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)/Metastatic (Stage IV) Melanoma
Overview
- Phase
- Phase 1
- Status
- Active, not recruiting
- Sponsor
- Richard Wu
- Enrollment
- 2
- Locations
- 1
- Primary Endpoint
- Incidence of grade >= 3 treatment-emergent adverse events (both immune and non-immune related) (Phase 2)
Overview
Brief Summary
This phase I/II trial tests the safety and side effects of LN-144 (Lifileucel) and pembrolizumab in treating patients with stage IIIB-D or stage IV melanoma that has spread to nearby tissue or lymph nodes. Biological therapies, such as LN-144 (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.
Detailed Description
PRIMARY OBJECTIVES:
I. To determine the feasibility of the neoadjuvant administration of Pembrolizumab and LN-144 (Lifileucel) isolated from tumor-involved metastatic lymph node(s) in 3 stage IIIB-D melanoma patients. (Part 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). (Part 2)
SECONDARY OBJECTIVES:
I. To evaluate the efficacy of 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. (Part 2 only) II. To further evaluate the efficacy of 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. (Part 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.
Study Design
- Study Type
- Interventional
- Allocation
- Na
- Intervention Model
- Single Group
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to 75 Years (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •Patient must be 18 to 75 years of age
- •Must have a confirmed diagnosis of Stage IIIB-D locally advanced or Stage IV 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
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
Arms & Interventions
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.
Intervention: Therapeutic Conventional Surgery (Procedure)
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.
Intervention: Cyclophosphamide (Drug)
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.
Intervention: Fludarabine (Drug)
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.
Intervention: Lifileucel (Biological)
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.
Intervention: Pembrolizumab (Biological)
Outcomes
Primary Outcomes
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.
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.
Secondary Outcomes
- Overall objective response rate(Up to 2 years)
- Relapse-free survival (RFS) rate(At 24 months)
Investigators
Richard Wu
Principal Investigator
Ohio State University Comprehensive Cancer Center