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Neoadj Admin Autologous Tumor Infiltrating Lymphocytes & Pembrolizumab for Treatment of Adv Melanoma Patients

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ClinicalTrials.gov Identifier: NCT05176470
Recruitment Status : Recruiting
First Posted : January 4, 2022
Last Update Posted : April 25, 2022
Sponsor:
Collaborator:
Iovance Biotherapeutics, Inc.
Information provided by (Responsible Party):
Richard Wu, Ohio State University Comprehensive Cancer Center

Brief Summary:
This phase I/II trial tests the safety and side effects of lifileucel and pembrolizumab in treating patients with stage IIIB-D melanoma that has spread to nearby tissue or lymph nodes (locally advanced). Biological therapies, such as lifileucel, use substances made from living organisms that may attack specific tumor cells and stop them from growing or kill them. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving lifileucel and pembrolizumab may make the tumor smaller.

Condition or disease Intervention/treatment Phase
Locally Advanced Melanoma Pathologic Stage IIIB Cutaneous Melanoma AJCC v8 Pathologic Stage IIIC Cutaneous Melanoma AJCC v8 Pathologic Stage IIID Cutaneous Melanoma AJCC v8 Drug: Cyclophosphamide Drug: Fludarabine Biological: Lifileucel Biological: Pembrolizumab Procedure: Therapeutic Conventional Surgery Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 15 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase IB Study to Assess the Safety and Efficacy of Neoadjuvant Administration of Autologous Tumor Infiltrating Lymphocytes (LN144/Lifileucel) and Pembrolizumab for Treatment of Patients With Locally Advanced (Stage IIIB-D) Melanoma
Estimated Study Start Date : May 31, 2022
Estimated Primary Completion Date : December 31, 2024
Estimated Study Completion Date : December 31, 2025

Resource links provided by the National Library of Medicine

MedlinePlus Genetics related topics: Melanoma
MedlinePlus related topics: Melanoma

Arm Intervention/treatment
Experimental: Treatment (pembrolizumab, lifileucel)

Patients receive pembrolizumab IV on day -14, cyclophosphamide IV QD on days -7 to -6, fludarabine IV over 30 minutes QD on days -5 to -1, and lifileucel IV infusion on day 0. Patients also receive pembrolizumab IV on day 28 and 70, and undergo surgery on day 80.

MAINTENANCE: Patients receive pembrolizumab IV every 6 weeks for up to 1 year in the absence of disease progression or unacceptable toxicity.

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
  • Cyclophosphamide Monohydrate
  • Cyclophosphamidum
  • Cyclophosphan
  • Cyclophosphane
  • Cyclophosphanum
  • Cyclostin
  • Cyclostine
  • Cytophosphan
  • Cytophosphane
  • Cytoxan
  • Fosfaseron
  • Genoxal
  • Genuxal
  • Ledoxina
  • Mitoxan
  • Neosar
  • Revimmune
  • Syklofosfamid
  • WR- 138719

Drug: Fludarabine
Given IV
Other Name: Fluradosa

Biological: Lifileucel
Given by IV infusion
Other Names:
  • Autologous TIL LN-144
  • Autologous Tumor Infiltrating Lymphocytes LN-144
  • Contego
  • LN-144

Biological: Pembrolizumab
Given IV
Other Names:
  • Keytruda
  • Lambrolizumab
  • MK-3475
  • SCH 900475

Procedure: Therapeutic Conventional Surgery
Undergo surgery




Primary Outcome Measures :
  1. Feasibility of neoadjuvant administration of MK-3475 and LN-144/Lifileucel in 3 stage IIIB-D melanoma patients (Phase 1) [ Time Frame: Up to 2 years ]
    Success rate of tumor infiltrating lymphocyte (TIL) expansion from all screened eligible patients who have had tumor-involved lymph node(s) removed; percentage of all eligible patients who have completed the screening and treated with LN-144/lifileucel.

  2. Incidence of grade >= 3 treatment-emergent adverse events (both immune and non-immune related) (Phase 2) [ Time Frame: Up to 2 years ]
    The severity of AEs will be graded according to CTCAE version 5.0, and frequencies and percentages of patients with AEs will be tabulated by severity grade.


Secondary Outcome Measures :
  1. Overall objective response rate [ Time Frame: Up to 2 years ]
    Evaluated by Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1) and immune-related RECIST (irRECIST) criteria.

  2. Relapse-free survival (RFS) rate [ Time Frame: At 24 months ]
    Kaplan-Meier method will be used to estimate the median time and the corresponding 95% CI.


Other Outcome Measures:
  1. Major pathologic response (MPR) rate [ Time Frame: Up to 2 years ]
    MPR will be summarized by number and percentage of patients with major pathologic response, as well as the corresponding 2-sided exact 95% confidence intervals (95% CI).

  2. Immune correlates (as described above) with respect to response and 24-month relapse free survival, of the TIL/LN-144 + pembrolizumab neoadjuvant therapy [ Time Frame: Up to 2 years ]
  3. Success rate of TIL growth from tumor-involved lymph node(s) [ Time Frame: Up to 2 years ]
  4. Doses of the infused TIL with respect to response and 24-month relapse-free survival [ Time Frame: Up to 2 years ]
  5. Changes in the patients' health-related quality of life [ Time Frame: Up to 2 years ]
    Measured by a standardized questionnaire during and after the study protocol.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patient must be 18 to 75 years of age
  • Must have a confirmed diagnosis of Stage IIIB-D locally advanced melanoma (American Joint Committee on Cancer [AJCC] 8th edition) with measurable disease in the lymph node(s) documented by computed tomography (CT) or ultrasound imaging (>= 15 mm short axis) or by physical exam. Patients must also have measurable primary site of disease, including cutaneous and/or intransit metastases by imRECIST (>= 20 mm chest x-ray [CXR], >= 10 mm CT, or >= 10 mm by exam)
  • No prior therapy is allowed
  • Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 and an estimated life expectancy of >= 3 months in the opinion of the investigator
  • Patients must have at least one easily accessible measurable tumor-involved lymph node(s) documented by CT or ultrasound imaging for TIL harvest
  • Patients must be amenable to have ultrasound examination of measurable lymph node(s) and have pathologic confirmation of melanoma metastases in the lymph node (fine needle aspiration [FNA] acceptable) in the 28 days preceding the first administration of the treatment
  • Patients with and without BRAF V600E/K mutations are included.
  • Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial.
  • Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class 2B or better.
  • Patients with a history of herpes simplex virus (HSV) infection must have been treated. Patients with a history of Epstein-Barr virus (EBV) or cytomegalovirus (CMV) infection must be asymptomatic and have low viral loads
  • Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial
  • Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional classification. To be eligible for this trial, patients should be class 2B or better
  • Women must not be pregnant or breast-feeding due to potential harm to an unborn fetus and possible risk of adverse events in nursing infants with the anti-PD-1 regimen(s) being used.

    • All females of childbearing potential must have a blood test or urine study within 14 days prior to registration to rule out pregnancy.
    • A female of childbearing potential is defined as any woman, regardless of sexual orientation, or whether they have undergone tubal ligation, who meets the following criteria: 1) has achieved menarche at some point, 2) has not undergone a hysterectomy or bilateral oophorectomy, or 3) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding consecutive months)
  • Women of childbearing potential and sexually active males must not conceive or father children by using accepted and effective method(s) of contraception or by abstaining from sexual intercourse from the time of study registration and continuing until at least 5 months after the last dose of anti-PD-1 treatment for female patients and for at least 7 months after the last dose of anti-PD-1 treatment for male patients who are sexually active with a woman of childbearing potential (WOCBP).
  • Patients must have adequate organ and marrow function as defined below at study enrollment and prior to surgical resection. (these labs must be obtained ≤ 4 weeks prior to protocol registration and ≤1 week prior to surgery):
  • Hemoglobin >= 10 g/dL
  • Neutrophils >= 1500/ul
  • Leukocytes >= 3000/ul
  • Lymphocytes >= 700/ul
  • Blood platelet >= 100,000/ul
  • Serum creatinine =< 1.5 x upper limit of normal or creatinine clearance (CrCl) >= 40 mL/min (if using the Cockcroft-Gault formula)
  • Serum bilirubin =< 2.0 mg/dL
  • Total bilirubin =< 1.5 x upper limit of normal (except for patients with Gilbert syndrome, who can have total bilirubin < 3 mg/dL)
  • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2 x upper limit of normal
  • Lactate dehydrogenase (LDH) =< 1.5 x upper limit of normal
  • Patients (or legally authorized representative) 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, including the RFS Follow-up Period

Exclusion Criteria:

  • Ocular/uveal melanoma
  • Chemotherapy or radiotherapy within 4 weeks before baseline (6 weeks for nitroso-urea and mitomycin C)
  • Contraindication for the use of vasopressor agents
  • Patients with HIV active infection or seropositivity are excluded. Patients with active Hep B or Hep C based on serology and viral load are excluded. Patients with active CMV or EBV based on serology and viral load are excluded.
  • History or current manifestation of severe progressive heart disease (congestive heart failure with LVEF < 50% by echocardiogram or MUGA scan, coronary artery disease, uncontrolled arterial hypertension, uncontrolled arrhythmia, or myocardial infarction in the past 6 months.
  • Patients with active interstitial lung disease (ILD)/pneumonitis or a history of ILD/pneumonitis requiring treatment with systemic steroids.
  • Patients should be excluded if they had prior treatment with an anti- PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA4 antibody, or any other antibody or drug specifically targeting T-cell costimulation or immune checkpoint pathways.
  • Patients who have a history of hypersensitivity to immune checkpoint therapy drug(s) or any component or excipient of LN-144 or other study drugs:

    • Nivolumab, pembrolizumab, or related products
    • Any monoclonal antibody
    • NMA-LD preconditioning regimen (cyclophosphamide, mesna, and fludarabine)
    • Proleukin, aldesleukin, IL-2
    • Antibiotics (ABX) of the aminoglycoside group (i.e., streptomycin, gentamicin); except those who are skin-test negative for gentamicin hypersensitivity
    • Any component of the LN-144 infusion product formulation including dimethyl sulfoxide (DMSO), human serum albumin (HSA), IL-2, and dextran-40
  • History of chronic autoimmune disease (Addison's disease, multiple sclerosis, Graves' disease, rheumatoid arthritis, systemic lupus erythematosus, etc…) except patient with active vitiligo or a history of vitiligo. Patients with history of psoriasis is allowed
  • History of inflammatory bowel disease, celiac disease, or other chronic gastrointestinal conditions associated with diarrhea.
  • Patients who have had another primary malignancy within the previous 3 years (except for those which do not require treatment or have been curatively treated >1 year ago, and in the judgment of the Investigator, does not pose a significant risk of recurrence including, but not limited to, non-melanoma skin cancer, DCIS, LCIS, prostate cancer Gleason score ≤6).
  • Any serious, acute or chronic illness (i.e., active infection) needing antibiotics administration, coagulation's disorders, or any medical disorder requiring unauthorized concomitant treatment described in this study.
  • Positive serology for HTLV1/HTLV2, or syphilis.
  • Patients should be excluded if they have a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days before study drug administration. Inhaled or topical steroids and adrenal replacement doses > 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease. Patients are permitted to use topical, ocular, intra-articular, intranasal, and inhalational corticosteroids (with minimal systemic absorption). Physiologic replacement doses of systemic corticosteroids are permitted, even if > 10 mg/day prednisone equivalents. A brief course of corticosteroids for prophylaxis (eg, contrast dye allergy) or for treatment of non-autoimmune conditions (eg, delayed-type hypersensitivity reaction caused by contact allergen) is permitted.
  • Patients who have obstructive or restrictive pulmonary disease and have a documented forced expiratory volume in 1 second (FEV1) of ≤ 60% of predicted normal:

    • If a patient is not able to perform reliable spirometry due to abnormal upper airway anatomy (i.e., tracheostomy), a 6- minute walk test may be used to assess pulmonary function.
    • Patients who are unable to walk a distance of at least 80% predicted for age and sex or demonstrates evidence of hypoxia at any point during the test (SpO2 < 90%) are excluded.
  • Active infections, including COVID-19, within 30 days.
  • Participated in another clinical study with an investigational product within 21 days of the initiation of treatment.
  • Adults under a legal protection regime (i.e., guardianship, trusteeship).

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): NCT05176470


Contacts
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Contact: The Ohio State University Comprehensive Cancer Center 800-293-5066 OSUCCCClinicaltrials@osumc.edu

Locations
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United States, Ohio
Ohio State University Comprehensive Cancer Center Recruiting
Columbus, Ohio, United States, 43210
Contact: Richard C. Wu, M.D. Ph.D.       Richard.Wu@osumc.edu   
Principal Investigator: Richard C. Wu, M.D. Ph.D.         
Sponsors and Collaborators
Richard Wu
Iovance Biotherapeutics, Inc.
Investigators
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Principal Investigator: Richard C Wu, M.D. Ph.D. Ohio State University Comprehensive Cancer Center
Additional Information:
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Responsible Party: Richard Wu, Principal Investigator, Ohio State University Comprehensive Cancer Center
ClinicalTrials.gov Identifier: NCT05176470    
Other Study ID Numbers: OSU-21202
NCI-2021-11063 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
First Posted: January 4, 2022    Key Record Dates
Last Update Posted: April 25, 2022
Last Verified: April 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Melanoma
Skin Neoplasms
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Nerve Tissue
Nevi and Melanomas
Neoplasms by Site
Skin Diseases
Cyclophosphamide
Pembrolizumab
Fludarabine
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Antineoplastic Agents, Immunological