Gene Modified Immune Cells (IL13Ralpha2 CAR T Cells) After Conditioning Regimen for the Treatment of Stage IIIC or IV Melanoma
Primary Purpose
Clinical Stage IV Cutaneous Melanoma AJCC v8, IL13RA2 Positive, Metastatic Melanoma
Status
Recruiting
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Cyclophosphamide
Fludarabine Phosphate
IL13Ralpha2-specific Hinge-optimized 4-1BB-co-stimulatory CAR/Truncated CD19-expressing Autologous TN/MEM Cells
Recombinant Interleukin-2
Sponsored by
About this trial
This is an interventional treatment trial for Clinical Stage IV Cutaneous Melanoma AJCC v8
Eligibility Criteria
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
Sites / Locations
- City of Hope Comprehensive Cancer Center
- UCLA / Jonsson Comprehensive Cancer CenterRecruiting
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
Treatment (chemotherapy, IL13Ralpha2, Il-2)
Arm Description
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.
Outcomes
Primary Outcome Measures
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.
Dose-limiting toxicity (DLT)
Secondary Outcome Measures
Objective response rate
Will be recorded following the Response Evaluation Criteria in Solid Tumors (RECIST) criteria.
Complete response
Partial response
Response for in-transit metastasis
Time to disease progression
Overall survival
IL13Ralpha2 CAR T cell persistence
IL13Ralpha2 CAR T Cell phenotypic monitoring
Impact of IL-2 on systemic persistence of CAR T cells
Impact of IL-2 on tumor infiltration of CAR T cells
Full Information
NCT ID
NCT04119024
First Posted
September 25, 2019
Last Updated
January 5, 2023
Sponsor
Jonsson Comprehensive Cancer Center
Collaborators
City of Hope National Medical Center
1. Study Identification
Unique Protocol Identification Number
NCT04119024
Brief Title
Gene Modified Immune Cells (IL13Ralpha2 CAR T Cells) After Conditioning Regimen for the Treatment of Stage IIIC or IV Melanoma
Official Title
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
Study Type
Interventional
2. Study Status
Record Verification Date
January 2023
Overall Recruitment Status
Recruiting
Study Start Date
November 27, 2019 (Actual)
Primary Completion Date
October 1, 2024 (Anticipated)
Study Completion Date
October 1, 2025 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Jonsson Comprehensive Cancer Center
Collaborators
City of Hope National Medical Center
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
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
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Clinical Stage IV Cutaneous Melanoma AJCC v8, IL13RA2 Positive, Metastatic Melanoma, Cutaneous Melanoma, Stage III, Cutaneous Melanoma, Stage IV
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
24 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
Treatment (chemotherapy, IL13Ralpha2, Il-2)
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Cyclophosphamide
Other Intervention Name(s)
(-)-Cyclophosphamide, 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate, Carloxan, Ciclofosfamida, Ciclofosfamide, Cicloxal, Clafen, Claphene, CP monohydrate, CTX, CYCLO-cell, Cycloblastin, Cycloblastine, Cyclophospham, Cyclophosphamid monohydrate, Cyclophosphamide Monohydrate, Cyclophosphamidum, Cyclophosphan, Cyclophosphane, Cyclophosphanum, Cyclostin, Cyclostine, Cytophosphan, Cytophosphane, Cytoxan, Fosfaseron, Genoxal, Genuxal, Ledoxina, Mitoxan, Neosar, Revimmune, Syklofosfamid, WR- 138719
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
Fludarabine Phosphate
Other Intervention Name(s)
2-F-ara-AMP, 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-, Beneflur, Fludara, SH T 586
Intervention Description
Given IV
Intervention Type
Biological
Intervention Name(s)
IL13Ralpha2-specific Hinge-optimized 4-1BB-co-stimulatory CAR/Truncated CD19-expressing Autologous TN/MEM Cells
Other Intervention Name(s)
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
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
Recombinant Interleukin-2
Other Intervention Name(s)
IL-2, Interleukin II, interleukin-2, Lymphocyte Mitogenic Factor, Mitogenic Factor, Ro-236019, T-Cell Growth Factor, TCGF, Thymocyte Stimulating Factor, TSF
Intervention Description
Given SC
Primary Outcome Measure Information:
Title
Incidence of adverse events
Description
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.
Time Frame
Up to 90 days from the day of CAR-transgenic cell infusion
Title
Dose-limiting toxicity (DLT)
Time Frame
Up to 90 days from the day of CAR-transgenic cell infusion
Secondary Outcome Measure Information:
Title
Objective response rate
Description
Will be recorded following the Response Evaluation Criteria in Solid Tumors (RECIST) criteria.
Time Frame
Up to 120 days
Title
Complete response
Time Frame
At day 60, 120, and every 2-3 months for up to 2 years
Title
Partial response
Time Frame
At day 60, 120, and every 2-3 months for up to 2 years
Title
Response for in-transit metastasis
Time Frame
Up to 2 years
Title
Time to disease progression
Time Frame
Up to 2 years
Title
Overall survival
Time Frame
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
Title
IL13Ralpha2 CAR T cell persistence
Time Frame
At days 1, 7, 14, 30, 60, 90, and 120
Title
IL13Ralpha2 CAR T Cell phenotypic monitoring
Time Frame
Up 2 years
Title
Impact of IL-2 on systemic persistence of CAR T cells
Time Frame
Up 2 years
Title
Impact of IL-2 on tumor infiltration of CAR T cells
Time Frame
Up 2 years
Other Pre-specified Outcome Measures:
Title
Cytokine release syndrome analysis
Description
Plasma or serum collected from the blood at multiple time points after CAR T cell infusion will be frozen and banked; cytokine levels will be quantified in patients exhibiting any > grade-2 CRS.
Time Frame
Up 2 years
Title
Evaluation of an endogenous T cell anti-tumor response
Description
The biopsies will be analyzed by hematoxylin and eosin staining (H&E), immunohistochemistry (IHC) to quantify the numbers of T lymphocytes. If sufficient quantity of tissue is available, the study investigators will attempt to monitor the phenotype of the TIL obtained from tumor biopsy samples by multicolor flow cytometry (FACS), and other immune monitoring assays.
Time Frame
Up 2 years
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Jacob Naparstek
Phone
310-206-9926
Email
JNaparstek@mednet.ucla.edu
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Anusha Kalbasi
Organizational Affiliation
UCLA / Jonsson Comprehensive Cancer Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
City of Hope Comprehensive Cancer Center
City
Duarte
State/Province
California
ZIP/Postal Code
91010
Country
United States
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Kim A. Margolin
Phone
626-256-4673
Ext
89200
Email
kmargolin@coh.org
First Name & Middle Initial & Last Name & Degree
Kim A. Margolin
Facility Name
UCLA / Jonsson Comprehensive Cancer Center
City
Los Angeles
State/Province
California
ZIP/Postal Code
90095
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Jacob Naparstek
Phone
310-206-9926
Email
JNaparstek@mednet.ucla.edu
First Name & Middle Initial & Last Name & Degree
Anusha Kalbasi
12. IPD Sharing Statement
Learn more about this trial
Gene Modified Immune Cells (IL13Ralpha2 CAR T Cells) After Conditioning Regimen for the Treatment of Stage IIIC or IV Melanoma
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