A Phase 1 Study to Evaluate IL13Rα2-Targeted Chimeric Antigen Receptor (CAR) T Cells Combined With Checkpoint Inhibition for Patients With Resectable Recurrent Glioblastoma
试验速览
- 阶段
- 1 期
- 状态
- 进行中（未招募）
- 发起方
- 入组人数
- 20
- 试验地点
- 2
- 主要终点
- Incidence of adverse events
研究概览
简要总结
This phase I trial studies the side effects and how well IL13Ralpha2-CAR 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-CAR 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-CAR T cells and nivolumab together may work better in treating patients with glioblastoma.
详细描述
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. To provide IL13Rα2-CAR T cell therapy for subjects who are unable to wait for randomization into Arms 1 and 2. This arm will provide additional safety data provided in COH IRB 13384 for the set dose schedule. (Arm 3) 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).
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Informed Consent and Willingness to Participate
- •1. Documented informed consent of the participant and/or legally authorized representative. Assent, when appropriate, will be obtained per institutional guidelines.
- •2. Agreement to allow the use of archival tissue from diagnostic tumor biopsies. If unavailable, exceptions may be granted with Study PI approval. Age Criteria, Performance status
- •3. Ages ≥18 years
- •4. KPS ≥ 60%, ECOG ≤ 2
- •5. Life expectancy ≥ 4 weeks Nature of Illness and Illness Related Criteria
- •6. Histologically confirmed diagnosis of WHO classification grade IV GBM, or has a prior histologicallyconfirmed diagnosis of a grade II or III glioma and now has radiographic progression consistent with a grade IV GBM after completing standard therapy.
- •7. Relapsed/refractory disease: radiographic evidence of recurrence/progression of measurable disease after standard therapy, and ≥ 12 weeks after completion of front-line radiation therapy.
- •8. COH Clinical Pathology confirms IL13Rα2+ tumor expression by IHC at the initial tumor presentation or recurrent disease (H-score > 50; reference Appendix B)
- •9. Participants with a known history of congestive heart failure (CHF) or cardiac symptoms consistent with 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 EKG and Echocardiogram (ECHO) performed within 42 days prior to registration and as clinically indicated while on treatment. Clinical Laboratory and Organ Function Criteria (To be performed within 14 days prior to leukapheresis unless otherwise stated.
- •10. WBC > 2000 /dl (or ANC ≥ 1,000/mm3)
- •11. Platelets ≥ 75,000/mm3
- •12. Fasting Blood glucose within ULN
- •13. Total bilirubin ≤ 1.5 ULN
- •14. AST ≤ 2.5x ULN
- •15. ALT ≤ 2.5x ULN
- •16. Serum creatinine ≤1.6 mg/dL
- •17. O2 saturation ≥ 95% on room air
- •18. Seronegative for HIV Ag/Ab combo, Hepatitis C Ab*, active HBV (Surface Antigen Negative), Hepatitis A Virus IgM Antibody
- •*If positive, Hepatitis C RNA quantitation must be performed.
- •19. Women of childbearing potential (WOCBP): negative urine or serum pregnancy test If the urine test is positive or cannot be
- •20. 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 cycle of CAR T cells.
排除标准
- •Prior and concomitant therapies
- •1. Prior CTLA-4, PD-1 or PD-L1 inhibitor therapy.
- •2. Participant is steroid-dependent, requiring more than 6 mg of dexamethasone per day at the time of enrollment.
- •3. Participant has not yet recovered from toxicities of prior therapy. Other illnesses or conditions
- •4. History of or active autoimmune disease
- •5. Uncontrolled seizure activity and/or clinically evident progressive encephalopathy
- •6. History of allergic reactions attributed to compounds of similar chemical or biologic composition to study agent
- •7. Active diarrhea
- •8. Clinically significant uncontrolled illness
- •9. Active infection requiring antibiotics
- •10. Known history of immunodeficiency virus (HIV) or hepatitis B or hepatitis C infection
- •11. Other active malignancy
- •12. Females only: Pregnant or breastfeeding
- •13. 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. Noncompliance
- •14. 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).
研究组 & 干预措施
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.
干预措施: Nivolumab (Biological)
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.
干预措施: Ipilimumab (Biological)
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.
干预措施: Nivolumab (Biological)
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.
干预措施: Questionnaire Administration (Other)
Arm III (IL13Ra2 CAR T cells)
Patients receive IL13Ralpha2 CAR T cells infusion over 5 minutes via Rickham catheter (ICV/ICT) every 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 at the discretion of the principal investigator and oncologist.
干预措施: Quality-of-Life Assessment (Other)
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.
干预措施: IL13Ralpha2-specific Hinge-optimized 4-1BB-co-stimulatory CAR/Truncated CD19-expressing Autologous TN/MEM Cells (Biological)
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.
干预措施: Quality-of-Life Assessment (Other)
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.
干预措施: Questionnaire Administration (Other)
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.
干预措施: IL13Ralpha2-specific Hinge-optimized 4-1BB-co-stimulatory CAR/Truncated CD19-expressing Autologous TN/MEM Cells (Biological)
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.
干预措施: Quality-of-Life Assessment (Other)
Arm III (IL13Ra2 CAR T cells)
Patients receive IL13Ralpha2 CAR T cells infusion over 5 minutes via Rickham catheter (ICV/ICT) every 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 at the discretion of the principal investigator and oncologist.
干预措施: IL13Ralpha2-specific Hinge-optimized 4-1BB-co-stimulatory CAR/Truncated CD19-expressing Autologous TN/MEM Cells (Biological)
Arm III (IL13Ra2 CAR T cells)
Patients receive IL13Ralpha2 CAR T cells infusion over 5 minutes via Rickham catheter (ICV/ICT) every 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 at the discretion of the principal investigator and oncologist.
干预措施: Questionnaire Administration (Other)
结局指标
主要结局
Incidence of adverse events
时间窗: 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.
Feasibility (adjuvant therapy)
时间窗: 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.
Feasibility (neoadjuvant therapy)
时间窗: 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.
Overall Survival
时间窗: At 9 months
The length of time from either the date of diagnosis or the start of treatment for a disease, such as cancer, that patients diagnosed with the disease are still alive.
Dose-limiting toxicity (DLT)
时间窗: Up to 28 days
A toxicity that causes side effects that are serious enough to prevent an increase in dose or level of that treatment.
次要结局
- IL13Ralpha2 antigen expression levels in tumor tissue(Up to 15 years)
- Area under the curve (AUC) for CD3, IFNgamma, and IP-10 levels over time for the DLT evaluation period(Up to 28 days)
- T cell levels(Up to 15 years)
- Cytokine levels in TCF, PB, and CSF(Up to 15 years)
- Biomathematical modeling of tumor growth(Up to 15 years)
- Progression free survival (PFS)(Up to 15 years)
- Disease response(Up to 15 years)
- Time to progression(Up to 15 years)
- Overall survival (OS)(Up to 15 years)
- Quality of life (QOL)(Up to 15 years)
- CAR T and endogenous cells detected in tumor tissue(Up to 15 years)
- PD-L1 levels on tumor cells(Pre- and post-therapy)