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Study of Lifileucel ( LN-144), Autologous Tumor Infiltrating Lymphocytes, in the Treatment of Patients With Metastatic Melanoma (LN-144)

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ClinicalTrials.gov Identifier: NCT02360579
Recruitment Status : Active, not recruiting
First Posted : February 10, 2015
Last Update Posted : October 29, 2018
Sponsor:
Information provided by (Responsible Party):
Iovance Biotherapeutics, Inc.

Brief Summary:
Prospective, interventional multicenter study evaluating adoptive cell therapy (ACT) with Lifileucel infusion (LN-144) followed by interleukin 2 (IL-2) after a nonmyeloablative lymphodepletion (NMA-LD) preparative regimen.

Condition or disease Intervention/treatment Phase
Metastatic Melanoma Biological: Lifileucel Phase 2

Detailed Description:
Lifileucel is an autologous adoptive cell transfer therapy that utilizes a TIL manufacturing process, as originally developed by the NCI, for the treatment of patients with metastatic melanoma. The adoptive cell transfer therapy used in this study involves patients receiving a lymphocyte depleting preconditioning regimen, prior to infusion of autologous TIL, followed by the administration of a regimen of IL-2.

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 85 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 2, Multicenter Study to Assess the Efficacy and Safety of Autologous Tumor Infiltrating Lymphocytes (LN-144) for Treatment of Patients With Metastatic Melanoma
Study Start Date : September 2015
Estimated Primary Completion Date : March 2019
Estimated Study Completion Date : September 2023

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Melanoma

Arm Intervention/treatment
Experimental: Cohort 1
Lifileucel (LN-144) without cryopreservation (Gen 1 infusion product) (Closed)
Biological: Lifileucel
A tumor sample is resected from each patient and cultured ex vivo to expand the population of tumor infiltrating lymphocytes. After lymphodepletion, patients are infused with Lifileucel followed by IL-2.
Other Name: LN - 144

Experimental: Cohort 2
Lifileucel (LN-144) with cryopreservation (Gen 2 infusion product) (Closed)
Biological: Lifileucel
A tumor sample is resected from each patient and cultured ex vivo to expand the population of tumor infiltrating lymphocytes. After lymphodepletion, patients are infused with Lifileucel followed by IL-2.
Other Name: LN - 144

Experimental: Cohort 3
Retreatment cohort: patients from Cohort 1 or Cohort 2 may rescreen for a second TIL regimen therapy if they meet all Inclusion and Exclusion Criteria (except exclusion criterion b).
Biological: Lifileucel
A tumor sample is resected from each patient and cultured ex vivo to expand the population of tumor infiltrating lymphocytes. After lymphodepletion, patients are infused with Lifileucel followed by IL-2.
Other Name: LN - 144




Primary Outcome Measures :
  1. Objective Response Rate [ Time Frame: 6 months ]
    To evaluate the efficacy of Lifileucel (LN-144) in patients with metastatic melanoma using the objective response rate (ORR) as assessed by the Investigator per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.


Secondary Outcome Measures :
  1. Disease Assessment for Duration of Response [ Time Frame: Every 6 week for 6 months, then every 3 months for a maximum of 18 months ]
    To evaluate the Duration of Response (DOR) measured from first observation of PR/CR to disease progression/death among responders. Response assessments are based on RECIST 1.1 per investigators' review and the independent review committee (IRC).

  2. Disease Assessment for Disease Control Rate [ Time Frame: Every 6 week for 6 months, then every 3 months for a maximum of 18 months ]
    To evaluate the Disease Control Rate (DCR) percentage of subjects who achieved either confirmed PR, CR, or SD in the efficacy analysis set. Response assessments are based on RECIST 1.1 per investigators' review and the independent review committee (IRC).

  3. Objective Response Rate [ Time Frame: 6 months ]
    To evaluate the efficacy of Lifileucel (LN-144) in patients with metastatic melanoma using the objective response rate (ORR) as assessed by the IRC.

  4. Overall Survival [ Time Frame: From the last treatment until death for a maximum of 5 years ]
    Overall Survival (OS) as the time to death for all patients in the efficacy analysis set.

  5. Disease Assessment for Progression-free Survival [ Time Frame: Every 6 week for 6 months, then every 3 months for a maximum of 18 months ]
    To evaluate the time to first disease progression/death for all patients in the efficacy analysis set. Response assessments are based on RECIST 1.1 per investigators' review and the independent review committee (IRC).

  6. Adverse Events [ Time Frame: Maximum 24 months from infusion of Lifileucel (LN-144) ]
    Incidence rate of treatment-emergent adverse events (AEs) and serious AEs by severity and relationship to Lifileucel (LN-144).



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Main Criteria for Inclusion:

  1. Patients with unresectable or metastatic melanoma (Stage IIIc or Stage IV) who progressed following ≥ 1 lines of prior systemic therapy, including immune checkpoint inhibitor (eg, anti-PD-1), and if BRAF mutation-positive, after BRAF inhibitor systemic therapy. Patients must have no other therapy options that are expected to have significant benefit in the opinion of the Investigator and must have:

    • At least 1 measurable target lesion, as defined by RECIST 1.1. Lesions in previously irradiated areas should not be selected as target lesion, unless treatment was ≥ 3 months prior, and there has been demonstrated disease progression in the lesion
    • At least 1 resectable target lesion to generate TIL of a minimum 1.5 cm in diameter post-resection; surgical removal with minimal morbidity (defined as any procedure for which expected hospitalization is ≤ 3 days)
  2. Patients must be ≥18 years and ≤70 years of age at the time of consent. Enrollment of patients >70 years of age may be allowed after consultation with the Medical Monitor
  3. Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 and an estimated life expectancy of ≥ 3 months
  4. In the opinion of the Investigator, patient must be able to complete all study-required procedures
  5. Patients of childbearing potential or their partners of childbearing potential must be willing to practice an approved method of birth control during treatment and for 12 months after receiving last protocol-related therapy

    Approved methods of birth control are as follows:

    • Combined (estrogen and progestogen containing) hormonal birth control associated with inhibition of ovulation: oral; intravaginal; transdermal
    • Progestogen-only hormonal birth control associated with inhibition of ovulation: oral; injectable; implantable
    • Intrauterine device (IUD)
    • Intrauterine hormone-releasing system (IUS)
    • Bilateral tubal occlusion
    • Vasectomized partner
    • True sexual abstinence when this is in line with the preferred and usual lifestyle of the patient. Periodic abstinence (eg, calendar ovulation, symptothermal, post-ovulation methods) is not acceptable.
  6. Patients must have the following hematologic parameters:

    • Absolute neutrophil count (ANC) ≥ 1000/mm3
    • Hemoglobin ≥ 9.0 g/dL
    • Platelet count ≥ 100,000/mm3
  7. Patients must have adequate organ function:

    • Serum alanine transaminase (ALT)/ serum glutamic-pyruvic transaminase (SGPT) and aspartate transaminase (AST)/serum glutamic oxaloacetic transaminase (SGOT) ≤ 3 times the upper limit of normal [ULN]), patients with liver metastasis ≤ 5 times ULN
    • An estimated creatinine clearance (eClCr) ≥ 40 mL/min using the Cockcroft Gault formula at Screening
    • Total bilirubin ≤ 2 mg/dL: Patients with Gilbert's syndrome must have a total bilirubin ≤ 3 mg/dL
  8. Patients must be seronegative for the human immunodeficiency virus (HIV) antibody, hepatitis B antigens, and hepatitis C antibody or antigen
  9. Patients must have recovered from all prior therapy-related adverse events (AEs) to ≤ Grade 1 (per Common Terminology Criteria for Adverse Events [CTCAE] v4.03), except for alopecia or vitiligo, prior to enrollment (tumor resection), with a washout period from prior anticancer therapy(ies) to the start of planned NMA-LD of a minimum duration detailed as follows:

    • Targeted therapy: prior targeted therapy with a MEK/BRAF or other-directed agent, is allowed provided the washout period is a ≥ 21 days or 5 half-lives, whichever is longer prior to the start of NMA-LD
    • Chemotherapy: adjuvant, neoadjuvant or definitive chemotherapy/ chemoradiation is allowed provided the washout period is ≥ 21 days or 5 half-lives, whichever is longer prior to the start of NMA-LD
    • Immunotherapy: prior checkpoint-targeted therapy with an anti-CTLA-4/anti-PD-1, other monoclonal antibody (mAb), or vaccine is allowed if disease progression is confirmed prior to or within the washout period of ≥ 21 days before the start of NMA-LD
    • Palliative radiation therapy is permitted between biopsy and NMA-LD if it does not involve lesions being selected as target or nontarget
    • Patients may undergo preplanned procedures if within 2 to 3 weeks prior to the start of NMA-LD
  10. Patients with documented Grade 2 or higher diarrhea or colitis as a result of previous treatment with immune checkpoint inhibitor(s) must have been asymptomatic for at least 6 months and/or had a normal colonoscopy post immune checkpoint inhibitor treatment by visual assessment, prior to start of NMA-LD
  11. Patients must have the ability to understand the requirements of the study, have provided written informed consent, as evidenced by signature on an informed consent form (ICF) approved by an Institutional Review Board/Independent Ethics Committee (IRB/IEC), and agree to abide by the study restrictions and return to the site for the required assessments
  12. Patients have provided written authorization for use and disclosure of protected health information

Criteria for Exclusion:

  1. Patients with melanoma of uveal/ocular origin
  2. Patients who have received an organ allograft or prior cell transfer therapy that included a nonmyeloablative or myeloablative chemotherapy regimen (not applicable for patients in the retreatment Cohort 3)
  3. Patients with symptomatic and/or untreated brain metastases (of any size and any number)

    • Patients with definitively treated brain metastases may be considered for enrollment after discussion with the Medical Monitor, and must be stable for ≥ 2 weeks prior to the start of NMA-LD
  4. Patients who are pregnant or breastfeeding
  5. Patients who are on a systemic steroid therapy at a dose of > 10 mg of prednisone or equivalent per day

    • A short course of higher-dose steroid therapy is allowed in cases of exacerbation of known disease or for treatments of new acute symptoms
  6. Patients who have active medical illness(es) that in the opinion of the Investigator would pose increased risk for study participation that may include active systemic infections, such as syphilis, or any other infections requiring antibiotics, coagulation disorders, or other active major medical illnesses of the cardiovascular, respiratory, or immune system
  7. Patients who have any form of primary immunodeficiency (such as severe combined immunodeficiency disease [SCID] or acquired immunodeficiency syndrome [AIDS])
  8. Patients who have a history of hypersensitivity to any component or excipient of the TIL therapy and other study drugs:

    • NMA-LD (cyclophosphamide, mesna, and fludarabine)
    • IL-2
    • Antibiotics of the aminoglycoside group (ie, streptomycin, gentamicin)
    • Any component of the TIL infusion product formulation including dimethyl sulfoxide [DMSO], human serum albumin [HSA], IL-2, and dextran-40
  9. Patients who have a left ventricular ejection fraction (LVEF) < 45% or New York Heart Association (NYHA) functional classification > Class 1 at Screening. All patients must have echocardiogram (ECHO) or multiple gated acquisition scan (MUGA) at Screening. For patients ≥ 60 years or patients who have a history of ischemic heart disease, chest pain, or clinically significant atrial and/or ventricular arrhythmias, a cardiac stress tests must be performed showing LVEF ≥45%, and if any wall movement abnormalities, they must be reversible.
  10. Patients who have obstructive or restrictive pulmonary disease and have a documented FEV1 (forced expiratory volume in 1 second) of ≤ 60%
  11. Patients who have had another primary malignancy within the previous 3 years (with the exception of carcinoma in situ of the breast, cervix, or bladder, localized prostate cancer and nonmelanoma skin cancer that has been adequately treated)
  12. Patients who have been shown to be BRAF mutation positive (V600), but have not received prior systemic therapy with a BRAF-directed kinase inhibitor
  13. Patients who have received a live or attenuated vaccine within 28 days of the start of NMA-LD
  14. Patients whose cancer requires immediate attention or who would otherwise suffer a disadvantage by participating in this trial
  15. Patients protected by the following constraints:

    • Hospitalized persons without consent or persons deprived of liberty because of a judiciary or administrative decision
    • Adult persons with a legal protection measure or persons who cannot express their consent
    • Patients in emergency situations who cannot consent to participate in the trial

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02360579


  Show 38 Study Locations
Sponsors and Collaborators
Iovance Biotherapeutics, Inc.
Investigators
Study Chair: Iovance Biotherapeutics Medical Monitor Iovance Biotherapeutics, Inc.

Responsible Party: Iovance Biotherapeutics, Inc.
ClinicalTrials.gov Identifier: NCT02360579     History of Changes
Other Study ID Numbers: C-144-01
First Posted: February 10, 2015    Key Record Dates
Last Update Posted: October 29, 2018
Last Verified: October 2018

Keywords provided by Iovance Biotherapeutics, Inc.:
Autologous Adoptive Cell Transfer
Autologous Adoptive Cell Therapy
Cellular Immuno-therapy
Cell Therapy
Tumor Infiltrating Lymphocytes
TIL
LN-144
IL-2
Melanoma
Lifileucel

Additional relevant MeSH terms:
Melanoma
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Nerve Tissue
Nevi and Melanomas