Inclusion Criteria:
Arm 1:
* Supratentorial unmethylated MGMT glioblastoma
* Gadolinium MRI or contrast CT within 28 days of starting treatment
* Karnofsky performance ≥ 70% (http://www.npcrc.org/files/news/karnofsky\_performance\_scale.pdf)
* Absolute neutrophil count \> 1500/mm3, platelets \> 100,000/mm3, Creatinine ≤ 1.7 mg/dl, total bilirubin ≤ 1.5mg/dl, transaminases ≤ 3 times above the upper limits of normal
* Must be able to provide written informed consent
* Patients of reproductive potential must use an acceptable form of birth control to avoid contraception during the period of therapy and up to 90 days after the last dose of study drug. (eg. implants, injectable, oral contraceptives, intrauterine device (IUD), abstinence, and a barrier method which includes, but is not limited to condoms, vaginal rings, and sponges)
* Female patients must have a negative pregnancy test upon study entry.
* No concurrent malignancy with the exception of curatively treated early stage bladder and prostate cancer, basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix and breast, adequately treated stage I or II cancer from which the patient is in complete remission. Any other prior malignancies must be disease free for ≥ 3 years.
* Prothrombin time (PT) / international normalized ratio (INR) \< 1.5 x upper limit of normal (ULN) and partial thromboplastin time (PTT) (aPTT) \< 1.5 x ULN
* Patient with any surgery more than stereotactic biopsy are eligible so that there is enough tissue for MGMT analysis.
Arm 2:
* Arm 1 inclusion criteria must be met with the exception of the histology of the cancer, which must be methylated MGMT glioblastoma
Exclusion Criteria:
* Serious concurrent infection or illness
* Patients who are pregnant or breastfeeding
* Patients receiving concurrent therapy for their tumor
* Concurrent or prior malignancy unless curatively treated carcinoma-in-situ or basal cell carcinoma of the skin.
* Repeat craniotomy for tumor therapy after receiving radiation and TMZ treatment.
* Patients who received other chemotherapy or investigational agents in addition to radiation therapy and accompanying TMZ treatment.
* Previous ibrutinib or other Bruton's tyrosine kinase (BTK) inhibitor use or allergies to components of the study drug.
* Use of anticoagulants (including warfarin, other coumadin-derivative anticoagulant, vitamin K antagonists, or low molecular weight heparin)
* Use of drugs known to be moderate and strong inhibitor or inducers of the P450 isoenzyme CYP3A. Participants must be off P450/CYP3A inhibitors and inducers for at least a week prior to starting the study drug.
* Active, significant liver impairment (Child-Pugh class B or C)
* Patient is using systemic immunosuppressant therapy, including cyclosporineA, tacrolimus, sirolimus, and other such medications, or chronic administration of \> 5 mg/day or prednisone or the equivalent.Participants must be off of immunosuppressant therapy for at least 21days prior to the first dose of the study drug. Patients can be on steroids for brain edema.
* Significant EKG abnormalities and active and significant cardiovascular disease within 6 months of screening.
* Pregnant or breastfeeding women. Male patients that intend to father a child while enrolled or 90 days after the last dose of the study drug.
* Unwillingness to comply with the protocol
* Uncontrolled, active systemic infection.
* Major surgery within 4 weeks of first dose of study drug.
* Vaccinated with live, attenuated vaccines within 4 weeks of first dose of study drug.
* Recent infection requiring systemic treatment that was completed ≤ 14 days before the first dose of study drug.
* Known bleeding disorders
