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|NCT02203526 : Phase 1 Study of Ibrutinib and Immuno-Chemotherapy Using Dose-Adjusted-Temozolomide, Etoposide, Doxil, Dexamethasone, Ibrutinib,Rituximab (DA-TEDDI-R) in Primary CNS Lymphoma|
|Ages||Min: 18 Years Max: 100 Years|
- ELIGIBILITY CRITERIA:
- Patients must have histologically or cytologically confirmed primary central nervous
system diffuse large B-cell lymphoma. Only patients with relapsed or refractory
disease are eligible. Patients with PCNSL that is only extracranial will not be
- At least 2 weeks have passed since prior chemotherapy, biological therapy, radiation
therapy, major surgery, other investigational or anti-cancer therapy that is
- 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
- Men and women age greater than or equal to 18 years.
- ECOG performance status less than or equal to 2(Karnofsky greater than or equal to
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 darbopoeitin which require at least 14 days
prior to screening and randomization.
- absolute neutrophil count greater than or equal to750 cells/mcL (0.75 x 10(9)/L)
- platelet count greater than or equal to 50,000 cells/mcL (50 X 10(9)/L)
- hemoglobin greater than 8.0 g/dL
- total bilirubin less than or equal to1.5 times ULN (unless Gilbert s syndrome or
disease infiltration of the liver is present)
- AST(SGOT)/ALT(SGPT) less than or equal to 3.0 times institutional ULN
- Serum Creatinine less than or equal to 1.5 mg/dL or creatinine clearance > 40
ml/min/1.73m2 unless lymphoma related.
- Prothrombin time/INR (PT) and activated partial thromboplastin time (aPTT) must be
less than or equal to 1.5 times 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
- Left ventricular ejection fraction (LVEF) > 40% as assessed by echocardiogram or MUGA
- 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, women of non-reproductive potential and men 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 greater than or equal to 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
- Male and female patients whomust agree to use highly effective methods of birth
control (e.g., condoms, implants, injectables, combined oral contraceptives, some
intrauterine devices [IUDs], complete sexual abstinence, or sterilized partner) during
the period of therapy and for 90 days after the last dose of study drug.
- 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
- Chemotherapy less than or equal to 21 days prior to first administration of study
treatment and/or monoclonal antibody less than or equal to 6 weeks prior to first
administration of study treatment.
- 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 micafungin and/or voriconazole or any of their
- Patients who received a strong cytochrome P450 (CYP) 3A inhibitor within 7 days prior
to the first dose of ibrutinib or patients who require continuous treatment with a
strong CYP3A inhibitor with the exception of voriconazole, which will 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 such as; 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.
- Systemic cytotoxic therapy within 2 weeks of treatment.
- 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
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
- 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. (PCR positive patients will be excluded.)
- 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 28 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 Common Terminology Criteria for Adverse Event (CTCAE, version 4), 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 4 weeks of first dose of study drug.
- Unwilling or unable to participate in all required study evaluations and procedures.
- Currently active, clinically significant hepatic impairment ( (Bullet) moderate
hepatic impairment according to the NCI/Child Pugh classification.
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