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Genetically Modified Therapeutic Autologous Lymphocytes Followed by Aldesleukin in Treating Patients With Stage III or Metastatic Melanoma

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01740557
Recruitment Status : Active, not recruiting
First Posted : December 4, 2012
Last Update Posted : February 17, 2020
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
M.D. Anderson Cancer Center

Tracking Information
First Submitted Date  ICMJE November 30, 2012
First Posted Date  ICMJE December 4, 2012
Last Update Posted Date February 17, 2020
Actual Study Start Date  ICMJE January 28, 2015
Estimated Primary Completion Date January 31, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 13, 2019)
  • Response assessed by immune-related response criteria and evaluated by positron emission tomography or computed tomography imaging [ Time Frame: Up to 1 year ]
    Response will be defined as a 50% or greater decrease in the tumor's linear dimension post treatment, compared to baseline.
  • Incidence of adverse events defined as possible grade 3 or worse toxicities [ Time Frame: Up to 8 weeks ]
    Possible grade 3 or worse toxicities not normally associated with lymphodepletion and high dose IL-2 will be reported.
Original Primary Outcome Measures  ICMJE
 (submitted: December 3, 2012)
Toxicity of CXCR2 Transduced Tumor Infiltrating Lymphocytes (TIL) [ Time Frame: 6 weeks ]
Study will utilize National Cancer Institute Common Terminology Criteria (CTC) for Adverse Events version 4.0 for toxicity and Adverse Event reporting. Toxicity, immunologic effects and anti-tumor efficacy of cell infusions will be performed. Toxicities monitored and documented on a daily basis beginning at day 0 (T-cell infusion) and continuing until discharged from hospital following the initial IL-2 infusion. Maximum tolerated dose (MTD) defined as dose having posterior mean probability to toxicity closest to the targeted value .20.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: May 13, 2019)
  • Number of CXCR2 transduced cells [ Time Frame: At infusion ]
    Regression analysis will be used to estimate the ability of the genetically transduced T-cells to differentially recognize the cancer cell cytokines. Logistic regression will be used to assess the effects of immunological variables on the probability of clinical response.
  • Number of nerve growth factor receptor (NGFR) transduced (control) cells [ Time Frame: At infusion ]
    Regression analysis will be used to estimate the ability of the genetically transduced T-cells to differentially recognize the cancer cell cytokines. Logistic regression will be used to assess the effects of immunological variables on the probability of clinical response.
  • Number of CXCR2 transduced cells based on tumor biopsy [ Time Frame: Day 21 ]
    Regression analysis will be used to estimate the ability of the genetically transduced T-cells to differentially recognize the cancer cell cytokines. Logistic regression will be used to assess the effects of immunological variables on the probability of clinical response.
  • Number of NGFR transduced cells based on tumor biopsy [ Time Frame: Day 21 ]
    Regression analysis will be used to estimate the ability of the genetically transduced T-cells to differentially recognize the cancer cell cytokines. Logistic regression will be used to assess the effects of immunological variables on the probability of clinical response.
  • Amount of CXCR2 cytokine [ Time Frame: 8 weeks ]
    Regression analysis will be used to estimate the ability of the genetically transduced T-cells to differentially recognize the cancer cell cytokines. Logistic regression will be used to assess the effects of immunological variables on the probability of clinical response.
  • Amount of CXCL8 cytokine [ Time Frame: 8 weeks ]
    Regression analysis will be used to estimate the ability of the genetically transduced T-cells to differentially recognize the cancer cell cytokines. Logistic regression will be used to assess the effects of immunological variables on the probability of clinical response.
Original Secondary Outcome Measures  ICMJE
 (submitted: December 3, 2012)
Tumor Response [ Time Frame: 6 weeks ]
Primary clinical endpoint response defined following immune-related response criteria as 50% or greater decrease in tumor's linear dimension post treatment, compared to baseline. Immunological endpoints include (i) at infusion, Xc = number of CXCR2 transduced cells and Xs = number of NGFR transduced (control) cells, (ii) post treatment, based on tumor biopsy, Yc = number of CXCR2 transduced cells and Ys = number of NGFR transduced cells, and (iii) post treatment, ZCXCR2 = amount of CXCR2 cytokine and ZCXCR8 = amount of CXCL8 (IL-8) cytokine.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Genetically Modified Therapeutic Autologous Lymphocytes Followed by Aldesleukin in Treating Patients With Stage III or Metastatic Melanoma
Official Title  ICMJE A Pilot Study of Lymphodepletion Plus Adoptive Cell Transfer With T -Cells Transduced With CXCR2 and NGFR Followed by High Dose Interleukin-2 in Patients With Metastatic Melanoma
Brief Summary This phase I/II trial studies how well genetically modified therapeutic autologous lymphocytes (patient's own white blood cells) followed by aldesleukin work in treating patients with stage III melanoma or melanoma that has spread to other places in the body (metastatic). Placing chemokine (C-X-C motif) receptor 2 (CXCR2) and nerve growth factor receptor (NGFR) into lymphocytes (white blood cells) may help the body build an immune response to kill melanoma cells. Aldesleukin may enhance this effect by stimulating white blood cells to kill more melanoma cells. Giving genetically modified therapeutic autologous lymphocytes together with aldesleukin may be a better treatment for melanoma.
Detailed Description

PRIMARY OBJECTIVES:

I. To assess the feasibility and safety of CXCR2 and NGFR transduced tumor-infiltrating lymphocytes (TIL) for treating metastatic malignant melanoma.

SECONDARY OBJECTIVES:

I. Determine whether CXCR2 transduction enhances the ability of TIL to migrate to melanoma tumors.

II. Determine the levels of CXCL1 and CXCL8 chemokines produced by melanoma tumors and assess whether this correlates with the tumor localization of CXCR2 transduced TIL.

III. Characterize the clinical response and correlate with migration of CXCR2 transduced TIL to the tumor and levels of CXCL1 and CXCL8 at the tumor site.

OUTLINE:

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 CXCR2-transduced autologous TIL and NGFR-transduced autologous TIL 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 weeks 6 and 12, every 3 months for a year, and then annually for up to 15 years.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Metastatic Melanoma
  • Stage III Cutaneous Melanoma AJCC v7
  • Stage IV Cutaneous Melanoma AJCC v6 and v7
Intervention  ICMJE
  • Biological: Aldesleukin
    Given IV
    Other Names:
    • 125-L-Serine-2-133-interleukin 2
    • Proleukin
    • r-serHuIL-2
    • Recombinant Human IL-2
    • Recombinant Human Interleukin-2
  • Biological: CXCR2-transduced Autologous Tumor Infiltrating Lymphocytes
    Given IV
    Other Name: CXCR2-transduced Autologous TILs
  • Drug: Cyclophosphamide
    Given IV
    Other Names:
    • (-)-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- 138719
  • Drug: Fludarabine Phosphate
    Given IV
    Other Names:
    • 2-F-ara-AMP
    • 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-
    • Beneflur
    • Fludara
    • SH T 586
  • Other: Laboratory Biomarker Analysis
    Correlative studies
  • Biological: NGFR-transduced Autologous T Lymphocytes
    Given IV
  • Other: Quality-of-Life Assessment
    Ancillary studies
    Other Name: Quality of Life Assessment
Study Arms  ICMJE Experimental: Treatment (genetically modified T-cells, high-dose aldesleukin
Patients 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 CXCR2-transduced autologous TIL and NGFR-transduced autologous TIL 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).
Interventions:
  • Biological: Aldesleukin
  • Biological: CXCR2-transduced Autologous Tumor Infiltrating Lymphocytes
  • Drug: Cyclophosphamide
  • Drug: Fludarabine Phosphate
  • Other: Laboratory Biomarker Analysis
  • Biological: NGFR-transduced Autologous T Lymphocytes
  • Other: Quality-of-Life Assessment
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: February 12, 2020)
10
Original Estimated Enrollment  ICMJE
 (submitted: December 3, 2012)
36
Estimated Study Completion Date  ICMJE January 31, 2021
Estimated Primary Completion Date January 31, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • TURNSTILE I 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 will be eligible; patients receiving cytotoxic agents will be evaluated by the PI or his designee
  • 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 (Turnstile I)
  • CHEMOTHERAPY/CELL INFUSION INCLUSION CRITERIA:
  • Patients must have adequate TIL available (Turnstile II)
  • Patients must have at least one biopsiable and measurable metastatic melanoma lesions >= 1 cm (Turnstile II)
  • Patients may have brain lesions which measure =< 1 cm each (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)
  • Pregnancy testing will be performed within 14 days prior to treatment (Turnstile II)
  • Clinical performance status of ECOG 0-2 within 14 days of lymphodepletion (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 transaminase (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 multigated acquisition [MUGA] scan, dobutamine echocardiogram or other stress test that will rule out cardiac ischemia) within 6 months of lymphodepletion (Turnstile II)
  • Forced expiratory volume in 1 second (FEV1) > 65% of predicted within 6 months of lymphodepletion (Turnstile II) 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

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)
  • Patients who are pregnant or nursing (Turnstile I)
  • CHEMOTHERAPY/CELL INFUSION EXCLUSION CRITERIA:
  • Has had prior systemic cancer therapy within the past four weeks at the time of the start of the lymphodepletion regimen (Turnstile II)
  • Women who are pregnant will be excluded (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)
  • Requires no steroids within 4 weeks and have not 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)
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01740557
Other Study ID Numbers  ICMJE 2009-0471
NCI-2014-02655 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
2009-0471 ( Other Identifier: M D Anderson Cancer Center )
P30CA016672 ( U.S. NIH Grant/Contract )
R01CA116206 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party M.D. Anderson Cancer Center
Study Sponsor  ICMJE M.D. Anderson Cancer Center
Collaborators  ICMJE National Cancer Institute (NCI)
Investigators  ICMJE
Principal Investigator: Rodabe N Amaria M.D. Anderson Cancer Center
PRS Account M.D. Anderson Cancer Center
Verification Date February 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP