PRIMARY OBJECTIVES:
I. To evaluate the influence of pembrolizumab on the cell cycle-related genetic signature
within the tumor microenvironment of progressive/recurrent glioblastoma.
II. To evaluate the influence of adjuvant autologous tumor lysatepulsed dendritic cell
(ATL-DC) vaccination on peripheral T cell responses.
III. To evaluate the safety and tolerability of pembrolizumab and ATL-DC vaccination in
progressive/recurrent glioblastoma.
SECONDARY OBJECTIVES:
I. To estimate the 6 month progression-free survival (PFS6) based on Response Assessment in
Neuro-Oncology (RANO) criteria in patients treated on both arms of the clinical trial.
II. To calculate the overall survival of recurrent glioblastoma patients treated on both arms
of the clinical trial.
EXPLORATORY OBJECTIVES:
I. To evaluate the associations between exploratory biomarkers, clinical outcomes, and
adverse events which include:
Ia. Estimating the correlation of quantitative assessments of tumor infiltrating lymphocyte
(TIL) density or the interferon (IFN) gamma-associated genetic signature with clinical
responses to pembrolizumab and ATL-DC in recurrent glioblastoma patients.
Ib. Estimating the efficacy of pembrolizumab and ATL-DC through PFS6, PFS and overall
survival (OS) as defined by RANO.
Ic. Estimating the efficacy of pembrolizumab and ATL-DC through PFS6, PFS, and OS as defined
by immunotherapy RANO (iRANO).
Id. Exploring whether oligoclonal T cell populations within tumor tissue are similarly
expanded in peripheral blood after ATL-DC vaccination and/or pembrolizumab, and correlating
with clinical responses.
Ie. Exploring whether changes in specific magnetic resonance imaging (MRI) parameters
correlate with tumor and peripheral blood immune responses.
OUTLINE: Patients are randomized to 1 of 2 groups.
GROUP A: Beginning 14 days prior to scheduled surgery, patients receive pembrolizumab
intravenously (IV) over 30 minutes. After surgery, patients receive pembrolizumab IV over 30
minutes on day 1. Cycle repeats every 3 weeks in the absence of disease progression or
unacceptable toxicity. Patients also receive ATL-DC intradermally (ID) with poly ICLC
intramuscularly (IM) every 2 weeks for up to 3 doses in the absence of disease progression or
unacceptable toxicity.
GROUP B: Beginning 14 days prior to scheduled surgery, patients receive placebo IV. After
surgery, patients receive placebo IV on day 1. Cycle repeats every 3 weeks in the absence of
disease progression or unacceptable toxicity. Patients also receive ATL-DC ID with poly ICLC
IM every 2 weeks for up to 3 doses in the absence of disease progression or unacceptable
toxicity.
After completion of study treatment, patients are followed up at 30 days and then every 3
months thereafter.
Inclusion Criteria:
- Participants with histologically confirmed diagnosis of surgically accessible
recurrent/progressive glioblastoma will be enrolled in this study
- 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)
- Must be undergoing surgery that is clinically indicated, and eligible for resection
with the expectation that the surgeon is able to resect at least 2 gram of tumor for
lysate and research with low risk of inducing neurological injury
- A male participant must agree to use a contraception during the treatment period and
for at least 120 days after the last dose of study treatment and refrain from donating
sperm during this period
- A female participant who has childbearing potential must have negative urine or serum
pregnancy test 72 hrs prior to the first dose and be willing to use adequate method of
contraception for course of study and 120 days after last dose
- The participant (or legally acceptable representative if applicable) provides written
informed consent for the trial
- Have unequivocal evidence for contrast enhancing tumor progression by RANO criteria
based 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 unequivocal histologic
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 for
submission following registration. The following amount of tissue is required: 1
formalin-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 days
prior to the start of study treatment)
- Platelets >= 100 000/uL (collected within 14 days prior to the start of study
treatment)
- Hemoglobin >= 9.0 g/dL or >= 5.6 mmol/L (collected within 14 days prior to the start
of study treatment)
- Criteria must be met without erythropoietin dependency and without packed red
blood cell (pRBC) transfusion within last 2 weeks
- Creatinine =< 1.5 x upper limit of normal (ULN) OR measured or calculated creatinine
clearance >= 30 mL/min for participant with creatinine levels > 1.5 x institutional
ULN (collected within 14 days prior to the start of study treatment) (glomerular
filtration rate [GFR] can also be used in place of creatinine or creatinine clearance
[CrCl])
- Creatinine clearance (CrCl) should be calculated per institutional standard
- Total bilirubin =< 1.5 x ULN OR direct bilirubin =< ULN for participants with total
bilirubin levels > 1.5 x ULN (collected within 14 days prior to the start of study
treatment)
- 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 14 days
prior to the start of study treatment)
- International normalized ratio (INR) OR prothrombin time (PT) =< 1.5 x ULN unless
participant is receiving anticoagulant therapy as long as PT or activated partial
thromboplastin time (aPTT) is within therapeutic range of intended use of
anticoagulants (collected within 14 days prior to the start of study treatment)
- aPTT =< 1.5 x ULN unless participant is receiving anticoagulant therapy as long as PT
or aPTT is within therapeutic range of intended use of anticoagulants (collected
within 14 days prior to the start of study treatment)
Exclusion Criteria:
- A woman of childbearing potential (WOCBP) who has a positive urine pregnancy test
within 72 hours prior to randomization. If the urine test is positive or cannot be
confirmed 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 or with
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 agents
within 4 weeks prior to randomization
- Note: Participants must have recovered from all adverse events (AEs) due to
previous therapies to =< grade 1 or baseline. Participants with =< grade 2
neuropathy may be eligible
- Note: If participant received major surgery, they must have recovered adequately
from the toxicity and/or complications from the intervention prior to 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 require
corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted
for palliative radiation (=< 2 weeks of radiotherapy) to non-central nervous 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, Bacillus
calmette-guerin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection
are generally killed virus vaccines and are allowed; however, intranasal influenza
vaccines (eg, FluMist) are live attenuated vaccines and are not allowed
- Is currently participating in or has participated in a study of an investigational
agent or has used an investigational device within 4 weeks prior to the first dose of
study treatment
- Note: Participants who have entered the follow-up phase of an investigational
study may participate as long as it has been 4 weeks after the last dose of the
previous 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 of
immunosuppressive therapy within 7 days prior to the first dose of study drug
- Has a known additional malignancy that is progressing or has required active treatment
within the past 3 years
- Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma
of the skin, or carcinoma in situ (e.g. breast carcinoma, cervical cancer in
situ) that have undergone potentially curative therapy are not excluded
- Has known tumor primarily localized to the brainstem or spinal cord
- Has severe hypersensitivity (>= grade 3) to pembrolizumab and/or any of its excipients
- Has active autoimmune disease that has required systemic treatment in the past 2 years
(i.e. with use of disease modifying agents, corticosteroids or immunosuppressive
drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid
replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a
form of systemic treatment
- Has a history of (non-infectious) pneumonitis that required steroids or has current
pneumonitis
- 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 and
hepatitis 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 laboratory abnormality
that might confound the results of the study, interfere with the subject's
participation for the full duration of the study, or is not in the best interest of
the subject to participate, in the opinion of the treating investigator
- Has known psychiatric or substance abuse disorders that would interfere with
cooperation with the requirements of the trial
- Is pregnant or breastfeeding, or expecting to conceive or father children within the
projected duration of the study, starting with the screening visit through 120 days
after the last dose of trial treatment
