Gene Modified Immune Cells (IL13Ralpha2 CAR T Cells) After Conditioning Regimen for the Treatment of Stage IIIC or IV Melanoma

Study Overview
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Brief Summary
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This phase I trial studies the side effects and best dose of modified immune cells (IL13Ralpha2 CAR T cells) after a chemotherapy conditioning regimen for the treatment of patients with stage IIIC or IV melanoma. The study agent is called IL13Ralpha2 CAR T cells. T cells are a special type of white blood cell (immune cells) that have the ability to kill tumor cells. The T cells are obtained from the patients own blood, grown in a laboratory, and modified by adding the IL13Ralpha2 CAR gene. The IL13Ralpha2 CAR gene is inserted into T cells with a virus called a lentivirus. The lentivirus allows cells to make the IL13Ralpha2 CAR protein. This CAR has been designed to bind to a protein on the surface of tumor cells called IL13Ralpha2. This study is being done to determine the dose at which the gene-modified immune cells are safe, how long the cells stay in the body, and if the cells are able to attack the cancer.

Detailed Description
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PRIMARY OBJECTIVE: I. Safety. SECONDARY OBJECTIVES: I. Clinical response. II. Chimeric antigen receptor (CAR) T-cell tumor infiltration and persistence. III. Impact of IL-2 on the persistence and tumor infiltration of IL13Ralpha2 CAR T cells. EXPLORATORY OBJECTIVES: I. Cytokine release syndrome analysis. II. Evaluation of endogenous anti-tumor immune response. OUTLINE: This is a dose-escalation study of IL13Ralpha2-specific hinge-optimized 4-1BB-co-stimulatory CAR/truncated (Cluster of Differentiation 19) CD19-expressing autologous TN/MEM cells (IL13Ralpha2 CAR T cells). Patients receive cyclophosphamide intravenously (IV) over 1 hour on days -5 to -4 and fludarabine phosphate IV over 15-30 minutes on days -4 to -1. Patients then receive IL13Ralpha2 CAR T cells IV on day 0. Patients may also receive recombinant interleukin-2 subcutaneously (SC) twice daily (BID) on days 1-7. After completion of study treatment, patients are followed every 2-3 months for 2 years, every 6 months for 3 years, then every year for at least 15 years.

Official Title
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Phase 1 Dose Escalation Study of Systemically Administered IL13Ra2 Chimeric Antigen Receptor (CAR) T Cells After a Nonmyeloablative Conditioning Regimen in Patients With Metastatic Melanoma

Conditions
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Clinical Stage IV Cutaneous Melanoma AJCC v8, IL13RA2 Positive, Metastatic Melanoma, Cutaneous Melanoma, Stage III, Cutaneous Melanoma, Stage IV

Intervention / Treatment
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* Drug: Cyclophosphamide
* Drug: Fludarabine Phosphate
* Biological: IL13Ralpha2-specific Hinge-optimized 4-1BB-co-stimulatory CAR/Truncated CD19-expressing Autologous TN/MEM Cells
* Drug: Recombinant Interleukin-2


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed melanoma that is considered surgically incurable with either: Stage IIIC melanoma including locally relapsed, satellite, in-transit lesions or bulky draining node metastasis Stage IV melanoma Confirmed IL13Ralpha2 tumor expression by immunohistochemistry (>= 20%, 1+) Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 A minimum of one measurable lesion defined as: Meeting the criteria for measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST), OR Skin lesion(s) selected as non-completely biopsied target lesion(s) that can be accurately measured and recorded by color photography with a ruler to document the size of the target lesion(s) Absolute neutrophil count (ANC) >= 1 x 10^9 cells/L (determined within 30?60 days prior to enrollment; re-evaluated within 14 days of beginning conditioning chemotherapy) Platelets >= 75 x 10^9/L (determined within 30?60 days prior to enrollment; re-evaluated within 14 days of beginning conditioning chemotherapy) Hemoglobin >= 8 g/dL (determined within 30?60 days prior to enrollment; re-evaluated within 14 days of beginning conditioning chemotherapy) Aspartate and alanine aminotransferases (AST, ALT) =< 2.5 x upper limit of normal (ULN) (determined within 30?60 days prior to enrollment; re-evaluated within 14 days of beginning conditioning chemotherapy) Total bilirubin =< 2 x ULN (except patients with documented Gilbert?s syndrome) (determined within 30?60 days prior to enrollment; re-evaluated within 14 days of beginning conditioning chemotherapy) Creatinine < 2 mg/dL (or a glomerular filtration rate > 45) (determined within 30?60 days prior to enrollment; re-evaluated within 14 days of beginning conditioning chemotherapy) Must have received at least one prior systemic therapy for advanced melanoma (i.e. anti-PD-1 therapy, BRAF plus MEK inhibitor therapy for BRAFV600 mutated melanoma) and is not considered to have an alternate treatment option with curative intent Must be willing and able to accept at least one leukapheresis procedure Must be willing and able to provide written informed consent Exclusion Criteria: Inability to purify >= 1 x 10^7 T cells from leukapheresis product Previously known hypersensitivity to any of the agents used in this study; known sensitivity to cyclophosphamide or fludarabine Received systemic treatment for cancer, including immunotherapy, within 14 days prior to initiation of conditioning chemotherapy administration within this protocol Potential requirement for systemic corticosteroids or concurrent immunosuppressive drugs based on prior history or received systemic steroids within the last 2 weeks prior to enrollment (inhaled or topical steroids at standard doses are allowed) Human immunodeficiency virus (HIV) seropositivity or other congenital or acquired immune deficiency state, which would increase the risk of opportunistic infections and other complications during chemotherapy-induced lymphodepletion. If there is a positive result in the infectious disease testing that was not previously known, the patient will be referred to their primary physician and/or infectious disease specialist Hepatitis B or C seropositivity with evidence of ongoing liver damage, which would increase the likelihood of hepatic toxicities from the chemotherapy conditioning regimen and supportive treatments. If there is a positive result in the infectious disease testing that was not previously known, the patient will be referred to their primary physician and/or infectious disease specialist Dementia or significantly altered mental status that would prohibit the understanding or rendering of informed consent and compliance with the requirements of this protocol A Tiffeneau-Pinelli index < 70% of the predicted value. Subjects will be excluded if pulmonary function tests indicate they have insufficient pulmonary capability Patients will be excluded if they have a history of clinically significant electrocardiography (ECG) abnormalities, symptoms of cardiac ischemia or arrhythmias and have a left ventricular ejection fraction (LVEF) < 45% on a cardiac stress test (stress thallium, stress multigated acquisition scan (MUGA), dobutamine echocardiogram, or other stress test) Patients with ECG results of any conduction delays (PR interval > 200 ms, corrected QT (QTC) > 480 ms), sinus bradycardia (resting heart rate < 50 beats per minute), sinus tachycardia (HR>120 beats per minute) will be evaluated by a cardiologist prior to starting the trial. Patients with any arrhythmias, including atrial fibrillation/atrial flutter, excessive ectopy (defined as > 20 premature ventricular complex [PVC]s per minute), ventricular tachycardia, 3rd degree heart block will be excluded from the study unless cleared by a cardiologist Pregnancy or breast-feeding. Female patients must be surgically sterile or be postmenopausal for two years, or must agree to use effective contraception during the period of treatment and for 6 months afterwards. All female patients with reproductive potential must have a negative pregnancy test (serum/urine) at screening and again within 14 days from starting the conditioning chemotherapy. The definition of effective contraception will be based on the judgment of the study investigators. Patients who are breastfeeding are not allowed on this study A concomitant active malignancy that would be considered to interfere with the assessment of the primary or secondary endpoints of the study

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (chemotherapy, IL13Ralpha2, Il-2)<br>Patients receive cyclophosphamide IV over 1 hour on days -5 to -4 and fludarabine phosphate IV over 15-30 minutes on days -4 to -1. Patients then receive IL13Ralpha2 CAR T cell IV on day 0. Patients may also receive recombinant interleukin-2 SC BID on days 1-7. | Drug: Cyclophosphamide<br>* Given IV<br>* Other names: WR- 138719;Drug: Fludarabine Phosphate<br>* Given IV<br>* Other names: SH T 586;Biological: IL13Ralpha2-specific Hinge-optimized 4-1BB-co-stimulatory CAR/Truncated CD19-expressing Autologous TN/MEM Cells<br>* Given IV<br>* Other names: IL13Ra2-specific-hinge-optimized-4-1BB-CAR/truncated CD19-expressing Autologous TN/MEM Lymphocytes;Drug: Recombinant Interleukin-2<br>* Given SC<br>* Other names: TSF;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of adverse events | Safety will be reported as incidence rates for adverse events, serious adverse events, and fatal adverse events for Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 grade 3 or higher. Adverse events will be tabulated by treatment group and will include the number of patients for whom the event occurred, the rate of occurrence, and the severity and relationship to study drug. | Up to 90 days from the day of CAR-transgenic cell infusion | 
| Dose-limiting toxicity (DLT) |  | Up to 90 days from the day of CAR-transgenic cell infusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective response rate | Will be recorded following the Response Evaluation Criteria in Solid Tumors (RECIST) criteria. | Up to 120 days | 
| Complete response |  | At day 60, 120, and every 2-3 months for up to 2 years | 
| Partial response |  | At day 60, 120, and every 2-3 months for up to 2 years | 
| Response for in-transit metastasis |  | Up to 2 years | 
| Time to disease progression |  | Up to 2 years | 
| Overall survival |  | From the date of CAR T cell infusion in the clinical trial until death, whether related to the trial or not, assessed up to 2 years | 
| IL13Ralpha2 CAR T cell persistence |  | At days 1, 7, 14, 30, 60, 90, and 120 | 
| IL13Ralpha2 CAR T Cell phenotypic monitoring |  | Up 2 years | 
| Impact of IL-2 on systemic persistence of CAR T cells |  | Up 2 years | 
| Impact of IL-2 on tumor infiltration of CAR T cells |  | Up 2 years |