Pembrolizumab and a Vaccine (ATL-DC) for the Treatment of Surgically Accessible Recurrent Glioblastoma

Inclusion Criteria:

• Participants with histologically confirmed diagnosis of surgically accessiblerecurrent/progressive glioblastoma will be enrolled in this study

• Be at first or second relapse (Note: relapse is defined as progression followinginitial therapy, i.e., radiation +/- chemotherapy. For participants who had priortherapy for a low-grade glioma, the surgical diagnosis of a high-grade glioma willbe considered the first relapse)

• Must be undergoing surgery that is clinically indicated, and eligible for resectionwith the expectation that the surgeon is able to resect at least 2 gram of tumor forlysate and research with low risk of inducing neurological injury

• A male participant must agree to use a contraception during the treatment period andfor at least 120 days after the last dose of study treatment and refrain fromdonating sperm during this period

• A female participant who has childbearing potential must have negative urine orserum pregnancy test 72 hrs prior to the first dose and be willing to use adequatemethod of contraception for course of study and 120 days after last dose

• The participant (or legally acceptable representative if applicable) provideswritten informed consent for the trial

• Have unequivocal evidence for contrast enhancing tumor progression by RANO criteriabased on MRI scan within 14 days prior to randomization

• Have a minimum tumor size of 2 x 2 cm^2 based on MRI scan prior to surgery

• An interval of the following durations prior to randomization:

• At least 28 days from prior surgical resection

• At least 7 days from prior stereotactic biopsy

• At least 12 weeks from prior radiotherapy, unless there is unequivocalhistologic confirmation of tumor progression

• At least 23 days from prior chemotherapy

• At least 42 days from nitrosureas

• Have sufficient archival tumor tissue confirming glioblastoma or variants forsubmission following registration. The following amount of tissue is required: 1formalin-fixed, paraffin embedded (FFPE) tissue block (preferred) or 10 FFPE ,unstained slides (5um thick)

• Have a Karnofsky performance status (KPS) >= 70

• Absolute neutrophil count (ANC) >= 1500/uL (uL=microliter) (collected within 14 daysprior to the start of study treatment)

• Platelets >= 100 000/uL (collected within 14 days prior to the start of studytreatment)

• Hemoglobin >= 9.0 g/dL or >= 5.6 mmol/L (collected within 14 days prior to the startof study treatment)

• Criteria must be met without erythropoietin dependency and without packed redblood cell (pRBC) transfusion within last 2 weeks

• Creatinine =< 1.5 x upper limit of normal (ULN) OR measured or calculated creatinineclearance >= 30 mL/min for participant with creatinine levels > 1.5 x institutionalULN (collected within 14 days prior to the start of study treatment) (glomerularfiltration rate [GFR] can also be used in place of creatinine or creatinineclearance [CrCl])

• Creatinine clearance (CrCl) should be calculated per institutional standard

• Total bilirubin =< 1.5 x ULN OR direct bilirubin =< ULN for participants with totalbilirubin levels > 1.5 x ULN (collected within 14 days prior to the start of studytreatment)

• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])and alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT[) =< 2.5 x ULN (=< 5 x ULN for participants with liver metastases) (collected within 14days prior to the start of study treatment)

• International normalized ratio (INR) OR prothrombin time (PT) =< 1.5 x ULN unlessparticipant is receiving anticoagulant therapy as long as PT or activated partialthromboplastin time (aPTT) is within therapeutic range of intended use ofanticoagulants (collected within 14 days prior to the start of study treatment)

• aPTT =< 1.5 x ULN unless participant is receiving anticoagulant therapy as long asPT or aPTT is within therapeutic range of intended use of anticoagulants (collectedwithin 14 days prior to the start of study treatment)

Exclusion Criteria:

• A woman of childbearing potential (WOCBP) who has a positive urine pregnancy testwithin 72 hours prior to randomization. If the urine test is positive or cannot beconfirmed as negative, a serum pregnancy test will be required

• Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent orwith an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g., CTLA-4, OX-40, CD137)

• Has received prior systemic anti-cancer therapy including investigational agentswithin 4 weeks prior to randomization

• Note: Participants must have recovered from all adverse events (AEs) due toprevious therapies to =< grade 1 or baseline. Participants with =< grade 2neuropathy may be eligible

• Note: If participant received major surgery, they must have recoveredadequately from the toxicity and/or complications from the intervention priorto starting study treatment

• Has received prior radiotherapy within 2 weeks of start of study treatment.Participants must have recovered from all radiation-related toxicities, not requirecorticosteroids, and not have had radiation pneumonitis. A 1-week washout ispermitted for palliative radiation (=< 2 weeks of radiotherapy) to non-centralnervous system (CNS) disease

• Has received a live vaccine within 30 days prior to the first dose of study drug.Examples of live vaccines include, but are not limited to, the following: measles,mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacilluscalmette-guerin (BCG), and typhoid vaccine. Seasonal influenza vaccines forinjection are generally killed virus vaccines and are allowed; however, intranasalinfluenza vaccines (eg, FluMist) are live attenuated vaccines and are not allowed

• Is currently participating in or has participated in a study of an investigationalagent or has used an investigational device within 4 weeks prior to the first doseof study treatment

• Note: Participants who have entered the follow-up phase of an investigationalstudy may participate as long as it has been 4 weeks after the last dose of theprevious investigational agent

• Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form ofimmunosuppressive therapy within 7 days prior to the first dose of study drug

• Has a known additional malignancy that is progressing or has required activetreatment within the past 3 years

• Note: Participants with basal cell carcinoma of the skin, squamous cellcarcinoma of the skin, or carcinoma in situ (e.g. breast carcinoma, cervicalcancer in situ) that have undergone potentially curative therapy are notexcluded

• Has known tumor primarily localized to the brainstem or spinal cord

• Has severe hypersensitivity (>= grade 3) to pembrolizumab and/or any of itsexcipients

• Has active autoimmune disease that has required systemic treatment in the past 2years (i.e. with use of disease modifying agents, corticosteroids orimmunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, orphysiologic corticosteroid replacement therapy for adrenal or pituitaryinsufficiency, etc.) is not considered a form of systemic treatment

• Has a history of (non-infectious) pneumonitis that required steroids or has currentpneumonitis

• Has an active infection requiring systemic therapy

• Has a known history of human immunodeficiency virus (HIV)

• Has a known history of hepatitis B (defined as hepatitis B surface antigen [HBsAg]reactive) or known active hepatitis C virus (defined as hepatitis C virus [HCV]ribonucleic acid [RNA] is detected) infection. Note: no testing for hepatitis B andhepatitis C is required unless mandated by local health authority

• Has a known history of active TB (Bacillus tuberculosis)

• Has a history or current evidence of any condition, therapy, or laboratoryabnormality that might confound the results of the study, interfere with thesubject's participation for the full duration of the study, or is not in the bestinterest of the subject to participate, in the opinion of the treating investigator

• Has known psychiatric or substance abuse disorders that would interfere withcooperation with the requirements of the trial

• Is pregnant or breastfeeding, or expecting to conceive or father children within theprojected duration of the study, starting with the screening visit through 120 daysafter the last dose of trial treatment