Inclusion Criteria:
- - Inclusion Criteria for Cohort 1:
1.
Age >= 18 years.
2. Karnofsky performance status (KPS) score of >=70.
3. All participants must have adequate organ function defined as:
1. Peripheral absolute neutrophil count >=1000/mm^3.
2. Platelet count >=100,000/mm^3 (transfusion independent, defined as not
receiving platelet transfusions for at least 7 days prior to enrollment).
3. Absolute lymphocyte count (ALC) >= 300/μL and/or Cluster of differentiation
3 (CD3) count of >=150/μL.
4. Creatinine clearance or radioisotope glomerular filtration rate >= 50
mL/min/1.73m^2.
5. Total Bilirubin <= 1.5 x ULN except for Gilbert's syndrome and. 6. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) <= 3x
upper limit of normal (ULN).
7. Left ventricular ejection fraction (LVEF) >= 40% by echocardiogram or
multi-gated acquisition scanning (MUGA).
8. Adequate pulmonary function, defined as no evidence of dyspnea at rest and
pulse oximetry > 92% while breathing room air.
4. Pathological criteria: EGFRvIII+ GBM from most recent surgery, confirmed by a
Clinical Laboratory Improvement Amendments (CLIA)-certified lab using a
next-generation sequencing panel.
5. MGMT promoter must be unmethylated or with a methylation index < 3.
6. Must have completed at least standard of care (SOC) external beam radiotherapy
(EBRT) as initial therapy.
7. Participants must be anticipated to be able to complete E-SYNC T cell infusion
within 12 weeks after completion of EBRT.
8. All participants must be off systemic steroids for 3 days or more prior to
leukapheresis.
9. Must be willing to provide voluntary informed consent for apheresis (and tissue
screening if needed) and for study treatment.
NOTE: There are two sets of eligibility criteria for Cohort 2. Step 1 defines eligibility
for tissue screening and apheresis, and Step 2 defines eligibility for study enrollment and
E-SYNC T cell treatment.
- - Inclusion Criteria for Cohort 2, Step 1:
1.
Age >=18 years.
2. KPS score >=70.
3. All participants must have adequate organ function defined as:
1. Peripheral absolute neutrophil count >=1000/mm^3.
2. Platelet count >=100,000/mm^3 (transfusion independent, defined as not
receiving platelet transfusions for at least 7 days prior to enrollment).
3. Absolute lymphocyte count (ALC) >= 300/μL and/or CD3 count of >=150/μL.
4. Creatinine clearance or radioisotope glomerular filtration rate >= 50
mL/min/1.73m^2.
5. Total Bilirubin <= 1.5 x ULN except for Gilbert's syndrome and. 6. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) <= 3x
upper limit of normal (ULN).
7. Left ventricular ejection fraction (LVEF) >= 40% by echocardiogram or
multi-gated acquisition scanning (MUGA).
8. Adequate pulmonary function, defined as no evidence of dyspnea at rest and
pulse oximetry > 92% while breathing room air.
4. Pathological criteria: EGFRvIII+ GBM from most recent surgery, as defined by an
EGFRvIII + H-score of >=250 based on central review.
5. All participants must be off systemic steroids for 3 days or more prior to
leukapheresis.
6. Must be willing to provide voluntary informed consent for apheresis (and tissue
screening if needed).
- - Inclusion Criteria for Cohort 2, Step 2.
Note: Prior to Step 2, participants must have
undergone leukapheresis in Step 1. In addition:
1. KPS score >=70.
2. Must have received at least SOC EBRT as initial therapy; any number of prior
recurrences is allowed.
3. Pathological criteria: EGFRvIII+ GBM from most recent surgery, as defined by an
EGFRvIII + H-score of >=250 based on central review.
4. Must have radiographic progression consistent with the Response assessment in
neuro-oncology criteria (RANO) criteria for progressive disease (PD)
5. Recurrence must be surgically amenable, with expectation for ability to resect at
least 500mg of tumor tissue. 6. Participants with reproductive potential agree to use reliable and double barrier
method of contraception during the study and for at least 6 months after the last
study intervention, including refraining from donating sperm during this period.
7. Females of childbearing potential must have a negative serum beta-Human Chorionic
Gonadotropin (hCG) pregnancy test prior to receiving study interventions.
8. All participants must have adequate organ function defined as:
1. Peripheral absolute neutrophil count >=1000/mm^3.
2. Platelet count >=100,000/mm^3 (transfusion independent, defined as not
receiving platelet transfusions for at least 7 days prior to enrollment).
3. Absolute lymphocyte count (ALC) >= 300/μL and/or CD3 count of >=150/μL.
4. Creatinine clearance or radioisotope glomerular filtration rate >= 50
mL/min/1.73m^2.
5. Total Bilirubin <= 1.5 x ULN except for Gilbert's syndrome and. 6. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) <= 3x
upper limit of normal (ULN).
7. Coagulation tests prothrombin time (PT) and partial thromboplastin time
(PTT) have to be within normal limits, unless the participant has been
therapeutically anticoagulated for previous venous thrombosis.
8. Adequate pulmonary function, defined as no evidence of dyspnea at rest and
pulse oximetry > 92% while breathing room air.
9. Adequate cardiac function, confirmed within the last 12 months, defined as
left ventricular ejection fraction (LVEF) >= 40% by echocardiogram or
multi-gated acquisition scanning (MUGA).
9. Must be willing to provide voluntary informed consent for apheresis (and tissue
screening if needed).
Exclusion Criteria:
- - Exclusion Criteria for Cohort 1.
1. Participant who has been treated with any investigational agents and chemotherapy
<= 4 weeks prior to date of leukapheresis. Exceptions to this include: must be
>=23 days from last dose of temozolomide (TMZ) or radiotherapy, mush be >= 6
weeks from last dose of nitrosurea.
2. Female participants of reproductive potential who are pregnant or lactating.
Female study participants of reproductive potential must have a negative serum
pregnancy test as part of eligibility confirmation.
3. Known addiction to alcohol or illicit drugs.
4. Prior treatment with any Epithelial Growth Factor Receptor (EGFR)-targeting
therapy.
5. Participants with leptomeningeal dissemination.
6. Participants with a known disorder that affects their immune system, such as
human immunodeficiency virus (HIV) or an autoimmune disorder requiring systemic
cytotoxic or immunosuppressive therapy. Participants who are currently using
non-systemic steroids (e.g., inhaled, intranasal, ocular, topical) are not
excluded from the study.
7. Participants with serologic status reflecting active hepatitis B or C infection.
Participants that are positive for hepatitis B surface antigen (HBsAg+) will be
excluded. Participants that are positive for hepatitis B core antibody or
hepatitis C antibody must have a negative polymerase chain reaction (PCR) prior
to enrollment. PCR positive participants will be excluded.
8. Participants who have received prior solid organ or bone marrow transplantation.
9. Uncontrolled intercurrent illness including, but not limited to, ongoing or
active infection, symptomatic congestive heart failure, unstable angina pectoris,
cardiac arrhythmia, second cancer currently receiving active treatment or
anticipated to receive treatment within the next year, or psychiatric
illness/social situations that would limit compliance with study requirements.
10. Participants who are unable to return for follow-up visits or obtain follow-up
studies required to assess toxicity to therapy.
- - Exclusion Criteria for Step 1 for Cohort 2.
1. Participant who has been treated with any investigational agents, chemotherapy or
radiotherapy this include: must be>= 23 days from last dose of TMZ, must be>=6
weeks from last dose of nitrosurea.
2. Female participants of reproductive potential who are pregnant or lactating.
Female study participants of reproductive potential must have a negative serum
pregnancy test as part of Step 1 eligibility confirmation.
3. Uncontrolled active infection.
4. Participants with a known disorder that affects their immune system, such as HIV
or an autoimmune disorder requiring systemic cytotoxic or immunosuppressive
therapy.
Participants who are currently using non-systemic steroids (e.g., inhaled,
intranasal, ocular, topical) are not excluded from the study.
5. Participants with serologic status reflecting active hepatitis B or C infection.
Participants that are positive for hepatitis B surface antigen (HBsAg+) will be
excluded. Participants that are positive for hepatitis B core antibody or
hepatitis C antibody must have a negative polymerase chain reaction (PCR) prior
to enrollment. PCR positive participants will be excluded.
6. Known addiction to alcohol or illicit drugs.
- - Exclusion Criteria for Step 2 for Cohort 2.
Prior to Step 2, participants must have undergone leukapheresis in Step 1. In addition:
1. Prior treatment with any EGFR-targeting therapy. 2. Participant who has been treated with any investigational agents, chemotherapy or
radiotherapy this include: must be>= 23 days from last dose of TMZ, must be>=12 weeks
from last dose of nitrosurea. 3. Participants with imaging or clinical evidence of uncontrolled tumor mass effect; the
assessment of mass effect will be made by the Investigators.
4. Participants with leptomeningeal dissemination.
5. Participants with a known disorder that affects their immune system, such as HIV or an
autoimmune disorder requiring systemic cytotoxic or immunosuppressive therapy.
Participants who are currently using inhaled, intranasal, ocular, topical, or other
non-oral or non-IV steroids are not necessarily excluded from the study.
6. Participants with serologic status reflecting active hepatitis B or C infection.
Participants that are positive for hepatitis B surface antigen (HBsAg+) will be
excluded. Participants that are positive for hepatitis B core antibody or hepatitis C
antibody must have a negative polymerase chain reaction (PCR) prior to enrollment. PCR
positive participants will be excluded.
7. Participants who have received prior solid organ or bone marrow transplantation.
8. Female participants who are pregnant or breast-feeding.
9. Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, second cancer currently receiving active treatment or anticipated to
receive treatment within the next year, or psychiatric illness/social situations that
would limit compliance with study requirements.
10. Participants who are unable to return for follow-up visits or obtain follow-up studies
required to assess toxicity to therapy.
