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

  • STATUS
    Recruiting
  • End date
    Dec 31, 2025
  • participants needed
    15
  • sponsor
    Richard Wu
Updated on 15 May 2022

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.

Description

PRIMARY OBJECTIVES:

I. To determine the feasibility of the neoadjuvant administration of MK-3475 (pembrolizumab) and LN-144/lifileucel isolated from tumor-involved metastatic lymph node(s) in 3 stage IIIB-D melanoma patients. (Phase 1) II. To evaluate the safety profile and surgical tolerability of MK-3475 (pembrolizumab) and LN-144/lifileucel in 12 patients, as measured by the incidence of grade >= 3 treatment-emergent adverse events (TEAEs). (Phase 2)

SECONDARY OBJECTIVES:

I. To evaluate the efficacy of MK-3475 (pembrolizumab) and LN-144/lifileucel in 12 patients by determining the overall objective response rate (ORR), using the Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1) and immune-related RECIST (irRECIST) criteria, as assessed by the investigator. (Phase 2 only) II. To further evaluate the efficacy of MK-3475 (pembrolizumab) and LN-144/Lifileucel in 12 patients using the 24-month relapse-free survival rate (RFS), using RECIST 1.1 and irRECIST, as assessed by the investigator. (Phase 2 only)

EXPLORATORY OBJECTIVES:

I. To determine rates of major pathologic response (MPR) for high-risk stage IIIB-D melanoma patients treated with neoadjuvant administration of MK-3475 (pembrolizumab) and LN-144/lifileucel.

II. To determine the association between the proportion of PD-1+CD4+ or CD8+ tumor infiltrating lymphocytes (TILs) isolated from tumor involved lymph node(s) via flow cytometry, and probability of MPR, ORR, and RFS.

III. To determine the association between neoantigen specificity and probability of MPR, ORR, and RFS.

IV. To determine the correlation between tumor mutation burden (TMB) and MPR, ORR, and RFS.

V. To determine the correlation between intratumoral IFN-gamma and T-effector gene signatures and probability of MPR, ORR, and RFS.

VI. To evaluate the correlation between serum cytokines (IL-8, IL-6), and probability of MPR, ORR, and RFS.

VII. To evaluate the success rates of growing TILs from lymph node metastases, and the potential predictive factors (i.e., patient's age, CD8/CD4 ratios, inhibitory receptor expressions).

VIII. To correlate the doses of TILs infused to patients and the probability of MPR, ORR, and RFS.

IX. To perform additional translational studies utilizing the unstained slides or FFPE (paraffin blocks) on the resected melanoma tumor specimen post LN-144/lifileucel neoadjuvant therapy.

OUTLINE

Patients receive pembrolizumab intravenously (IV) on day -14, cyclophosphamide IV once daily (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.

After completion of study treatment, patients are followed up every 3 months for up to 2 years.

Details
Condition Locally Advanced Melanoma, Pathologic Stage IIIB Cutaneous Melanoma AJCC v8, Pathologic Stage IIIC Cutaneous Melanoma AJCC v8, Pathologic Stage IIID Cutaneous Melanoma AJCC v8
Treatment cyclophosphamide, Fludarabine, Pembrolizumab, therapeutic conventional surgery, Lifileucel
Clinical Study IdentifierNCT05176470
SponsorRichard Wu
Last Modified on15 May 2022

Eligibility

Yes No Not Sure

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)
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