A Pilot Surgical Trial To Evaluate Early Immunologic Pharmacodynamic Parameters For The PD-1 Checkpoint Inhibitor, Pembrolizumab (MK-3475), In Patients With Surgically Accessible Recurrent/Progressive Glioblastoma

Be willing and able to provide written informed consent/assent for the trial.

Be 18 years of age on day of signing informed consent.

Have a Karnofsky performance status (KPS) ≥ 70 (Appendix A).

Previous first line therapy with at least radiotherapy.

Be at first or second relapse. Note: Relapse is defined as progression following initial therapy (i.e., radiation ± chemotherapy). For participants who had prior therapy for a low-grade glioma, the surgical diagnosis of a high-grade glioma will be considered the first relapse.

Participants must have shown unequivocal evidence for tumor progression by MRI or CT scan.

Demonstrate adequate organ function as defined in Table 1, all screening labs should be performed within 14 days of registration.

Table 1 Adequate Organ Function Laboratory Values

System Laboratory Value

Hematological

* Absolute neutrophil count (ANC) ≥1,500 /mcL

* Platelets ≥100,000 / mcL

* Hemoglobin ≥9 g/dL or ≥5.6 mmol/L without transfusion or EPO dependency (within 7 days of assessment)

Renal

* Serum creatinine OR Measured or calculated creatinine clearance (GFR can also be used in place of creatinine or CrCl) ≤1.5 X institutional upper limit of normal (ULN) OR ≥60 mL/min for subject with creatinine levels \> 1.5 X institutional ULN Hepatic

* Serum total bilirubin ≤ 1.5 X institutional ULN OR Direct bilirubin ≤ institutional ULN for subjects with total bilirubin levels \> 1.5 institutional ULN

* AST (SGOT) and ALT (SGPT) ≤ 2.5 X institutional ULN OR ≤ 5 X institutional ULN for subjects with Gilberts syndrome

* Albumin \>2.5 mg/dL

Coagulation

* International Normalized Ratio (INR) or Prothrombin Time (PT)

* Activated Partial Thromboplastin Time (aPTT) ≤1.5 X institutional ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants

≤1.5 X institutional ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants

* Creatinine clearance should be calculated per institutional standard.

CT or MRI within 14 days prior of registration.

An interval of at least 4 weeks (to registration) between prior surgical resection or one week for stereotactic biopsy.

An interval of at least 12 weeks from the completion of radiation therapy to registration unless there is unequivocal histologic confirmation of tumor progression.

From registration, the following time periods must have elapsed: 5 half-lives from any investigational agent, 4 weeks from cytotoxic therapy (except 23 days for temozolomide and 6 weeks from nitrosoureas), 6 weeks from antibodies, or 4 weeks (or 5 half-lives, whichever is shorter) from other anti-tumor therapies (including vaccines). No wash-out period required from TTF.

Participants must have sufficient tissue from prior surgery revealing glioblastoma or variants for submission following registration. The following amount of tissue is required:

* 1 formalin-fixed paraffin-embedded (FFPE) tumor tissue block (preferred) OR

* 10 FFPE unstained slides (5 μm thick)

Patients must be undergoing surgery that is clinically indicated as determined by their care providers. Patients must be eligible for surgical resection with the expectation that the surgeon is able to resect at least 400mg of tumor with low risk of inducing neurological injury.

Female subject of childbearing potential must have a negative urine or serum pregnancy within 72 hours prior to registration. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. Women are considered post-menopausal and not of child bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g., age appropriate, history of vasomotor symptoms) or six months of spontaneous amenorrhea with serum FSH levels \> 40 mIU/mL and estradiol \< 20 pg/mL or have had surgical bilateral oophorectomy (with or without hysterectomy) at least six weeks ago. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of child bearing potential.

Women of child-bearing potential (WOCBP), defined as all women physiologically capable of becoming pregnant, must agree to use highly effective contraception during study treatment and for 120 days after study discontinuation. Highly effective contraception is defined as either:

* True Abstinence: When this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception.

* Sterilization: Surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks ago. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment (as described in item 3.1.16 above).

* Male Partner Sterilization (with the appropriate post-vasectomy documentation of the absence of sperm in the ejaculate). For female subjects on the study, the vasectomised male partner must be the sole partner for that participant.

* Use of a combination of any two of the following:

* Placement of an intrauterine device (IUD) or intrauterine system (IUS)

* Barrier methods of contraception: Condom or Occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository

* Appropriate hormonal contraceptives (including any registered and marketed contraceptive agent that contains an estrogen and/or a progestational agent - including oral, subcutaneous, intrauterine, or intramuscular agents)

Male subjects must agree to use adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of therapy.

What this study is about