Genetically Modified T-cells in Treating Patients With Recurrent or Refractory Malignant Glioma

PRIMARY OBJECTIVES:

I. To assess the feasibility and safety of cellular immunotherapy utilizing ex vivo expanded
autologous memory-enriched T cells that are genetically modified using a self-inactivating
(SIN) lentiviral vector to express an interleukin 13 receptor alpha 2 (IL13R alpha
2)-specific, hinge-optimized, 41BB-costimulatory chimeric antigen receptor (CAR), as well as
a truncated human cluster of differentiation 19 (CD19) for participants with
recurrent/refractory malignant glioma in one of the following ways: stratum 1 (intratumoral
delivery of IL13 [EQ]BBzeta/truncated CD19[t]+ central memory T cells [Tcm]) (IL13R alpha
2-specific, hinge-optimized, 41BB-costimulatory CAR/truncated CD19-expressing T lymphocytes),
stratum 2 (intracavitary delivery of IL13 [EQ]BBzeta/truncated CD19[t]+ Tcm, stratum 3
(intraventricular delivery of IL13 [EQ]BBzeta/truncated CD19[t]+ Tcm), stratum 4 (dual
delivery [both intratumoral and intraventricular] of IL13 [EQ]BBzeta/truncated CD19[t]+ Tcm),
or stratum 5 (dual delivery of IL13 [EQ]BBzeta/truncated CD19[t]+ naive and memory T cells
[Tn/mem]).II. To determine maximum tolerated dose schedule (MTD) and a recommended phase II
dosing plan (RP2D) for each stratum based on dose limiting toxicities (DLTs) and the full
toxicity profile.

SECONDARY OBJECTIVES:

I. To assess the timing and extent of brain inflammation, as assessed by magnetic resonance
imaging (MRI)/magnetic resonance spectroscopy (MRS), following T cell administration.

II. To describe cytokine levels (cyst fluid, peripheral blood) over the study period.

III. In research participants who receive the full schedule of three CAR+ T cell doses:
estimate the six month progression free survival rate, disease response rates, and median
overall survival.

IV. In research participants who receive intraventricular infusions after progressing
following intratumoral/intracranial infusions (stratum 1 or 2): estimate disease response.

V. In research participants who receive at least one dose of CAR+ T cells estimate the mean
change from baseline in quality of life using the European Organization for Research and
Treatment of Cancer (EORTC) quality of life questionnaire (QLQ)-C30 and EORTC QLQ brain
neoplasm (BN)-20 survey scale, domain and item scores during and post treatment.

VI. To evaluate CAR T cell persistence in the tumor micro-environment and the location of the
CAR T cells with respect to the injection. (For research participants who undergo a second
resection or autopsy).

VII. To evaluate IL13R alpha 2 antigen expression levels pre and post CAR T cell therapy.
(For research participants who undergo a second resection or autopsy) OUTLINE: This is a
dose-escalation study. Patients are assigned to 1 of 5 strata.

STRATUM I (Intratumoral delivery) CLOSED TO ACCRUAL 03/02/2018: Patients receive IL13R alpha
2-specific, hinge-optimized, 41BB-costimulatory CAR/truncated CD19-expressing T lymphocytes
via intratumoral catheter over 5 minutes weekly for 3 weeks. Beginning as early as 1 week
later, patients may receive additional T cell infusions as long as patients remain eligible
and there is product available. Patients who progress on intracavitary or intratumoral
administration may move to intraventricular catheter for the optional infusions.

STRATUM II (Intracavitary delivery): Patients receive IL13R alpha 2-specific,
hinge-optimized, 41BB-costimulatory CAR/truncated CD19-expressing T lymphocytes via
intracavitary catheter over 5 minutes weekly for 3 weeks. Beginning as early as 1 week later,
patients may receive additional T cell infusions as long as patients continue to remain
eligible and there is product available. Patients who progress on intracavitary or
intratumoral administration may move to intraventricular catheter for the optional infusions.

STRATUM III (Intraventricular delivery): Patients receive IL13R alpha 2-specific,
hinge-optimized, 41BB-costimulatory CAR/truncated CD19-expressing T lymphocytes via
intraventricular catheter over 5 minutes weekly for 3 weeks. Beginning as early as 1 week
later, patients may receive additional T cell infusions as long as patients continue to
remain eligible and there is product available.

STRATUM IV (Dual delivery): Patients receive IL13R alpha 2-specific, hinge-optimized,
41BB-costimulatory CAR/truncated CD19-expressing T lymphocytes via intratumoral catheter and
intraventricular catheter over 5 minutes weekly for 3 weeks. Beginning as early as 1 week
later, patients may receive additional T cell infusions as long as patients continue to
remain eligible and there is product available. Based on clinical response after the first 3
infusions, the study principal investigator may decide to continue with the optional
infusions at either one or both sites (instead of requiring injections at both sites).

STRATUM V (Dual delivery): Patients receive IL13 [EQ]BBzeta/truncated CD19[t]+ Tn/mem via
intratumoral catheter and intraventricular catheter over 5 minutes weekly for 3 weeks.
Beginning as early as 1 week later, patients may receive additional T cell infusions as long
as patients continue to remain eligible and there is product available. Based on clinical
response after the first 3 infusions, the study principal investigator may decide to continue
with the optional infusions at either one or both sites (instead of requiring injections at
both sites).

After completion of study treatment, patients are followed up at 4 weeks, 3, 6, 8, 10 and 12
months and then yearly for 15 years.

Inclusion Criteria:

SCREENING INCLUSION CRITERIA

- Participant has a prior histologically-confirmed diagnosis of a grade III or IV
glioma, or has a prior histologically-confirmed diagnosis of a grade II glioma and now
has radiographic progression consistent with a grade III or IV malignant glioma (MG)
after completing standard therapy

- Radiographic evidence of progression/recurrence of the measurable disease more than 12
weeks after the end of the initial radiation therapy

- Karnofsky performance status (KPS) >= 60%

- Life expectancy > 4 weeks

- Women of child-bearing potential and men must agree to use adequate contraception
(hormonal or barrier method of birth control or abstinence) prior to study entry and
for six months following duration of study participation; should a woman become
pregnant or suspect that she is pregnant while participating on the trial, she should
inform her treating physician immediately

- COH Clinical Pathology confirms IL13R alpha 2+ tumor expression by
immunohistochemistry (>= 20%, 1+)

- All research participants must have the ability to understand and the willingness to
sign a written informed consent

ELIGIBILITY TO PROCEED WITH PBMC COLLECTION:

- Research participant must not require more than 2 mg TID of Dexamethasone on the day
of PBMC collection

- Research participant must have appropriate venous access

- At least 2 weeks must have elapsed since the research participant received his/her
last dose of prior chemotherapy or radiation

ELIGIBILITY TO PROCEED WITH RICKHAM PLACEMENT:

- Creatinine < 1.6 mg/dL

- White blood cell (WBC) > 2,000/dl

- Absolute neutrophil count (ANC) > 1,000

- Platelets >= 100,000/dl

- International normalized ratio (INR) < 1.3

- Bilirubin < 1.5 mg/dL

- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 2.5 x upper
limits of normal

- An interval of at least 12 weeks must have elapsed since the completion of initial
radiation therapy

- At least 6 weeks since the completion of a nitrosourea-containing chemotherapy regimen

- At least 23 days since the completion of Temodar and/or 4 weeks for any other
non-nitrosourea-containing cytotoxic chemotherapy regimen; if a patient's most recent
treatment was with a targeted agent only, and s/he has recovered from any toxicity of
this targeted agent, then a waiting period of only 2 weeks is needed from the last
dose and the start of study treatment, with the exception of bevacizumab where a wash
out period of at least 4 weeks is required before starting study treatment

ELIGIBILITY FOR ENROLLMENT AND TO PROCEED WITH CAR T CELL INFUSION:

- Research participant has a released cryopreserved T cell product

- Research participant does not require supplemental oxygen to keep saturation greater
than 95% and/or does not have presence of any radiographic abnormalities on chest
x-ray that are progressive

- Research participant does not require pressor support and/or does not have symptomatic
cardiac arrhythmias

- Research participant does not have a fever exceeding 38.5° Celsius (C); there is an
absence of positive blood cultures for bacteria, fungus, or virus within 48-hours
prior to T cell infusion and/or there aren't any indications of meningitis

- Serum total bilirubin does not exceed 2 x normal limit

- Transaminases does not exceed 2 x normal limit

- Serum creatinine =< 1.8 mg/dL

- Research participant does not have uncontrolled seizure activity following surgery
prior to starting the first T cell dose

- Platelet count must be >= 100,000; however, if platelet level is between
75,000-99,000, then T-cell infusion may proceed after platelet transfusion is given
and the post transfusion platelet count is >= 100,000

- Research participants must not require more than 2 mg thrice daily (TID) of
dexamethasone during T cell therapy

Exclusion Criteria:

SCREENING EXCLUSION CRITERIA

- Research participant requires supplemental oxygen to keep saturation greater than 95%
and the situation is not expected to resolve within 2 weeks

- Research participant requires pressor support and/or has symptomatic cardiac
arrhythmias

- Research participant requires dialysis

- Research participant has uncontrolled seizure activity and/or clinically evident
progressive encephalopathy

- Failure of research participant to understand the basic elements of the protocol
and/or the risks/benefits of participating in this phase I study; a legal guardian may
substitute for the research participant

- Research participants with any non-malignant intercurrent illness which is either
poorly controlled with currently available treatment, or which is of such severity
that the investigators deem it unwise to enter the research participant on protocol
shall be ineligible

- Research participants with any other active malignancies

- Research participants being treated for severe infection or who are recovering from
major surgery are ineligible until recovery is deemed complete by the investigator

- Research participants with any uncontrolled illness including ongoing or active
infection; research participants with known active hepatitis B or C infection;
research participants with any signs or symptoms of active infection, positive blood
cultures or radiological evidence of infections

- Research participants who have confirmed HIV positivity within 4 weeks of screening

- Subjects, who in the opinion of the investigator, may not be able to comply with the
safety monitoring requirements of the study