RECRUITING

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

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Study Overview

This clinical trial focuses on testing the efficacy of different digital interventions to promote re-engagement in cancer-related long-term follow-up care for adolescent and young adult (AYA) survivors of childhood cancer.

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 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.

Official Title

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

Quick Facts

Study Start:2014-08-14

Study Completion:2027-06-15

Study Type:Not specified

Phase:Not Applicable

Enrollment:Not specified

Status:RECRUITING

Study ID

NCT02203526

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Ages Eligible for Study:18 Years to 120 Years

Sexes Eligible for Study:ALL

Accepts Healthy Volunteers:No

Standard Ages:ADULT, OLDER_ADULT

Inclusion Criteria	Exclusion Criteria
Age 18 years or older Willing and able to provide informed consent Able to understand and follow study procedures Stable medical condition	* 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 greater than 14 days before the first dose of study drug. * Pregnant and breastfeeding 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, breastfeeding 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. * 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. * Serologic status reflecting active hepatitis B or C infection. Patients that are positive for hepatitis B core antibody, hepatitis B surface antigen (HBsAg), or hepatitis C antibody must have a negative polymerase chain reaction (PCR) prior to enrollment. Those who are PCR positive will be excluded. Those with a negative PCR for hepatitis B will be treated with antivirals designed to prevent hepatitis B reactivation (e.g., entecavir) and have monitoring for hepatitis B reactivation with PCR. * History of stroke or intracranial hemorrhage within 6 months prior to enrollment. * Any life-threatening illness, medical condition, or organ system dysfunction that, in the Investigator s opinion, could compromise the patient s safety, or put the study at undue risk. Patients with suspicious radiologic evidence of aspergillosis infection (i.e., Chest CT and/or Brain MRI) will not be eligible unless confirmatory laboratory testing of Beta-D glucan and aspergillus antigen are negative. * Concomitant use of warfarin or other vitamin K antagonists within the last 7 days. * Concurrent systemic immunosuppressant therapy other than corticosteroids (e.g., cyclosporine A, tacrolimus, etc.) within 28 days of the first dose of study drug. * Vaccinated with live, attenuated vaccines within 4 weeks of first dose of study drug. * Unresolved toxicities from prior anti-cancer therapy, defined as having not resolved to grade less than or equal to1, or to the levels dictated in the inclusion/exclusion criteria with the exception of alopecia. * Known bleeding disorders (e.g., von Willebrand s disease) or hemophilia. * Major surgery within 7 days of first dose of study drug. * Unwilling or unable to participate in all required study evaluations and procedures. * Currently active, clinically significant hepatic impairment (greater than or equal to moderate hepatic impairment according to the NCI/Child Pugh classification.

Inclusion Criteria

Exclusion Criteria

Age 18 years or older
Willing and able to provide informed consent
Able to understand and follow study procedures
Stable medical condition

* 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 greater than 14 days before the first dose of study drug.
* Pregnant and breastfeeding 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, breastfeeding 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.
* 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.
* Serologic status reflecting active hepatitis B or C infection. Patients that are positive for hepatitis B core antibody, hepatitis B surface antigen (HBsAg), or hepatitis C antibody must have a negative polymerase chain reaction (PCR) prior to enrollment. Those who are PCR positive will be excluded. Those with a negative PCR for hepatitis B will be treated with antivirals designed to prevent hepatitis B reactivation (e.g., entecavir) and have monitoring for hepatitis B reactivation with PCR.
* History of stroke or intracranial hemorrhage within 6 months prior to enrollment.
* Any life-threatening illness, medical condition, or organ system dysfunction that, in the Investigator s opinion, could compromise the patient s safety, or put the study at undue risk. Patients with suspicious radiologic evidence of aspergillosis infection (i.e., Chest CT and/or Brain MRI) will not be eligible unless confirmatory laboratory testing of Beta-D glucan and aspergillus antigen are negative.
* Concomitant use of warfarin or other vitamin K antagonists within the last 7 days.
* Concurrent systemic immunosuppressant therapy other than corticosteroids (e.g., cyclosporine A, tacrolimus, etc.) within 28 days of the first dose of study drug.
* Vaccinated with live, attenuated vaccines within 4 weeks of first dose of study drug.
* Unresolved toxicities from prior anti-cancer therapy, defined as having not resolved to grade less than or equal to1, or to the levels dictated in the inclusion/exclusion criteria with the exception of alopecia.
* Known bleeding disorders (e.g., von Willebrand s disease) or hemophilia.
* Major surgery within 7 days of first dose of study drug.
* Unwilling or unable to participate in all required study evaluations and procedures.
* Currently active, clinically significant hepatic impairment (greater than or equal to moderate hepatic impairment according to the NCI/Child Pugh classification.

Contacts and Locations

Study Contact

Kimberly A Johnson, R.N.

CONTACT

(240) 271-8477

kim.johnson@nih.gov

Mark J Roschewski, M.D.

CONTACT

(240) 760-6183

mark.roschewski@nih.gov

Principal Investigator

Mark J Roschewski, M.D.

PRINCIPAL_INVESTIGATOR

National Cancer Institute (NCI)

Study Locations (Sites)

National Institutes of Health Clinical Center

Bethesda, Maryland, 20892

United States

Collaborators and Investigators

Sponsor: National Cancer Institute (NCI)

Mark J Roschewski, M.D., PRINCIPAL_INVESTIGATOR, National Cancer Institute (NCI)

Study Record Dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Registration Dates

Study Start Date2014-08-14

Study Completion Date2027-06-15

Study Record Updates

Study Start Date2014-08-14

Study Completion Date2027-06-15

Terms related to this study

Keywords Provided by Researchers

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

Additional Relevant MeSH Terms

Primary Central Nervous System Lymphoma