• Incidence of adverse events [ Time Frame: Up to 15 years ]
  Will assess dose limiting toxicity and all toxicities. Toxicity is the primary endpoint and will be assessed using the National Cancer Institute (NCI)'s Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Rates and associated 95% Clopper and Pearson binomial confidence limits (95% confidence interval [CI]) will be estimated for participants' experiencing dose limiting toxicity (DLT) during neoadjuvant treatment period (DLT period 1), during adjuvant treatment period (DLT period 2), neo-adjuvant and adjuvant feasibility, as well as survival at 9 months. All toxicities and side effects will be summarized in tables by dose, time period, organ, and severity.
• Dose-limiting toxicity (DLT) [ Time Frame: Up to 14 days ]
  Will be described.
• Dose-limiting toxicity (DLT) [ Time Frame: Up to 28 days ]
  Will be described.
• Feasibility (neoadjuvant therapy) [ Time Frame: Up to 14 days ]
  As measured by the ability of patients receive ipilimumab/nivolumab (> 80% of the assigned doses) and undergo undergo surgery so that they can go on to receive the first dose of CAR T cells.
• Feasibility (adjuvant therapy) [ Time Frame: Up to 28 days ]
  Defined as the ability of patients to complete 4 cycles of CAR T infusions (> 80% of the assigned dose) and 2 doses of nivolumab.
• Survival [ Time Frame: At 9 months ]

• Dose limiting Toxicities [ Time Frame: 28-42 days ]
  Rates and associated 95% Clopper and Pearson binomial confidence limits
• Cytokine Release Syndrome based on (Appendix C) [ Time Frame: 28-42 days ]
  Rates and associated 95% Clopper and Pearson binomial confidence limits.
• All other toxicities will be assessed using the NCI's Common Terminology Criteria for Adverse Events (CTCAE v5.0, released on 11/27/2017). [ Time Frame: up to 15 years ]
  All toxicities and side effects will be summarized in tables by dose, time period, organ, and severity
• Feasibility of participants to either (i) receive Ipi/Nivo followed by 4 weekly CAR T cell with alternating weeks of Nivo infusions OR (ii) 4 weekly CAR T cell with alternating weeks of Nivo infusions [ Time Frame: 14- 28 days ]
  Rates and associated 95% Clopper and Pearson binomial confidence limits
• Survival at 9 months [ Time Frame: Up to 9 months ]
  Rates and associated 95% Clopper and Pearson binomial confidence limits

• T cell levels [ Time Frame: Up to 15 years ]
  Will assess chimeric antigen receptor (CAR) T and endogenous T cell levels and phenotype detected in tumor cyst fluid (TCF), peripheral blood (PB), and cerebral spinal fluid (CSF) (absolute number per ul by flow). Statistical and graphical methods will be used to describe persistence and expansion.
• Cytokine levels in TCF, PB, and CSF [ Time Frame: Up to 15 years ]
  Statistical and graphical methods will be used to describe persistence and expansion.
• Disease response [ Time Frame: Up to 15 years ]
  By Response Assessment in Neuro-Oncology (RANO) criteria with the need for Avastin as an additional indicator of progression.
• Time to progression [ Time Frame: Up to 15 years ]
  Progression is defined by RANO with the need for Avastin as an additional indicator of progression.
• Overall survival (OS) [ Time Frame: Up to 15 years ]
  Kaplan Meier methods will be used to estimate median OS and graph the results.
• Quality of life [ Time Frame: Up to 15 years ]
  Will estimate the mean and standard error for change from baseline during treatment and post treatment in the quality of life functioning scale, symptom scale and item scores from the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 and the domain scale and items scores from the Quality of Life Questionnaire Brian Tumor Patients 20. Will be estimated for each treatment arm.
• Area under the curve (AUC) for CD3, IFNgamma, and IP-10 levels over time for the DLT evaluation period [ Time Frame: Up to 28 days ]
  A two-tailed two-sample Students T test with a 0.05 level of significance will be used to determine if the AUCs over the adjuvant treatment DLT period (DLT period 2) for CD3, IFNgamma, and IP-10 are higher in one arm over the other.
• CAR T and endogenous cells detected in tumor tissue [ Time Frame: Up to 15 years ]
  By immunohistochemistry. Will be described.
• IL13Ralpha2 antigen expression levels in tumor tissue [ Time Frame: Up to 15 years ]
  By pathology H score. Will be described.
• PD-L1 levels on tumor cells [ Time Frame: Pre- and post-therapy ]
  Will be described.
• Biomathematical modeling of tumor growth [ Time Frame: Up to 15 years ]
  Will assess perfusion and growth parameters based on serial brain magnetic resonance imaging (MRI)s.
• Progression free survival (PFS) [ Time Frame: Up to 15 years ]
  Kaplan Meier methods will be used to estimate median PFS and graph the results.

• T cell levels [ Time Frame: Up to 15 years ]
  Will assess chimeric antigen receptor (CAR) T and endogenous T cell levels and phenotype detected in tumor cyst fluid (TCF), peripheral blood (PB), and cerebral spinal fluid (CSF) (absolute number per ul by flow). Statistical and graphical methods will be used to describe persistence and expansion.
• Cytokine (IFN-γ, IL-2, IL-6, TNF-α, and VEGF) levels in TCF, PB, and CSF [ Time Frame: Up to 1 years ]
  Descriptive statistical and graphical methods will be used to describe cytokine levels over the 1 year period
• Disease response [ Time Frame: Up to 15 years ]
  By Response Assessment in Neuro-Oncology (RANO) criteria with the need for Avastin as an additional indicator of progression.
• Time to progression [ Time Frame: Up to 15 years ]
  Progression is defined by RANO with the need for Avastin as an additional indicator of progression.
• Overall survival (OS) [ Time Frame: Up to 15 years ]
  Kaplan Meier methods will be used to estimate median OS and graph the results.
• Quality of Life Questionnaires [ Time Frame: Up to 15 years ]
  Will estimate the mean and standard error for change from baseline during treatment and post treatment in the quality of life functioning scale, symptom scale and item scores from the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 and the domain scale and items scores from the Quality of Life Questionnaire Brian Tumor Patients 20. Will be estimated for each treatment arm.
• Area under the curve (AUC) for CD3, IFNgamma, and IP-10 levels over time for the DLT evaluation period [ Time Frame: Up to 28 days ]
  A two-tailed two-sample Students T test with a 0.05 level of significance will be used to determine if the AUCs over the adjuvant treatment DLT period (DLT period 2) for CD3, IFNgamma, and IP-10 are higher in one arm over the other.
• CAR T and endogenous cells detected in tumor tissue [ Time Frame: Up to 15 years ]
  By immunohistochemistry. Will be described.
• IL13Ralpha2 antigen expression levels in tumor tissue [ Time Frame: Up to 15 years ]
  By pathology H score. Will be described.
• PD-L1 levels on tumor cells [ Time Frame: 1 year ]
  Change in PD-L1 levels (post -pre) will be presented using means and standard deviations
• Biomathematical modeling of tumor growth [ Time Frame: Up to 15 years ]
  Will assess perfusion and growth parameters based on serial brain magnetic resonance imaging (MRI)s.
• Progression free survival (PFS) [ Time Frame: Up to 15 years ]
  Kaplan Meier methods will be used to estimate median PFS and graph the results.

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.

• Recurrent Glioblastoma
• Refractory Glioblastoma

• Biological: IL13Ralpha2-specific Hinge-optimized 4-1BB-co-stimulatory CAR/Truncated CD19-expressing Autologous TN/MEM Cells
  Given ITV/ITC
  Other Names:

  • IL13 [EQ]BBzeta/truncated CD19[t]+ Naive and Memory T Cells
  • IL13 [EQ]BBzeta/truncated CD19[t]+ TN/MEM Cells
  • IL13Ra2-specific-hinge-optimized-4-1BB-CAR/truncated CD19-expressing Autologous TN/MEM Lymphocytes
• Biological: Ipilimumab
  Given IV
  Other Names:

  • Anti-Cytotoxic T-Lymphocyte-Associated Antigen-4 Monoclonal Antibody
  • BMS-734016
  • MDX-010
  • MDX-CTLA4
  • Yervoy
• Biological: Nivolumab
  Given IV
  Other Names:

  • BMS-936558
  • MDX-1106
  • NIVO
  • ONO-4538
  • Opdivo
• Other: Quality-of-Life Assessment
  Ancillary studies
  Other Name: Quality of Life Assessment
• Other: Questionnaire Administration
  Ancillary studies

• Experimental: Arm I (nivolumab, ipilimumab, IL13Ralpha2 CAR T cells)
  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 (ICV/intracranital 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.
  Interventions:

  • Biological: IL13Ralpha2-specific Hinge-optimized 4-1BB-co-stimulatory CAR/Truncated CD19-expressing Autologous TN/MEM Cells
  • Biological: Ipilimumab
  • Biological: Nivolumab
  • Other: Quality-of-Life Assessment
  • Other: Questionnaire Administration
• Experimental: Arm II (nivolumab, IL13Ra2 CAR T cells)
  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.
  Interventions:

  • Biological: IL13Ralpha2-specific Hinge-optimized 4-1BB-co-stimulatory CAR/Truncated CD19-expressing Autologous TN/MEM Cells
  • Biological: Nivolumab
  • Other: Quality-of-Life Assessment
  • Other: Questionnaire Administration

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)