Phase I Study of Cellular Immunotherapy Using Memory-Enriched T Cells Lentivirally Transduced to Express a HER2-Specific, Hinge-Optimized, 41BB-Costimulatory Chimeric Receptor and a Truncated CD19 for Patients With Recurrent/Refractory Malignant Glioma
Overview
- Phase
- Phase 1
- Intervention
- HER2(EQ)BBζ/CD19t+ T cells
- Conditions
- Glioblastoma
- Sponsor
- City of Hope Medical Center
- Enrollment
- 29
- Locations
- 1
- Primary Endpoint
- Incidence of adverse events
- Status
- Active, not recruiting
- Last Updated
- 2 months ago
Overview
Brief Summary
This phase I trial studies the side effects and best dose of memory-enriched T cells in treating patients with grade II-IV glioma that has come back (recurrent) or does not respond to treatment (refractory). Memory enriched T cells such as HER2(EQ)BBζ/CD19t+ T cells may enter and express its genes in immune cells. Immune cells can be engineered to kill glioma cells in the laboratory by inserting a piece of deoxyribonucleic acid (DNA) into the immune cells that allows them to recognize glioma cells. A vector called lentivirus is used to carry the piece of DNA into the immune cell. It is not known whether these immune cells will kill glioma tumor cells when given to patients.
Detailed Description
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 a HER2-specific, hinge-optimized, 41BB-costimulatory chimeric antigen receptor (CAR), as well as a truncated human CD19 (HER2\[EQ\]BBzeta/CD19t+) for participants with recurrent/refractory malignant glioma in one of the following ways: Arm 1 (intracavitary/intratumoral HER2(EQ)BBzeta/CD19+ T CM), Arm 2 (dual delivery \[both intracavitary/intratumoral and intraventricular\] of HER2(EQ)BBzeta/CD19+ T CM), or Arm 3 (dual delivery \[both intracavitary/intratumoral and intraventricular\] of HER2(EQ)BBzeta/CD19+ T N/MEM). II. To determine maximum tolerated dose schedule (MTD) and a recommended Phase II dosing plan (RP2D) for arm 3 (dual delivery). SECONDARY OBJECTIVES: I. To describe persistence and expansion of CAR T cells in tumor cyst fluid, peripheral blood and cerebral spinal fluid (CSF). II. To describe cytokine levels (tumor cyst fluid, peripheral blood, and CSF) over the study period. III. In research participants who receive the full schedule of 3 CAR T cell doses: IIIa. To estimate median progression free survival (PFS) rate. IIIb. To estimate disease response rates. IIIc. To estimate median overall survival (OS). IV. In research participants who continue to receive infusions after progressing: IVa. Estimate disease response. IVb. Describe CAR T cell and endogenous immune populations, as well as cytokine and microenvironment profiles (cerebral spinal fluid \[CSF\], cyst fluid, peripheral blood) considering post progression therapy(ies), if applicable. V. For study participants who undergo an additional biopsy/resection or autopsy: Va. Evaluate CAR T cell persistence in the tumor micro-environment and the location of the CAR T cells with respect to the injection. Vb. Evaluate HER2 antigen expression levels pre and post CAR T cell therapy. OUTLINE: This is a dose-escalation study of autologous HER2(EQ)BBζ/CD19t+ T cells. Participants are assigned to 1 of 3 arms. ARM I: Patients receive autologous HER2(EQ)BBzeta/CD19t+ Tcm cells via intratumoral/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 remain eligible and there is product available. Patients who progress on intracavitary or intratumoral administration may move to alternative delivery routes for the optional infusions. ARM II: Patients receive autologous HER2(EQ)BBzeta/CD19t+ Tcm cells via intratumoral/intracavitary 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). ARM III: Patients receive autologous HER2(EQ)BBzeta/CD19t+ Tn/mem cells via intratumoral/intracavitary 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, then annually for at least 15 years.
Investigators
Eligibility Criteria
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)
- •Karnofsky performance status (KPS) \>= 60%
- •Life expectancy \> 4 weeks
- •The effects of HER2(EQBBzeta/CD19t+ T cells on the developing fetus are unknown. For this reason, 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
- •City of Hope (COH) Clinical Pathology confirms HER2+ tumor expression by immunohistochemistry (\>= 20%, 1+)
- •All research participants must have the ability to understand and the willingness to sign a written informed consent
- •Note: For research participants who do not speak English, a short form consent may be used with a COH certified interpreter/translator to proceed with screening and leukapheresis, while the request for a translated full consent is processed; however, the research participant is allowed to proceed with rickham placement and CAR T cell infusion only after the translated full consent form is signed
- •ELIGIBILITY TO PROCEED WITH PERIPHERAL BLOOD MONONUCLEAR CELL (PBMC) COLLECTION
- •Research participant must not require more than 2 mg three times daily (TID) of dexamethasone on the day of PBMC collection.
- •Research participant must have appropriate venous access
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 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
- •Research participants with new symptoms of CHF, cardiomyopathy, myocarditis, MI, or exposure to cardiotoxic medications must have a cardiac consultation, creatinine phosphokinase (CPK), and troponin testing at pre -study and as clinically indicated
- •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
Arms & Interventions
Arm I (intratumoral/intracavitary delivery)
Patients receive autologous HER2(EQ)BBzeta/CD19t+ Tcm cells via intratumoral/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 remain eligible and there is product available. Patients who progress on intracavitary or intratumoral administration may move to alternative delivery routes for the optional infusions.
Intervention: HER2(EQ)BBζ/CD19t+ T cells
Arm I (intratumoral/intracavitary delivery)
Patients receive autologous HER2(EQ)BBzeta/CD19t+ Tcm cells via intratumoral/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 remain eligible and there is product available. Patients who progress on intracavitary or intratumoral administration may move to alternative delivery routes for the optional infusions.
Intervention: Laboratory Biomarker Analysis
Arm I (intratumoral/intracavitary delivery)
Patients receive autologous HER2(EQ)BBzeta/CD19t+ Tcm cells via intratumoral/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 remain eligible and there is product available. Patients who progress on intracavitary or intratumoral administration may move to alternative delivery routes for the optional infusions.
Intervention: Leukapheresis
Arm II (dual delivery Tcm enriched)
Patients receive autologous HER2(EQ)BBzeta/CD19t+ Tcm cells via intratumoral/intracavitary 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).
Intervention: HER2(EQ)BBζ/CD19t+ T cells
Arm II (dual delivery Tcm enriched)
Patients receive autologous HER2(EQ)BBzeta/CD19t+ Tcm cells via intratumoral/intracavitary 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).
Intervention: Laboratory Biomarker Analysis
Arm II (dual delivery Tcm enriched)
Patients receive autologous HER2(EQ)BBzeta/CD19t+ Tcm cells via intratumoral/intracavitary 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).
Intervention: Leukapheresis
ARM III (dual delivery Tn/mem enriched)
Patients receive autologous HER2(EQ)BBzeta/CD19t+ Tn/mem cells via intratumoral/intracavitary 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).
Intervention: HER2(EQ)BBζ/CD19t+ T cells
ARM III (dual delivery Tn/mem enriched)
Patients receive autologous HER2(EQ)BBzeta/CD19t+ Tn/mem cells via intratumoral/intracavitary 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).
Intervention: Laboratory Biomarker Analysis
ARM III (dual delivery Tn/mem enriched)
Patients receive autologous HER2(EQ)BBzeta/CD19t+ Tn/mem cells via intratumoral/intracavitary 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).
Intervention: Leukapheresis
Outcomes
Primary Outcomes
Incidence of adverse events
Time Frame: Up to 3 years
Will be graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Tables will be created to summarize all toxicities and side effects by dose, time post treatment, organ, severity and arm.
Incidence of grade 3 adverse events
Time Frame: Up to 3 years
Tables will be created to summarize all toxicities and side effects by dose, time post treatment, organ, severity and arm.
Dose limiting toxicities (DLT)
Time Frame: Up to 3 years
Rate and associated 90% Clopper and Pearson binomial confidence limits (90% confidence interval \[CI\]) will be estimated for participants' experiencing DLTs at the recommended phase 2 dose (RP2D) schedule.
Secondary Outcomes
- Chimeric antigen receptor (CAR) T cells detected in tumor tissue(Up to 3 years)
- Progression free survival(At 6 months)
- Overall Survival (OS)(At 6 months)
- Disease response(Up to 3 years)
- HER2 antigen expression levels in tumor tissue(Up to 3 years)
- Chimeric antigen receptor (CAR) T cells detected in tumor cyst fluid, peripheral blood, and cerebrospinal fluid (CSF)(Up to 3 years)
- Tumor cyst fluid, peripheral blood, and cerebrospinal fluid (CSF) cytokine levels(Up to 3 years)