IL13Ralpha2-Targeted Chimeric Antigen Receptor (CAR) T Cells With or Without Nivolumab and Ipilimumab in Treating Patients With Recurrent or Refractory Glioblastoma
IL13Ralpha2-Targeted Chimeric Antigen Receptor (CAR) T Cells With or Without Nivolumab and Ipilimumab in Treating Patients With Recurrent or Refractory Glioblastoma
This phase I trial studies the side effects and how well IL13Ralpha2-CRT T cells work when
 given alone or together with nivolumab and ipilimumab in treating patients with glioblastoma
 that has come back (recurrent) or does not respond to treatment (refractory). Biological
 therapies, such as IL13Ralpha2-CRT T cells, use substances made from living organisms that
 may attack specific glioma cells and stop them from growing or kill them. Immunotherapy with
 monoclonal antibodies, such as nivolumab and ipilimumab, may help the body's immune system
 attack the cancer, and may interfere with the ability of tumor cells to grow and spread. It
 is not yet known whether giving IL13Ralpha2-CRT T cells and nivolumab together may work
 better in treating patients with glioblastoma.
PRIMARY OBJECTIVES:

 I. To examine and describe the safety and feasibility of nivolumab plus ipilimumab as
 neoadjuvant therapy. (Arm 1) II. To examine and describe the safety and feasibility of
 IL13Ralpha2-CAR T cell plus nivolumab as adjuvant therapy. (Arms 1 and 2) III. In arms
 determined to be safe and feasible, a selection design based on two Southwest Oncology Group
 (SWOG) two stage designs will be used to assess which arm(s) goes on for further study based
 on survival rate at 9 months.

 SECONDARY OBJECTIVES:

 I. Describe persistence, expansion and phenotype of endogenous and IL13Ralpha2-CAR CAR T
 cells in tumor cyst fluid (TCF), peripheral blood (PB), and cerebral spinal fluid (CSF).

 II. Describe cytokine levels (PB, TCF, CSF) over the study period for each arm. (Arm 1 or Arm
 2).

 III. Estimate disease response rates. IV. Estimate time to progression. V. Estimate median
 overall survival (OS).

 VI. In study participants who have completed the adjuvant dose-limiting toxicity (DLT)
 period:

 VIa. 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-Core
 (QLQ-C)30 and EORTC QLQ Brain Cancer Patients (BN-20) survey scale, domain and item scores
 during and post treatment.

 VIb. Assess if the area under the curve (AUC) for CD3 T cells, IFNgamma and IP-10 for the DLT
 period is greater in one arm versus (vs.) the other.

 VII. In study participants who undergo an additional biopsy/resection or autopsy:

 VIIa. Evaluate CAR T cell persistence in the tumor tissue and the location of the CAR T cells
 with respect to the injection, and VIIb. Evaluate IL13Ralpha2 antigen and PD-L1 levels on
 tumor tissue pre and post CAR T cell therapy.

 VIII. Use biomathematical modeling of tumor growth to evaluate benefit of treatment.

 OUTLINE: Patients are randomized to 1 of 2 arms.

 ARM I: Patients receive nivolumab intravenously (IV) over 60 minutes and ipilimumab IV over
 90 minutes on day -14. Patients then receive IL13Ralpha2 CAR T cells infusion over 5 minutes
 via Rickham catheter (intracranial intraventricular [ICV]/intracranital intratumoral [ICT])
 every week and nivolumab IV over 30 minutes every other week. Treatment repeats weekly for up
 to 4 cycles in the absence of disease progression or unacceptable toxicity. After cycle 4,
 patients may receive additional CAR T cells weekly and nivolumab IV every other week or
 monthly at the discretion of the principal investigator and oncologist.

 ARM II: Patients receive IL13Ralpha2 CAR T cells infusion over 5 minutes via Rickham catheter
 (ICV/ICT) every week and nivolumab IV over 30 minutes every other week. Treatment repeats
 weekly for up to 4 cycles in the absence of disease progression or unacceptable toxicity.
 After cycle 4, patients may receive additional CAR T cells weekly and nivolumab IV every
 other week or monthly at the discretion of the principal investigator and oncologist.

 After completion of study treatment, patients are followed up at 30 days, 3, 6, and 12
 months, and then annually for 15 years.
Inclusion Criteria:

 -  Documented informed consent of the participant and/or legally authorized
 representative. Assent, when appropriate, will be obtained per institutional
 guidelines

 -  Agreement to allow the use of archival tissue from diagnostic tumor biopsies. If
 unavailable, exceptions may be granted with study principal investigator (PI) approval

 -  Karnofsky performance status (KPS) >= 60%, Eastern Cooperative Oncology Group (ECOG)
 =< 2

 -  Life expectancy >= 4 weeks

 -  Histologically confirmed diagnosis of World Health Organization (WHO) classification
 grade IV glioblastoma (GBM), or has a prior histologically-confirmed diagnosis of a
 grade II or III glioma and now has radiographic progression consistent with a grade IV
 GBM after completing standard therapy.

 -  Note, subjects with leptomeningeal involvement will be excluded from enrollment

 -  Relapsed/refractory disease: radiographic evidence of 1st or 2nd
 recurrence/progression of measurable disease after standard therapy, and >= 12 weeks
 after completion of front-line radiation therapy

 -  Resectable GBM assessed by PI at enrollment with >= 75% debulking feasibility

 -  City of Hope (COH) Clinical Pathology confirms IL13Ralpha2+ tumor expression by
 immunohistochemistry (IHC) at the initial tumor presentation or recurrent disease
 (H-score >= 50)

 -  Participants with a known history of congestive heart failure (CHF) or cardiac
 symptoms consistent with New York Heart Association (NYHA) classification III-IV
 within 6 months prior to day 1 of protocol treatment, cardiomyopathy, myocarditis,
 myocardial infarction (MI), exposure to cardiotoxic medications or with clinical
 history suggestive of the above must have an electrocardiogram (EKG) and
 echocardiogram (ECHO) performed within 42 days prior to registration and as clinically
 indicated while on treatment

 -  White blood cell (WBC) > 2000/dl (or absolute neutrophil count [ANC] >= 1,000/mm^3)
 (to be performed within 14 days prior to leukapheresis unless otherwise stated)

 -  Platelets >= 75,000/mm^3 (to be performed within 14 days prior to leukapheresis unless
 otherwise stated)

 -  Fasting blood glucose within upper limit of normal (ULN) (to be performed within 14
 days prior to leukapheresis unless otherwise stated)

 -  Total bilirubin =< 1.5 ULN (to be performed within 14 days prior to leukapheresis
 unless otherwise stated)

 -  Aspartate aminotransferase (AST) =< 2.5 x ULN (to be performed within 14 days prior to
 leukapheresis unless otherwise stated)

 -  Alanine aminotransferase (ALT) =< 2.5 x ULN (to be performed within 14 days prior to
 leukapheresis unless otherwise stated)

 -  Serum creatinine =< 1.6 mg/dL (to be performed within 14 days prior to leukapheresis
 unless otherwise stated)

 -  Oxygen (O2) saturation >= 95% on room air (to be performed within 14 days prior to
 leukapheresis unless otherwise stated)

 -  Seronegative for human immunodeficiency virus (HIV) antigen (Ag)/antibody (Ab) combo,
 hepatitis C Ab*, active hepatitis B virus (HBV) (surface antigen negative), hepatitis
 A virus IgM antibody (to be performed within 14 days prior to leukapheresis unless
 otherwise stated)

 -  If positive, hepatitis C ribonucleic acid (RNA) quantitation must be performed

 -  Women of childbearing potential (WOCBP): negative urine or serum pregnancy test, if
 the urine test is positive or cannot be confirmed as negative, a serum pregnancy test
 will be required (to be performed within 14 days prior to leukapheresis unless
 otherwise stated)

 -  Agreement by females and males of childbearing potential* to use an effective method
 of birth control or abstain from heterosexual activity for the course of the study
 through at least 5 months after the last dose of nivolumab and/or 3 months after the
 last dose of CAR T cells.

 -  Childbearing potential defined as not being surgically sterilized (men and women)
 or have not been free from menses for > 1 year (women only)

 -  CRITERIA TO PROCEED WITH PBMC COLLECTION: Research participant must not require more
 than 6 mg daily of dexamethasone on the day of PBMC collection

 -  CRITERIA TO PROCEED WITH PBMC COLLECTION: Research participant must have appropriate
 venous access or be willing to undergo central catheter line placement

 -  CRITERIA TO PROCEED WITH PBMC COLLECTION: At least 2 weeks must have elapsed since the
 research participant received his/her last dose of prior chemotherapy or radiation

 -  CRITERIA TO PROCEED WITH PBMC COLLECTION: Research participants has signed
 leukapheresis informed consent

 -  CRITERIA FOR TREATMENT CONSENT AND ARM ASSIGNMENT/RANDOMIZATION: In the opinion of the
 manufacturing team, the research participant's selected Tn/mem population is
 sufficient to generate an acceptable CAR T cell product (this will be verified by
 email correspondence from the manufacturing team to the study team)

 -  CRITERIA TO PROCEED WITH NEOADJUVANT THERAPY (Arm 1 Only): KPS >= 60%

 -  CRITERIA TO PROCEED WITH NEOADJUVANT THERAPY (Arm 1 Only): Creatinine =< 1.6 mg/dL

 -  CRITERIA TO PROCEED WITH NEOADJUVANT THERAPY (Arm 1 Only): WBC >= 2,000/dl (or ANC >=
 1,000)

 -  CRITERIA TO PROCEED WITH NEOADJUVANT THERAPY (Arm 1 Only): INR =< 1.3, but may give
 fresh frozen plasma to bring to 1.3

 -  CRITERIA TO PROCEED WITH NEOADJUVANT THERAPY (Arm 1 Only): Bilirubin =< 1.5 ULN

 -  CRITERIA TO PROCEED WITH NEOADJUVANT THERAPY (Arm 1 Only): ALT and AST =< 2.5 X upper
 limits of normal

 -  CRITERIA TO PROCEED WITH NEOADJUVANT THERAPY (Arm 1 Only): Research participants must
 not require more than =< 6 mg daily of dexamethasone during T cell therapy

 -  CRITERIA TO PROCEED WITH NEOADJUVANT THERAPY (Arm 1 Only): Washout requirements:

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

 -  At least 23 days since the completion of temozolomide 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

 -  For bevacizumab the wash out period of at least 4 weeks is required before
 starting study treatment

 -  CRITERIA TO PROCEED WITH SURGICAL RESECTION/RICKHAM CATHETER PLACEMENT: KPS >= 60%

 -  CRITERIA TO PROCEED WITH SURGICAL RESECTION/RICKHAM CATHETER PLACEMENT: Creatinine =<
 1.6 mg/dL

 -  CRITERIA TO PROCEED WITH SURGICAL RESECTION/RICKHAM CATHETER PLACEMENT: WBC >=
 2,000/dl (or ANC >= 1,000)

 -  CRITERIA TO PROCEED WITH SURGICAL RESECTION/RICKHAM CATHETER PLACEMENT: INR =< 1.3,
 but may give fresh frozen plasma to bring to 1.3

 -  CRITERIA TO PROCEED WITH SURGICAL RESECTION/RICKHAM CATHETER PLACEMENT: Bilirubin =<
 1.5 ULN

 -  CRITERIA TO PROCEED WITH SURGICAL RESECTION/RICKHAM CATHETER PLACEMENT: ALT and AST =<
 2.5 X upper limits of normal

 -  CRITERIA TO PROCEED WITH SURGICAL RESECTION/RICKHAM CATHETER PLACEMENT: Second-line
 radiation therapy (post-leukapheresis) within 4 weeks of surgical resection/Rickham
 placement

 -  CRITERIA TO PROCEED WITH SURGICAL RESECTION/RICKHAM CATHETER PLACEMENT: Washout
 requirements (required for Arm 2 only):

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

 -  At least 23 days since the completion of temozolomide 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

 -  For bevacizumab the wash out period of at least 4 weeks is required before
 starting study treatment

 -  CRITERIA TO PROCEED WITH CAR T CELL AND/OR NIVOLUMAB INFUSION: Research participant
 has a released cryopreserved CAR T cell product

 -  CRITERIA TO PROCEED WITH CAR T CELL AND/OR NIVOLUMAB INFUSION: Participant has
 completed neoadjuvant therapy (Arm 1 only)

 -  CRITERIA TO PROCEED WITH CAR T CELL AND/OR NIVOLUMAB INFUSION: Participant has
 undergone Rickham catheter placements

 -  CRITERIA TO PROCEED WITH CAR T CELL AND/OR NIVOLUMAB INFUSION: Research participant
 does not require supplemental oxygen to keep saturation >= 95% and/or does not have
 presence of any radiographic abnormalities on chest x-ray that are progressive

 -  CRITERIA TO PROCEED WITH CAR T CELL AND/OR NIVOLUMAB INFUSION: Research participant
 does not require pressor support and/or does not have symptomatic cardiac arrhythmias

 -  CRITERIA TO PROCEED WITH CAR T CELL AND/OR NIVOLUMAB INFUSION: Research participant
 does not have a fever exceeding 38.5 degrees 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

 -  CRITERIA TO PROCEED WITH CAR T CELL AND/OR NIVOLUMAB INFUSION: Serum total bilirubin
 >= 1.5 x ULN.

 -  CRITERIA TO PROCEED WITH CAR T CELL AND/OR NIVOLUMAB INFUSION: AST and ALT do not
 exceed =< 2.5 x ULN

 -  CRITERIA TO PROCEED WITH CAR T CELL AND/OR NIVOLUMAB INFUSION: Research participant's
 serum creatinine =< 1.6 mg/dL

 -  CRITERIA TO PROCEED WITH CAR T CELL AND/OR NIVOLUMAB INFUSION: Research participant
 does not have uncontrolled seizure activity following surgery prior to starting the
 first T cell dose

 -  CRITERIA TO PROCEED WITH CAR T CELL AND/OR NIVOLUMAB INFUSION: Research participant
 platelet count must be >= 100,000. However, if platelet level is between
 75,000-99,000, then T-cell infusion may proceed if after platelet transfusion the
 count is >= 100,000

 -  CRITERIA TO PROCEED WITH CAR T CELL AND/OR NIVOLUMAB INFUSION: For cycles 1-4:
 Research participants must not require more than 6 mg daily of dexamethasone during
 CAR T cell therapy

 -  CRITERIA TO PROCEED WITH CAR T CELL AND/OR NIVOLUMAB INFUSION: For cycles 5+: Research
 participants must not require more than 12 mg daily of dexamethasone during CAR T cell
 therapy

 -  CRITERIA TO PROCEED WITH CAR T CELL AND/OR NIVOLUMAB INFUSION: Wash-out requirements
 (standard or investigational):

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

 -  At least 23 days since the completion of temozolomide 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

 Exclusion Criteria:

 -  Prior CTLA-4, PD-1 or PD-L1 inhibitor therapy

 -  Participant is steroid-dependent, requiring more than 6 mg of dexamethasone per day

 -  Participant has not yet recovered from toxicities of prior therapy

 -  History of or active autoimmune disease

 -  Uncontrolled seizure activity and/or clinically evident progressive encephalopathy

 -  History of allergic reactions attributed to compounds of similar chemical or biologic
 composition to study agent

 -  Active diarrhea

 -  Clinically significant uncontrolled illness

 -  Active infection requiring antibiotics

 -  Known history of immunodeficiency virus (HIV) or hepatitis B or hepatitis C infection

 -  Other active malignancy

 -  Females only: Pregnant or breastfeeding

 -  Any other condition that would, in the investigator's judgment, contraindicate the
 subject's participation in the clinical study due to safety concerns with clinical
 study procedures

 -  Prospective participants who, in the opinion of the investigator, may not be able to
 comply with all study procedures (including compliance issues related to
 feasibility/logistics)