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

NCT02203526 | Active Not Recruiting Phase 1 FDA Drug

• 2 other identifiers: 14015714-C-0157
• Study Type: interventional
• Target: 68
• Locations: 1 country
• Sites: 1

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.
• 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.
• 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

Keywords

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

Outcome Measures

Primary Outcomes (4)

• safety and feasibility in untreated PCNSL patients

  Incidence of adverse events (i.e., grade and frequency)

  Initiation of ibrutinib until 30 days after treatment

• MTD of ibrutinib with anti-fungal prophylaxis when given with TEDD-R

  AEs will be tabulated and reported

  after one cycle

• MTD of ibrutinib when given with TEDD-R

  AEs will be tabulated and reported

  after one cycle

• Complete Response rate in untreated PCNSL patients

  The response rate will be determined and reported along with a 95% confidence interval

  every 3 months for 1 year, every 4 months year 2, every 6 months year 3 then yearly

Secondary Outcomes (3)

• Safety and Tolerability

  Initiation of ibrutinib until 30 days after treatment

• Progression-free survival

  every 3 months for 1 year, every 4 months year 2, every 6 months year 3 then yearly

• Overall survival

  every 3 months for 1 year, every 4 months year 2, every 6 months year 3 then yearly

Study Arms (5)

Arm 1-A (original study design - prior to Amendment G)

EXPERIMENTAL

TEDD-R (cycle 1) with ibrutinib; TEDDI-R with cytarabine (cycles 2-6)

Drug: TEDDI; Biological: Rituximab; Drug: Cytarabine; Drug: TEDD; Drug: Ibrutinib (Arms 2, 3 and 4); Drug: Ibrutinib (Arm 1 - Closed with Amendment G); Drug: Ibrutinib (Arm 4)

Arm 1-B (original study design-prior to Amendment G)

EXPERIMENTAL

TEDDI-R with cytarabine

Drug: TEDDI; Biological: Rituximab; Drug: Cytarabine

Arm 2 (Dose Escalation; prior to Amendment 06/04/2021)

EXPERIMENTAL

TEDDI-R with cytarabine, and isavuconazole

Drug: Isavuconazole; Drug: TEDDI; Biological: Rituximab; Drug: Cytarabine

Arm 3 (Dose Expansion; prior to Amendment 06/04/2021)

EXPERIMENTAL

TEDDI-R with cytarabine and isavuconazole

Drug: Isavuconazole; Drug: TEDDI; Biological: Rituximab; Drug: Cytarabine

Arm 4 (Dose Expansion; Amendment 06/04/21)

EXPERIMENTAL

TEDDI-R, cytarabine or methotrexate, isavuconazole, ibrutinib for 10 days

Drug: Isavuconazole; Drug: TEDDI; Biological: Rituximab; Drug: Cytarabine; Drug: Methotrexate; Drug: Ibrutinib (Arm 4)

Interventions

TEDD DRUG

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

Arm 1-A (original study design - prior to Amendment G)

Ibrutinib (Arms 2, 3 and 4) DRUG

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

Arm 1-A (original study design - prior to Amendment G)

Methotrexate DRUG

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

Arm 4 (Dose Expansion; Amendment 06/04/21)

Isavuconazole DRUG

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

Arm 2 (Dose Escalation; prior to Amendment 06/04/2021); Arm 3 (Dose Expansion; prior to Amendment 06/04/2021); Arm 4 (Dose Expansion; Amendment 06/04/21)

TEDDI DRUG

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)

Arm 1-A (original study design - prior to Amendment G); Arm 1-B (original study design-prior to Amendment G); Arm 2 (Dose Escalation; prior to Amendment 06/04/2021); Arm 3 (Dose Expansion; prior to Amendment 06/04/2021); Arm 4 (Dose Expansion; Amendment 06/04/21)

Rituximab BIOLOGICAL

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

Arm 1-A (original study design - prior to Amendment G); Arm 1-B (original study design-prior to Amendment G); Arm 2 (Dose Escalation; prior to Amendment 06/04/2021); Arm 3 (Dose Expansion; prior to Amendment 06/04/2021); Arm 4 (Dose Expansion; Amendment 06/04/21)

Cytarabine DRUG

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

Arm 1-A (original study design - prior to Amendment G); Arm 1-B (original study design-prior to Amendment G); Arm 2 (Dose Escalation; prior to Amendment 06/04/2021); Arm 3 (Dose Expansion; prior to Amendment 06/04/2021); Arm 4 (Dose Expansion; Amendment 06/04/21)

Ibrutinib (Arm 1 - Closed with Amendment G) DRUG

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

Arm 1-A (original study design - prior to Amendment G)

Ibrutinib (Arm 4) DRUG

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

Arm 1-A (original study design - prior to Amendment G); Arm 4 (Dose Expansion; Amendment 06/04/21)

Eligibility Criteria

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

You may not qualify if:

• Prior exposure to a BTK inhibitor.
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to ibrutinib or other agents used in study.
• Patients who are allergic to isavuconazole or any of its ingredients.
• Patients 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 patients 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).
• 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 patient 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 patient is considering a new over-the-counter medicine or herbal product.
• HIV positive patients 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 individuals are excluded from this study. Pregnant individuals 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 with a nursing participant ibrutinib, nursing should be discontinued if the mother is treated with ibrutinib.
• Uncontrolled Autoimmune Hemolytic Anemia or ITP resulting in (or as evidenced by) declining platelet or Hgb levels within the 4 weeks prior to first dose of study drug.
• 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 3 years prior to Screening and felt to be at low risk for recurrence by treating physician
• Adequately treated non-melanomatous skin cancer or lentigo maligna 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.

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

isavuconazole; Rituximab; Cytarabine; ibrutinib; Methotrexate

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Murine-Derived; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; 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 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 29, 2014
• First Posted: July 30, 2014
• Study Start: August 14, 2014
• Primary Completion (Estimated): September 1, 2026
• Study Completion (Estimated): December 1, 2027
• Last Updated: April 27, 2026

Record last verified: 2026-04-17

Data Sharing

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

Locations

US (1)