Clinical Trials /

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

NCT04119024

Description:

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.

Related Conditions:
  • Melanoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • 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

Clinical Trial IDs

  • ORG STUDY ID: 19-001145
  • SECONDARY ID: NCI-2019-05764
  • SECONDARY ID: 19-001145
  • SECONDARY ID: P30CA016042
  • NCT ID: NCT04119024

Conditions

  • Clinical Stage IV Cutaneous Melanoma AJCC v8 (American Joint Committee on Cancer )
  • IL13RA2 Positive
  • Metastatic Melanoma
  • Pathologic Stage IIIC Cutaneous Melanoma AJCC v8
  • Pathologic Stage IV Cutaneous Melanoma AJCC v8

Interventions

DrugSynonymsArms
Cyclophosphamide(-)-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- 138719Treatment (chemotherapy, IL13Ralpha2, Il-2)
Fludarabine Phosphate2-F-ara-AMP, 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-, Beneflur, Fludara, SH T 586Treatment (chemotherapy, IL13Ralpha2, Il-2)
IL13Ralpha2-specific Hinge-optimized 4-1BB-co-stimulatory CAR/Truncated CD19-expressing Autologous TN/MEM CellsIL13 [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 LymphocytesTreatment (chemotherapy, IL13Ralpha2, Il-2)
Recombinant Interleukin-2IL-2, Interleukin II, interleukin-2, Lymphocyte Mitogenic Factor, Mitogenic Factor, Ro-236019, T-Cell Growth Factor, TCGF, Thymocyte Stimulating Factor, TSFTreatment (chemotherapy, IL13Ralpha2, Il-2)

Purpose

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.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (chemotherapy, IL13Ralpha2, Il-2)ExperimentalPatients 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.
  • Cyclophosphamide
  • Fludarabine Phosphate
  • IL13Ralpha2-specific Hinge-optimized 4-1BB-co-stimulatory CAR/Truncated CD19-expressing Autologous TN/MEM Cells
  • Recombinant Interleukin-2

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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Incidence of adverse events
Time Frame:Up to 90 days from the day of CAR-transgenic cell infusion
Safety Issue:
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.

Secondary Outcome Measures

Measure:Objective response rate
Time Frame:Up to 120 days
Safety Issue:
Description:Will be recorded following the Response Evaluation Criteria in Solid Tumors (RECIST) criteria.
Measure:Complete response
Time Frame:At day 60, 120, and every 2-3 months for up to 2 years
Safety Issue:
Description:
Measure:Partial response
Time Frame:At day 60, 120, and every 2-3 months for up to 2 years
Safety Issue:
Description:
Measure:Response for in-transit metastasis
Time Frame:Up to 2 years
Safety Issue:
Description:
Measure:Time to disease progression
Time Frame:Up to 2 years
Safety Issue:
Description:
Measure: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
Safety Issue:
Description:
Measure:IL13Ralpha2 CAR T cell persistence
Time Frame:At days 1, 7, 14, 30, 60, 90, and 120
Safety Issue:
Description:
Measure:IL13Ralpha2 CAR T Cell phenotypic monitoring
Time Frame:Up 2 years
Safety Issue:
Description:
Measure:Impact of IL-2 on systemic persistence of CAR T cells
Time Frame:Up 2 years
Safety Issue:
Description:
Measure:Impact of IL-2 on tumor infiltration of CAR T cells
Time Frame:Up 2 years
Safety Issue:
Description:

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Jonsson Comprehensive Cancer Center

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