Clinical Trials /

Genetically Modified T-Cells Followed by Aldesleukin in Treating Patients With Stage III-IV Melanoma

NCT01955460

Description:

This pilot phase I trial studies the side effects and best dose of genetically modified T-cells followed by aldesleukin in treating patients with stage III-IV melanoma. T-cells are a type of white blood cell that help the body fight infections. Genes that may help the T-cells recognize melanoma cells are placed into the T-cells in the laboratory. Adding these genes to the T cells may help them kill more tumor cells when they are put back in the body. Aldesleukin may enhance this effect by stimulating white blood cells to kill more melanoma cells.

Related Conditions:
  • Melanoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Genetically Modified T-Cells Followed by Aldesleukin in Treating Patients With Stage III-IV Melanoma
  • Official Title: A Pilot Study of Lymphodepletion Plus Adoptive Cell Transfer With TGF-Beta Resistant (DNRII) and NGFR Transduced T-Cells Followed by High Dose Interleukin-2 in Patients With Metastatic Melanoma

Clinical Trial IDs

  • ORG STUDY ID: 2012-0758
  • SECONDARY ID: NCI-2014-01211
  • SECONDARY ID: RP110553-P4
  • SECONDARY ID: RM1012-012-1
  • SECONDARY ID: 2012-0758
  • NCT ID: NCT01955460

Conditions

  • Metastatic Melanoma
  • Stage III Cutaneous Melanoma AJCC v7
  • Stage IIIA Cutaneous Melanoma AJCC v7
  • Stage IIIB Cutaneous Melanoma AJCC v7
  • Stage IIIC Cutaneous Melanoma AJCC v7
  • Stage IV Cutaneous Melanoma AJCC v6 and v7

Interventions

DrugSynonymsArms
Aldesleukin125-L-Serine-2-133-interleukin 2, Proleukin, r-serHuIL-2, Recombinant Human IL-2, Recombinant Human Interleukin-2Treatment (chemotherapy, autologous T-cell immunotherapy)
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, Cyclophosphamidum, Cyclophosphan, Cyclophosphane, Cyclophosphanum, Cyclostin, Cyclostine, Cytophosphan, Cytophosphane, Cytoxan, Fosfaseron, Genoxal, Genuxal, Ledoxina, Mitoxan, Neosar, Revimmune, Syklofosfamid, WR- 138719Treatment (chemotherapy, autologous T-cell immunotherapy)
Fludarabine Phosphate2-F-ara-AMP, 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-, Beneflur, Fludara, SH T 586Treatment (chemotherapy, autologous T-cell immunotherapy)
NGFR-transduced Autologous T LymphocytesTreatment (chemotherapy, autologous T-cell immunotherapy)
TGFbDNRII-transduced Autologous Tumor Infiltrating LymphocytesTGFbDNRII-transduced Autologous TILsTreatment (chemotherapy, autologous T-cell immunotherapy)

Purpose

This pilot phase I trial studies the side effects and best dose of genetically modified T-cells followed by aldesleukin in treating patients with stage III-IV melanoma. T-cells are a type of white blood cell that help the body fight infections. Genes that may help the T-cells recognize melanoma cells are placed into the T-cells in the laboratory. Adding these genes to the T cells may help them kill more tumor cells when they are put back in the body. Aldesleukin may enhance this effect by stimulating white blood cells to kill more melanoma cells.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To assess the feasibility and safety of autologous transforming growth factor beta (TGFb)
      resistant (DNRII transduced) and NGFR transduced tumor infiltrating lymphocytes (TIL) in
      patients with metastatic melanoma.

      SECONDARY OBJECTIVES:

      I. To determine the survival and immune function of TGFb resistant (DNRII transduced) TIL in
      vivo.

      II. To assess the anti-tumor effects of TGFb resistant (DNRII transduced) TIL.

      OUTLINE: This is a dose-escalation study of TGFb DNRII-transduced autologous TIL and nerve
      growth factor receptor (NGFR)-transduced autologous T lymphocytes.

      Patients receive cyclophosphamide intravenously (IV) over 2 hours on days -7 and -6,
      fludarabine phosphate IV daily over 15-30 minutes on days -5 to -1, and TGFb DNRII-transduced
      autologous TIL and NGFR-transduced autologous T lymphocytes IV over up to 4 hours on day 0.
      Patients then receive high-dose aldesleukin IV over 15 minutes every 8-16 hours on days 1-5
      (up to 15 doses) and 22-26 (up to 15 doses).

      After completion of study treatment, patients are followed up at 6 and 12 weeks, every 3
      months for 1 year and then yearly for 10 years.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (chemotherapy, autologous T-cell immunotherapy)ExperimentalPatients receive cyclophosphamide IV over 2 hours on days -7 and -6, fludarabine phosphate IV daily over 15-30 minutes on days -5 to -1, and TGFb DNRII-transduced autologous TIL and NGFR-transduced autologous T lymphocytes IV over up to 4 hours on day 0. Patients then receive high-dose aldesleukin IV over 15 minutes every 8-16 hours on days 1-5 (up to 15 doses) and 22-26 (up to 15 doses).
  • Aldesleukin
  • Cyclophosphamide
  • Fludarabine Phosphate
  • NGFR-transduced Autologous T Lymphocytes
  • TGFbDNRII-transduced Autologous Tumor Infiltrating Lymphocytes

Eligibility Criteria

        Inclusion Criteria:

          -  Patients must have metastatic melanoma or stage III in-transit, subcutaneous, or
             regional nodal disease (Turnstile I)

          -  Patients must have a lesion amenable to resection for the generation of TIL (Turnstile
             I)

          -  Patients must receive a magnetic resonance imaging (MRI)/computed tomography
             (CT)/positron emission tomography (PET) of the brain within 6 months of signing
             informed consent; if new lesions are present, patient must have definitive treatment;
             principal investigator (PI) or his designee should make final determination regarding
             enrollment (Turnstile I)

          -  Clinical performance status of Eastern Cooperative Oncology Group (ECOG) 0-2 within 30
             days of signing informed consent (Turnstile I)

          -  Patients previously treated with immunotherapy, targeted therapy, or no therapy
             (treatment naive) will be eligible (Turnstile I)

          -  Patients receiving cytotoxic agents will be evaluated by the PI or his designee for
             eligibility suitability (Turnstile I)

          -  Patients with a negative pregnancy test (urine or serum) must be documented within 14
             days of screening for women of childbearing potential (WOCBP); a WOCBP has not
             undergone a hysterectomy or who has not been naturally postmenopausal for at least 12
             consecutive months (i.e. who has not had menses at any time in the preceding 12
             consecutive months) (Turnstile I)

          -  Patients must have adequate TIL available (Turnstile II); pre-rapid expansion
             procedure (Pre-REP) TIL generated in the similar clinical trial 2004-0069 may also be
             utilized for Turnstile II

          -  Patients must have at least one biopsiable measurable metastatic melanoma, lesion > or
             = to 1 cm (Turnstile II)

          -  Patients may have brain lesions =< 1 cm each; the PI or designee will approve the
             treatment (Turnstile II)

          -  Patients of both genders must practice birth control for four months after receiving
             the preparative regimen (lymphodepletion) and continue to practice birth control
             throughout the study; patients must have a documented negative pregnancy test (urine
             or serum) for women who have menstruation in the past 12 months and without
             sterilization surgery (Turnstile II)

          -  Unless surgically sterile by bilateral tubal ligation or vasectomy of partner(s), the
             patient agrees to continue to use a barrier method of contraception throughout the
             study such as: condom, diaphragm, hormonal, intrauterine device (IUD), or sponge plus
             spermicide; abstinence is an acceptable form of birth control (Turnstile II)

          -  Patients with negative pregnancy test (urine or serum) must be documented within 14
             days of screening for WOCBP; a WOCBP has not undergone a hysterectomy or who has not
             been naturally postmenopausal for at least 12 consecutive months (i.e. who has not
             menses at any time in the preceding 12 consecutive months) (Turnstile II)

          -  Clinical performance status of ECOG 0-2 within 30 days of signing informed consent
             (Turnstile II)

          -  Absolute neutrophil count greater than or equal to 1000/mm^3 (Turnstile II)

          -  Platelet count greater than or equal to 100,000/mm^3 (Turnstile II)

          -  Hemoglobin greater than or equal to 8.0 g/dl (Turnstile II)

          -  Serum alanine aminotransferase (ALT) less than three times the upper limit of normal
             (Turnstile II)

          -  Serum creatinine less than or equal to 1.6 mg/dl (Turnstile II)

          -  Total bilirubin less than or equal to 2.0 mg/dl, except in patients with Gilbert's
             syndrome who must have a total bilirubin less than 3.0 mg/dl (Turnstile II)

          -  A stress cardiac test (stress thallium, stress multi gated acquisition scan [MUGA],
             dobutamine echocardiogram or other stress test that will rule out cardiac ischemia)
             within 6 months of lymphodepletion (Turnstile II)

          -  Pulmonary function tests (forced expiratory volume in one second [FEV1] > 65% or
             forced vital capacity [FVC] > 65% of predicted) within 6 months of lymphodepletion
             (Turnstile II)

          -  MRI/CT/PET of the brain within 30 days of lymphodepletion (Turnstile II)

        Exclusion Criteria:

          -  Active systemic infections requiring intravenous antibiotics, coagulation disorders or
             other major medical illnesses of the cardiovascular, respiratory or immune system; PI
             or his designee shall make the final determination regarding appropriateness of
             enrollment (Turnstile I)

          -  Primary immunodeficiency and need for chronic steroid therapy, however prednisone is
             allowed at < 10 mg/day (Turnstile I)

          -  Patients who are pregnant or nursing (Turnstile I)

          -  Presence of a significant psychiatric disease, which in the opinion of the principal
             investigator or his designee, would prevent adequate informed consent (Turnstile I)

          -  Has had prior systemic cancer therapy within the past four weeks or v-raf murine
             sarcoma viral oncogene homolog B (B-RAF) or mitogen-activated protein kinase (MEK)
             inhibitors within 7 days at the time of the start of the lymphodepletion regimen
             (Turnstile II)

          -  Women who are pregnant will be excluded because of the potentially dangerous effects
             of the preparative chemotherapy on the fetus (Turnstile II)

          -  Any active systemic infections requiring intravenous antibiotics, coagulation
             disorders or other major medical illnesses of the cardiovascular, respiratory or
             immune system, such as abnormal stress thallium or comparable test, myocardial
             infarction, cardiac arrhythmias, obstructive or restrictive pulmonary disease; PI or
             his designee shall make the final determination regarding appropriateness of
             enrollment (Turnstile II)

          -  Any form of primary or secondary immunodeficiency; must have recovered immune
             competence after chemotherapy or radiation therapy as evidenced by lymphocyte counts
             (> 500/mm^3), white blood cell (WBC) (> 3,000/mm^3) or absence of opportunistic
             infections (Turnstile II)

          -  Require steroid therapy or steroid-containing compounds, or have used systemic
             steroids in the past 4 weeks, or have used topical or inhalational steroids in the
             past 2 weeks prior to lymphodepletion; the exception being patients on chronic
             physiologic dose of steroid (Turnstile II)

          -  Presence of a significant psychiatric disease, which in the opinion of the principal
             investigator or his designee, would prevent adequate informed consent or render
             immunotherapy unsafe or contraindicated (Turnstile II)
      
Maximum Eligible Age:N/A
Minimum Eligible Age:12 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Generation of TGF alpha (TGFa)-DNRII and NGFR transduced tumor infiltrating lymphocytes (TILs)
Time Frame:Up to 5 years
Safety Issue:
Description:Feasibility of generating TGFa-DNRII and NGFR transduced TILs and safety of treating patients with genetically modified T cells will be assessed. Feasibility will be defined as the production of virally transduced T cells and treatment of patients with these cells.

Secondary Outcome Measures

Measure:Response
Time Frame:Up to 24 months
Safety Issue:
Description:Will be defined following immune-related response criteria as a 50% or greater decrease in the tumor's linear dimension post treatment compared to baseline.
Measure:Number of DNRII transduced cells
Time Frame:6 months
Safety Issue:
Description:A linear regression model will be used to test the hypothesis that the DNRII cells are more likely to survive longer in the tumor environment than the NGFR (control) cells. Dose will be included as a covariate. Separate analyses will be performed at each post-treatment time point (6 weeks, 12 weeks, 6 months, 12 months, and 24 months), with the 6-month time point considered primary. If there is evidence of a linear relationship over time, a generalized linear mixed model (GLMM) approach may be used to model the DNRII/NGFR ratio over time.
Measure:Number of NGFR transduced cells at infusion
Time Frame:Day 0
Safety Issue:
Description:A linear regression model will be used to test the hypothesis that the DNRII cells are more likely to survive longer in the tumor environment than the NGFR (control) cells. Dose will be included as a covariate. Separate analyses will be performed at each post-treatment time point (6 weeks, 12 weeks, 6 months, 12 months, and 24 months), with the 6-month time point considered primary. If there is evidence of a linear relationship over time, a GLMM approach may be used to model the DNRII/NGFR ratio over time.
Measure:Number of NGFR transduced cells based on tumor biopsy
Time Frame:Up to 24 months
Safety Issue:
Description:A linear regression model will be used to test the hypothesis that the DNRII cells are more likely to survive longer in the tumor environment than the NGFR (control) cells. Dose will be included as a covariate. Separate analyses will be performed at each post-treatment time point (6 weeks, 12 weeks, 6 months, 12 months, and 24 months), with the 6-month time point considered primary. If there is evidence of a linear relationship over time, a GLMM approach may be used to model the DNRII/NGFR ratio over time.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:M.D. Anderson Cancer Center

Last Updated

December 11, 2020