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

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 (DA-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).

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 52 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 less than or equal to 100 nM in the CSF, when given in
combination with DA-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 DATEDDI- R in
10 patients. Secondary objectives will be PFS and OS.

- Revised Study Design: Effective with Amendment G (version date: 7/31/2017), 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.

- 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
eligible.

- 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
greater than or equal to 7 days before initiating treatment, and/or must have
completed minor surgery greater than or equal to 3 days before initiating treatment.

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

- 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 to 750 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 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
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
Anticoagulant.

- 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
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:

- Women: If you can have children, you 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 90 days.

- Men: You 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. You
should not donate sperm while you are taking the study drug and for 3 months
after you stop taking the 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
regulations).

EXCLUSION CRITERIA:

- 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 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 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
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. (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 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.