Trials Today

Condition

• Primary Central Nervous System Lymphoma

Eligibility

Eligible Ages

Between 18 Years and 120 Years

Eligible Sex

All

Accepts Healthy Volunteers

No

Criteria

- ELIGIBILITY CRITERIA:

- Patients must have histologically or cytologically confirmed primary central nervous
system diffuse large B-cell lymphoma. Patients with PCNSL that is only extracranial
will not be eligible. Patients with relapsed or refractory disease, as well as
untreated patients,

are eligible. Untreated patients must not have high dose chemotherapy and autologous stem
cell transplantation (ASCT) planned as part of frontline therapy to be eligible for the
trial.

- At least 2 weeks have passed since prior chemotherapy, biological therapy, radiation
therapy, other investigational or anti-cancer therapy that is considered
disease-directed.

- Ibrutinib must be discontinued 7 days before (when possible) until 7 days after
major surgery, and 3 days before (when possible) until 3 days after minor surgery.
Thus, patients to be enrolled on an ibrutinib trial must have completed major
surgery >= 7 days before initiating treatment, and/or must have completed minor
surgery >= 3 days before initiating treatment.

- Recovered from prior toxicities to Grade 0-1 at least 2 weeks prior to
investigational therapy.

- Age >=18 years. Because no dosing or adverse event data are currently available on
the use of ibrutinib and TEDDI-R in patients <18 years of age, children are excluded
from this study, but may be eligible for future pediatric trials.

- ECOG performance status <=2 (Karnofsky >=60%) unless due to neurologic deficits
caused by CNS lymphoma with the following exceptions: patients with ECOG PS = 4
where neurologic deficits are unlikely to resolve with tumor resolution and may
cause clinical management problems are excluded.

- Patients must have normal organ and marrow function as defined below, independent of
growth factor or transfusion support. Patients should not receive growth factors or
transfusions for at least 7 days prior to first dose of study drug with the
exception of pegylated G-CSF (pegfilgrastim) and darbepoeitin which require at least
14 days prior to screening and randomization.

- absolute neutrophil count >= 750 cells/mcL (0.75 x 10(9)/L)

- platelet count >= 50,000 cells/mcL (50 X 10(9)/L)

- Hemoglobin > 8.0 g/dL

- total bilirubin <=1.5 x ULN (unless Gilbert's syndrome or disease infiltration
of the liver is present)

- AST(SGOT)/ALT(SGPT) <= 3.0 x institutional ULN

- Serum Creatinine <= 1.5 mg/dL OR creatinine clearance >= 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 elevated because of a positive Lupus Anticoagulant.

- Left ventricular ejection fraction (LVEF) > 40% as assessed by echocardiogram

- The effects of ibrutinib on the developing human fetus are unknown. For this reason
and because tyrosine kinase inhibitors as well as other therapeutic agents used in
this trial may be teratogenic, individuals of reproductive potential and individuals
who can father children must agree to use adequate contraception (hormonal or
barrier method of birth control; abstinence) prior to study entry.

- Female patients who are of non-reproductive potential (i.e., post-menopausal by
history - no menses for >=1 year; OR history of hysterectomy; OR history of
bilateral tubal ligation; OR history of bilateral oophorectomy). Female patients of
childbearing potential must have a negative serum pregnancy test upon study entry.

- Male and female patients must agree to use highly effective methods of birth
control. A "highly effective method of birth control" is defined as a method that
has a low failure rate (i.e., less than 1% per year) when used consistently and
correctly and includes implants, injectables, birth control pills with two hormones,
some intrauterine devices (IUDs). Male subject cannot use highly effective methods
and are required to use barrier. The specific guidelines are as follows:

- Individuals that bear children, must use a highly effective method of birth
control and a barrier method, or sexual abstinence (which is defined as
refraining from all aspects of sexual activity), while taking study treatment,
as well as for 12 months after the last dose of rituximab.

- Individuals who can father children must use a barrier method while on
treatment with ibrutinib and for 3 months after the last dose of treatment to
prevent pregnancy of your partner. Such individuals should donate sperm while
you are taking the study drug and for 12 months after the last dose of
rituximab.

- Patient or appointed surrogate decision-maker or legally authorized representative
must have ability to understand the purpose and risks of the study and willingness
to provide a signed and dated informed consent form (ICF) and authorization to use
protected health information (in accordance with national and local subject privacy
regulations).

EXCLUSION CRITERIA:

- 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.

- 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 <=1, 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 (>= moderate hepatic
impairment according to the NCI/Child Pugh classification)

Study Contact

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) - 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 nursing individuals. - 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: 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. - 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. - 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.