2 unless lymphoma related
• Prothrombin time/INR (PT) and activated partial thromboplastin time (aPTT) must be \< 1.5 x the upper limit of the normal range (ULN); except if, in the opinion of the Investigator, the aPTT is prolonged because of a positive Lupus Anticoagulant.
• Women of childbearing potential must have a negative pregnancy test upon study entry. This is not required for women who are of non-reproductive potential (i.e., post-menopausal by history - defined as: no menses for greater than or equal to 1 year; OR, history of hysterectomy; OR, history of bilateral tubal ligation; OR, history of bilateral oophorectomy).

You may not qualify if:

• Systemic chemotherapy less than or equal to 14 days prior to ibrutinib window study
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to ibrutinib or other agents used in study
• Participants who are allergic to isavuconazole or any of its ingredients
• Participants who received a strong cytochrome P450 (CYP) 3A inhibitor or inducer within 7 days prior to the first dose of protocol anti-fungal prophylaxis, or participants who require continuous treatment with a strong CYP3A inhibitor/inducer (i.e., with the exception of any medication to be specifically studied in this protocol).
• NOTE: In addition, because the lists of these agents are constantly changing, it is important to regularly consult a frequently-updated list; medical reference texts such as the Physicians Desk Reference may also provide this information. As part of the enrollment/informed consent procedures, the participant will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the participant is considering a new over-the-counter medicine or herbal product.
• HIV positive participants will be excluded because of their increased susceptibility to fungal infections which outweighs the potential benefit of participation.
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection or an infection requiring systemic antibiotics, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. Recent infections requiring systemic treatment need to have completed therapy \>14 days before the first dose of study drug.
• Pregnant and nursing women are excluded from this study. Pregnant women are excluded in this study because ibrutinib is a tyrosine kinase inhibitor with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with ibrutinib, nursing should be discontinued if the mother is treated with ibrutinib.
• Presence of transfusion-dependent thrombocytopenia.
• History of prior malignancy, with the exception of the following:
• Malignancy treated with curative intent and with no evidence of active disease present for more than 2 years prior to screening and felt to be at low risk for recurrence by treating physician
• Adequately treated non-melanomatous skin cancer or lentigo malignant melanoma without current evidence of disease
• Adequately treated carcinoma in situ without current evidence of disease.
• Currently active clinically significant cardiovascular disease such as uncontrolled arrhythmia, congestive heart failure, or Class 3 or 4 congestive heart failure as defined by the New York Heart Association Functional Classification, or history of myocardial infarction unstable angina, or acute coronary syndrome within 6 months prior to enrollment in the study.
• Unable to swallow capsules, or disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel, or symptomatic inflammatory bowel disease or ulcerative colitis, or partial or complete bowel obstruction.

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (1)

National Institutes of Health Clinical Center

Bethesda, Maryland, 20892, United States

Location

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Interventions

ibrutinib; Cytarabine; isavuconazole; Methotrexate

Intervention Hierarchy (Ancestors)

Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Arabinonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Aminopterin; Pterins; Pteridines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring

Study Officials

• Rahul Lakhotia, M.D.

  National Cancer Institute (NCI)

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 24, 2019
• First Posted: May 28, 2019
• Study Start: June 27, 2019
• Primary Completion (Estimated): July 1, 2027
• Study Completion (Estimated): July 1, 2028
• Last Updated: April 30, 2026

Record last verified: 2025-12-12

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• Time Frame: Clinical data available during the study and indefinitely. @@@@@@@@@@@@Genomic data are available once genomic data are uploaded per protocol GDS plan.
• Access Criteria: Clinical data will be made available via subscription to BTRIS and with the permission of the study PI. @@@@@@@@@@@@Genomic data are made available via dbGaP through requests to the data custodians.

Locations

US (1)