This phase I/II trial studies the side effects and best dose of autologous cytomegalovirus
(CMV)-specific cytotoxic T cells when given together with temozolomide and to see how well
they work in treating patients with glioblastoma. Autologous CMV-specific cytotoxic T cells
may stimulate the immune system to attack specific tumor cells and stop them from growing or
kill them. Drugs used in chemotherapy, such as temozolomide, may work in different ways to
stop the growth of tumor cells, either by killing the cells, by stopping them from dividing,
or by stopping them from spreading. Giving autologous CMV-specific cytotoxic T cells with
temozolomide may be a better treatment for patients with glioblastoma.
PRIMARY OBJECTIVES:
I. To determine the maximum feasible dose (MFD) or maximum tolerated dose (MTD) and safety of
cytomegalovirus (CMV)-specific T cells in combination with dose-dense temozolomide in
patients with recurrent glioblastoma. (Phase I) II. To evaluate the immunological effects in
resected glioblastoma after intravenous administered cytomegalovirus (CMV)-stimulated
adoptive T cells in patients with recurrent glioblastoma (GBM). (Phase II: recurrent
glioblastoma undergoing resection) III. To correlate 6-month progression-free survival rate
(PFS6) with objective clearance of CMV antigens as measured by immunohistochemistry (IHC) and
by ex vivo T-cell-specific effector responses using intracellular cytokine profiling. (Phase
II: recurrent glioblastoma undergoing resection) IV. Overall survival (OS). (Phase II: newly
diagnosed glioblastoma)
SECONDARY OBJECTIVES:
I. Time to progression, overall survival (OS) as well as immunological reactivity and safety.
(Phase II: recurrent glioblastoma undergoing resection) II. Safety and tolerability of
dose-dense temozolomide in combination with intravenous administered CMV-stimulated adoptive
T cells in patients receiving adjuvant therapy after completing external beam radiotherapy
with concurrent temozolomide for newly diagnosed glioblastoma. (Phase II: newly diagnosed
glioblastoma) III. Overall objective response rate (ORR), median duration of response, PFS6.
(Phase II: newly diagnosed glioblastoma)
EXPLORATORY OBJECTIVES:
I. To determine the persistence and expansion of adoptively-infused CMV-specific T cells by
multiparameter flow cytometry in serially-sampled peripheral blood. (Phase I) II. To identify
imaging characteristics such as magnetic resonance imaging (MRI) textural analysis associated
with immunological changes in tumor following treatment with CMV-stimulated adoptive T cells.
(Phase II: recurrent glioblastoma undergoing resection) III. To ascertain if adoptive
transfer of CMV-specific T cells leads to the expansion of T cells with specificity to other
glioblastoma antigens (i.e. epitope spreading) by performing longitudinally monitoring of
antigen-specific T cell frequency with enzyme-linked immunosorbent spot assay (ELISPOT).
(Phase II: recurrent glioblastoma undergoing resection) IV. To determine the persistence and
expansion of adoptively-infused CMV-specific T cells by multiparameter flow cytometry in
serially-sampled peripheral blood. (Phase II: newly diagnosed glioblastoma)
OUTLINE: This is a phase I, dose-escalation study of CMV-specific T cells followed by a phase
II study. Patients are assigned to 1 of 2 treatment arms.
ARM I: Patients receive temozolomide orally (PO) once a day (QD) on days 1-21 and
CMV-specific T cell transfer intravenously (IV) over 1-5 minutes on day 22. Patients undergo
surgery on day 30 of cycle 1. Treatment repeats every 42 days for up to 4 cycles in the
absence of disease progression or unacceptable toxicity. Patients then receive temozolomide
PO QD on days 1-21. Treatment repeats every 42 days for up to 12 cycles in the absence of
disease progression or unacceptable toxicity.
ARM II: Patients receive temozolomide PO QD on days 1-21 and CMV-specific T cell transfer
intravenously IV over 1-5 minutes on day 22. Treatment repeats every 42 days for up to 4
cycles in the absence of disease progression or unacceptable toxicity. Patients then receive
temozolomide PO QD on days 1-5. Treatment repeats every 28 days for up to 12 cycles in the
absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up at 30 days and every 3 months.
Inclusion Criteria:
- Be willing and able to provide written informed consent for the trial
- PHASE II DOSE EXPANSION IN RECURRENT GBM UNDERGOING RESECTION: Have histologically
confirmed World Health Organization grade IV malignant glioma (glioblastoma or
gliosarcoma); participants will also be eligible if the original histology was lower
grade glioma and there is suspected transformation to glioblastoma based on imaging
findings; if the final pathology report after resection fails to confirm recurrent
glioblastoma or gliosarcoma, the subject will be followed for adverse events (AEs) and
survival, but excluded for other primary and secondary objective analysis; the subject
will be replaced
- PHASE II DOSE EXPANSION IN NEWLY DIAGNOSED GBM: Have histologically confirmed World
Health Organization grade IV glioma (glioblastoma or gliosarcoma)
- PHASE II DOSE EXPANSION IN RECURRENT GBM UNDERGOING RESECTION: Be at first relapse;
Note: relapse is defined as progression following initial therapy (i.e., radiation,
chemotherapy, or radiation plus (+) chemotherapy); if the participant had a surgical
resection for relapsed disease and no antitumor therapy instituted for up to 12 weeks,
this is considered one relapse; for participants who had prior therapy for a lower
grade glioma, the surgical diagnosis of glioblastoma or gliosarcoma will be considered
first relapse
- PHASE II DOSE EXPANSION IN NEWLY DIAGNOSED GBM: Patients must have completed standard
radiation therapy with concurrent temozolomide (TMZ) within 5 weeks (wks) of
enrollment and must not have evidence of progressive disease on post treatment
imaging; progression can only be defined using diagnostic imaging if there is new
enhancement outside of the radiation field (beyond the high-dose region or 80% isodose
line) or if there is unequivocal evidence of viable tumor on histopathologic sampling
(e.g., solid tumor areas [i.e,> 70% tumor cell nuclei in areas], high or progressive
increase in mindbomb homolog 1[MIB-1] proliferation index compared with prior biopsy,
or evidence for histologic progression or increased anaplasia in tumor); Note: given
the difficulty of differentiating true progression from pseudoprogression, clinical
decline alone, in the absence of radiographic or histologic confirmation of
progression, will not be sufficient for definition of progressive disease in the first
12 weeks after completion of concurrent chemoradiotherapy
- PHASE II DOSE EXPANSION IN RECURRENT GBM UNDERGOING RESECTION: Have measurable disease
consisting of a minimal volume of 1 cm^3
- CMV seropositive
- PHASE I AND PHASE II DOSE EXPANSION IN RECURRENT GBM UNDERGOING RESECTION: Be willing
to provide tissue from an archival tissue sample or newly obtained core or excisional
biopsy of a tumor lesion
- PHASE II DOSE EXPANSION IN NEWLY DIAGNOSED GBM: Be willing to provide tissue from an
archival tissue sample
- Have a performance status of >= 60 on the Karnofsky performance status (KPS)
- If patient is on steroids, patient must be on a stable or decreasing dose of steroids
for 5 days, no more than 2 mg dexamethasone (or equivalent) total per day at the time
of screening and consent; if on steroids at the time of screening, the dose will need
to be tapered and discontinued at least 5 days prior to CMV T cell infusion
- Absolute neutrophil count (ANC) >= 1,500 /mcL (performed within 14 days [+3 working
days] of treatment initiation)
- Platelets >= 100,000 / mcL (performed within 14 days [+3 working days] of treatment
initiation)
- Hemoglobin >= 9 g/dL or >= 5.6 mmol/L (performed within 14 days [+3 working days] of
treatment initiation)
- Serum creatinine OR measured or calculated (creatinine clearance should be calculated
per institutional standard) creatinine clearance (glomerular filtration rate [GFR] can
also be used in place of creatinine or creatinine clearance [CrCl]) =< 1.5 X upper
limit of normal (ULN) OR >= 60 mL/min for subject with creatinine levels > 1.5 X
institutional ULN (performed within 14 days [+3 working days] of treatment initiation)
- Serum total bilirubin =< 1.5 X ULN OR direct bilirubin =< ULN for subjects with total
bilirubin levels > 1.5 ULN (performed within 14 days [+3 working days] of treatment
initiation)
- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and
alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) =< 2.5 X
ULN (performed within 14 days [+3 working days] of treatment initiation)
- Coagulation international normalized ratio (INR) or prothrombin time (PT), activated
partial thromboplastin time (aPTT) =< 1.5 X ULN (performed within 14 days [+3 working
days] of treatment initiation)
- Female subject of childbearing potential should have a negative urine or serum
pregnancy within 72 hours of study enrollment; if the urine test is positive or cannot
be confirmed as negative, a serum pregnancy test will be required
- Female subjects of childbearing potential should be willing to use 2 methods of birth
control during the study and for 30 days after the last dose of the study drug or be
surgically sterile; subjects of childbearing potential are those who have not been
surgically sterilized or have not been free from menses for > 1 year
- Male subjects should agree to use an adequate method of contraception during the
course of the study and for 30 days after the last dose of the study drug
- PHASE I: Have histologically confirmed World Health Organization WHO grade IV glioma
(glioblastoma or gliosarcoma); participants will be eligible if the original histology
was low-grade glioma and a subsequent histological diagnosis of glioblastoma or
variants is made
- PHASE I: A baseline brain MRI must be obtained no more than 14 days (+ 3 working days)
prior to study enrollment; the patient must either be on no steroids or a stable dose
of dexamethasone no greater than 2 mg a day for at least 5 days prior to entrance onto
the study; patients having undergone recent surgery are eligible as long as they are
at least 3 weeks from resection or 1 week from stereotactic biopsy, and recovering
from any operative or perioperative complications; no measurable disease post
resection will be required
- PHASE 1: Patients having undergone recent surgery are eligible as long as they are at
least 3 weeks from resection or 1 week from stereotactic biopsy, and recovering from
any operative or perioperative complications; no measurable disease post resection
will be required
- PHASE I: Any number of prior relapses
- PHASE II DOSE EXPANSION IN RECURRENT GBM UNDERGOING RESECTION: A baseline brain MRI
must be obtained no more than 14 days (+ 3 working days) prior to study enrollment;
the patient must either be on no steroids or a stable dose of dexamethasone no greater
than 2 mg a day for at least 5 days prior to entrance onto the study
- PHASE II DOSE EXPANSION IN NEWLY DIAGNOSED GBM: A baseline brain MRI obtained no more
than 14 days (+ 3 working days) prior to study enrollment on a stable dose of steroids
no greater than 2 mg a day of dexamethasone for at least 5 days, is required prior to
entrance of a patient onto the study; patients must be registered on the study within
5 weeks of completion of concurrent chemoradiation
Exclusion Criteria:
- Has been treated previously with bevacizumab
- PHASE II DOSE EXPANSION IN RECURRENT GBM UNDERGOING RESECTION: Has tumor localized
primarily to the posterior fossa, spinal cord, or an unresectable location
- Has received prior interstitial brachytherapy, implanted chemotherapy, or therapeutics
delivered by local injection or convection enhanced delivery; prior treatment with
Gliadel wafers will be excluded
- PHASE I AND PHASE II DOSE EXPANSION IN RECURRENT GBM UNDERGOING RESECTION: Is =< 12
weeks from completing external beam radiotherapy; patients with proven progressive
disease (PD) by resection or with new lesions outside of the radiation field should
not be excluded even if they are within 12 weeks of external radiation therapy (XRT),
per Response Assessment in Neuro-Oncology (RANO) criteria for early PD
- PHASE I AND PHASE II DOSE EXPANSION IN RECURRENT GBM UNDERGOING RESECTION: Is
currently participating in a study of an investigational agent or using an
investigational device for therapeutic purposes; concurrent use of Optune device is
not allowed
- PHASE II DOSE EXPANSION IN NEWLY DIAGNOSED GBM: Is currently participating or has
participated in any other newly diagnosed therapeutic trial before or after
chemoradiation
- CMV seronegative
- Has a known history of human immunodeficiency virus (HIV) (positive HIV 1/2
antibodies); human T-cell lymphotropic virus (HTLV) 1 antibody (HTLV1) and/or HTLV2;
active hepatitis B (e.g., hepatitis B virus surface antigen [HBsAg] reactive) or
hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is
detected); patients with prior hepatitis B virus (HBV) vaccination (anti-hepatitis B
surface antibody [HBs] positive, HBsAg negative, anti-hepatitis B core antibody [HBc]
negative) will NOT be excluded
- Has a diagnosis of immunodeficiency or is receiving systemic immunosuppressive therapy
within 7 days of study entrance
- PHASE II DOSE EXPANSION IN RECURRENT GBM UNDERGOING RESECTION: Has had prior
chemotherapy, or targeted small molecule therapy, within 2 weeks prior to study day 1
or who has not recovered (i.e., =< grade 1 or at baseline) from adverse events due to
a previously administered agent; Note: subjects with =< grade 2 neuropathy are an
exception to this criterion and may qualify for the study; Note: if subject received
major surgery, they must have recovered adequately from the toxicity and/or
complications from the intervention prior to starting therapy
- Has a known additional malignancy that is progressing or requires active treatment;
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
- PHASE II DOSE EXPANSION IN RECURRENT GBM UNDERGOING RESECTION: Has known gliomatous
meningitis, subependymal spread, extracranial disease, or multifocal disease
- PHASE II DOSE EXPANSION IN NEWLY DIAGNOSED GBM: Has known gliomatous meningitis,
extracranial disease, or multifocal disease
- 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 systemic steroids or immunosuppressive agents; 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 would not be
excluded from the study; subjects with hypothyroidism stable on hormone replacement or
Sjogren's syndrome will not be excluded from the study
- Has evidence of interstitial lung disease or active, non-infectious pneumonitis
- Has an active infection requiring systemic therapy
- 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
- 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 trial, starting with the screening visit
- PHASE II DOSE EXPANSION IN RECURRENT GBM UNDERGOING RESECTION AND IN NEWLY DIAGNOSED
GBM: Has received prior therapy with any antibody or drug specifically targeting
T-cell co-stimulation or checkpoint pathways
- Has received a live vaccine within 30 days prior to the first dose of trial treatment
- Contraindication for undergoing MRIs
- PHASE II DOSE EXPANSION IN RECURRENT GBM UNDERGOING RESECTION: Evidence of bleeding
diathesis or use of anticoagulant medication or any medication that may increase the
risk of bleeding that cannot be stopped prior to surgery
- PHASE I: Tumor localized primarily to the posterior fossa or spinal cord
- PHASE I: Has known gliomatous meningitis, subependymal spread, or extracranial disease
