Radiation Therapy Plus Temozolomide and Pembrolizumab With and Without HSPPC-96 in Newly Diagnosed Glioblastoma (GBM)

* INCLUSION CRITERIA:

Pre-Surgery (Step 1) Inclusion:

* Magnetic resonance imaging (MRI) findings consistent with a suspected glioblastoma (GBM) or a histologically confirmed newly diagnosed GBM that has not been treated and would benefit from further surgical resection. As vaccine needs to be generated from the patient's tumor, patients will need to be identified prior to definitive surgery.
* Preliminary assessment by the neurosurgeons that \>80% of the tumor can be resected with an expectation that \>7gm of tissue would be resected
* Age greater than or equal to 18 years on day of signing informed consent.
* Karnofsky performance status greater than or equal to 70.
* Tumor must be supratentorial only.
* Stereotactic biopsy will not be allowed unless there is plans for second surgery to remove greater than or equal to 80 % of the tumor.
* No prior treatment with radiation or chemotherapy for their GBM.
* No prior treatment with carmustine (Gliadel) wafers.

Post-Surgery (Step 2) Inclusion:

* Pathology must be a GBM, O6-methylguanine-deoxyribonucleic acid (DNA) methyltransferase (MGMT) promoter region determined to be unmethylated and isocitrate Dehydrogenase (IDH) wild type greater than or equal to 80 % resection of contrast enhanced tumor on post operative MRI and greater than 7 grams of tumor resected are required otherwise patient is ineligible.
* Treatment must be initiated greater than or equal to 14 days and \< 6 weeks from surgery.
* Craniotomy site must be adequately healed and free of drainage or cellulitis, and the underlying cranioplasty must appear intact at the time of radiation. Radiation must start within 6 weeks of surgery.
* Dexamethasone dose should be less than or equal to 4 mg/day or steroid equivalent prior to starting treatment. If higher doses are needed, consult with Study Chair.
* Female subjects of childbearing potential should have a negative urine or serum pregnancy within 7 days prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a negative serum pregnancy test will be required.
* Patients must have adequate organ and bone marrow function within 14 days prior to step 2 registration, as defined below:

  * Absolute neutrophil count (ANC) \> 1.5 x10(9)/L; platelet count \> 100 x 10(9)/L; and hemoglobin (Hb) \>9.0 g/dL within 7 days prior to step 2 registration. Note: The use of transfusion or other intervention to achieve Hb greater than or equal to 9.0 g/dL is acceptable.
  * Total bilirubin \< 1.5 x ULN (except in patients diagnosed with Gilbert's disease)
  * Aspartate aminotransferase (AST) serum glutamic-oxaloacetic transaminase (SGOT), alanine aminotransferase (ALT) serum glutamate-pyruvate transaminase (SGPT), and alkaline phosphatase (ALP) \< 2.5 x ULN
  * Serum creatinine \< 1.5 x ULN
  * International normalized ratio (INR), prothrombin time (PT), or activated partial thromboplastin time (APTT) as follows: In the absence of therapeutic intent to anticoagulate the patient: INR \< 1.5 or PT \< 1.5 x ULN or aPTT \< 1.5 x ULN. In the presence of therapeutic intent to anticoagulate the patient: INR or PT and aPTT within therapeutic limits (according to the medical standard in the institution) and the patient has been on a stable dose of anticoagulants for at least 2 weeks before registration.
* Females of child-bearing potential (FOCBP) and males must agree to use two adequate contraception methods (give examples, e.g., hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for 120 days following completion of therapy. Should a female patient become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately. Male patients who father a child should notify the treating physician.

NOTE: A FOCBP is any woman (regardless of sexual orientation, having undergone a tubal ligation, or remaining celibate by choice) who meets the following criteria:

1. Has not undergone a hysterectomy or bilateral oophorectomy
2. Has had menses at any time in the preceding 12 consecutive months (and therefore has not been naturally postmenopausal for \> 12 months)

   * Patients must have the ability to understand and the willingness to sign a written informed consent prior to registration on study.
   * Diagnosis must be made by surgical excision.
   * Patients should not be on antibiotics for any infection, but post operative antibiotics are allowed if used prophylactically but should be completed prior to starting RT.

   EXCLUSION CRITERIA:

   Pre-Surgery (Step 1) Exclusion:
   * Known history of immunodeficiency (HIV). This medical entity can be exacerbated by programmed cell death protein 1 (PD-1) blockade.
   * History of another malignancy in the previous 3 years, with a disease-free interval of \< 3 years. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone potentially curative therapy. Patients who have undergone a bone marrow or stem-cell transplant for any malignancy are excluded.
   * Has an active autoimmune disease requiring systemic treatment within the past 3 months or a documented history of clinically severe autoimmune disease, or a syndrome that requires chronic systemic steroids or immunosuppressive agents except as noted above. Subjects with vitiligo or resolved childhood asthma/atopy would be an exception to this rule. Subjects that require intermittent use of bronchodilators or local steroid injections will not be excluded from the study. Subjects with hypothyroidism stable on hormone replacement or Sjorgren's syndrome will not be excluded from the study.
   * Has a history of interstitial lung disease, non-infectious pneumonitis, or pneumonitis.
   * Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator. Examples include:

     * Hypertension (defined as 160/95) that is not controlled on medication
     * Ongoing or active infection requiring systemic treatment
     * Symptomatic congestive heart failure
     * Unstable angina pectoris
     * Cardiac arrhythmia
     * Psychiatric illness/social situations or substance abuse disorders that would limit compliance with study requirements
     * Any other illness or condition that the treating investigator feels would interfere with study compliance or would compromise the patient's safety or study endpoints.
   * Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment.
   * The effects of pembrolizumab and HSPPC-96 on the developing human fetus are unknown. For this reason and because checkpoint inhibitors and immunotherapeutic vaccines as well as other therapeutic agents used in this trial are known to be teratogenic, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately.
   * Has received prior therapy with an anti-PD-1, anti-programmed death-ligand 1 (PD-L1), anti-PD-L2, anti-4-1BB (CD137), or anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways).
   * On treatment for Hepatitis B or Hepatitis C or history of tuberculosis (TB).
   * Patients who have a history of allergic reactions attributed to compounds of similar chemical or biologic composition to Pembrolizumab are not eligible. Known hypersensitivity to any excipients of Pembrolizumab.

   Post-Surgery (Step 2) Exclusion:
   * Patients are ineligible if the tumor is not a GBM, MGMT promoter region determined to be unmethylated and IDH wild type, or if \< 80 % resection of contrast enhanced tumor on post-operative MRI or \< 7 grams of tumor is resected.
   * Patients who are receiving any other investigational agents.
   * Known history of immunodeficiency (HIV). This medical entity can be exacerbated by PD-1 blockade.
   * Any form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment excluding steroids. Attempts should be made to have patient on lowest possible dose of steroids. These medical entities can be exacerbated by PD-1 blockade.
   * History of another malignancy in the previous 3 years, with a disease-free interval of \< 3 years. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone potentially curative therapy. Patients who have undergone a bone marrow or stem-cell transplant for any malignancy are excluded.
   * Has an active autoimmune disease requiring systemic treatment within the past 3 months or a documented history of clinically severe autoimmune disease, or a syndrome that requires chronic systemic steroids or immunosuppressive agents except as noted above. Subjects with vitiligo or resolved childhood asthma/atopy would be an exception to this rule. Subjects that require intermittent use of bronchodilators or local steroid injections will not be excluded from the study. Subjects with hypothyroidism stable on hormone replacement or Sjorgen's syndrome will not be excluded from the study.
   * Has a history of interstitial lung disease, non-infectious pneumonitis, or pneumonitis.
   * Has an active infection requiring systemic antibiotics within 10 days of surgery.
   * Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator. Examples include:

     * Hypertension (defined as 160/95) that is not controlled on medication
     * Ongoing or active infection requiring systemic treatment
     * Symptomatic congestive heart failure
     * Unstable angina pectoris
     * Cardiac arrhythmia
     * Psychiatric illness/social situations or substance abuse disorders that would limit compliance with study requirements
     * Any other illness or condition that the treating investigator feels would interfere with study compliance or would compromise the patient's safety or study endpoints.
   * Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment.
   * The effects of pembrolizumab and HSPPC-96 on the developing human fetus are unknown. For this reason and because checkpoint inhibitors and immunotherapeutic vaccines as well as other therapeutic agents used in this trial are known to be teratogenic, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately.
   * Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti- Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways).
   * On treatment for Hepatitis B or Hepatitis C or history of TB.
   * Has received a live vaccine within 30 days prior to the first dose of trial treatment
   * Patients who have a history of allergic reactions attributed to compounds of similar chemical or biologic composition to Pembrolizumab are not eligible. Known hypersensitivity to any excipients of Pembrolizumab.