E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
Advanced melanoma, a type of skin cancer that spreads to other places in the body |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10027480 |
E.1.2 | Term | Metastatic malignant melanoma |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To evaluate the efficacy of LN-144 in patients with metastatic melanoma using the objective response rate (ORR) |
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E.2.2 | Secondary objectives of the trial |
To further evaluate efficacy of LN-144 in patients with metastatic melanoma such as complete response (CR) rate, duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) To characterize the safety profile of LN-144 in patients with metastatic melanoma |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
a. Patients with unresectable metastatic melanoma (Stage IIIc or Stage IV) who progressed following ≥1 line of prior systemic therapy, including immune checkpoint inhibitor (e.g., anti-PD-1), and if BRAF mutation-positive, after BRAF inhibitor systemic therapy - At least one measurable target lesion as defined by RECIST version 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 progression in the lesion - At least one resectable lesion to generate TILs of a minimum 1.5 cm in diameter post-resection
b. 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
c. Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and estimated life expectancy of ≥3 months
d. In the opinion of the Investigator, patient must be able to complete all study-required procedures
e. 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 4 months after receiving all protocol related therapy
f. Patients must have the following hematologic parameters: • absolute neutrophil count (ANC) > 1000/mm3 • hemoglobin > 9.0 g/dL • platelet count > 100,000/mm3
g. Patients must have adequate organ function: - serum ALT/SGPT and AST/SGOT < 3 times the upper limit of normal ULN), patients with liver metastasis < 5 times ULN - an estimated creatinine clearance (eCCr) ≥ 40 mL/min using the Cockcroft Gault formula at Screening - total bilirubin ≤ 2 mg/dL o Patients with Gilbert's Syndrome must have a total bilirubin < 3 mg/dL
h. Patients must be seronegative for the HIV antibody, hepatitis B antigen, and hepatitis C antibody or antigen
i. Patients must have recovered from all prior therapy-related AEs to Grade 1 or less (per CTCAE v4.03), except for alopecia or vitiligo, prior to enrollment (tumor resection) - A minimal washout period of 4 weeks is required prior to enrollment (tumor resection) - Palliative radiation therapy is permitted between biopsy and nonmyeloablative lymphodepletion if it does not involve lesions being selected as target or non-target lesions - Patients may undergo pre-planned procedures if within 2-3 weeks prior to the start of nonmyeloablative lymphodepletion
j. Patients with documented Grade 2 or greater 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 nonmyeloablative lymphodepletion
k. 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
l. Patients have provided written for use and disclosure of protected health information |
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E.4 | Principal exclusion criteria |
a. Patients with melanoma of uveal/ocular origin
b. Patients who have received prior cell transfer therapy that included a nonmyeloablative or myeloablative chemotherapy regimen (not applicable for patients in the retreatment Cohort 3)
c. Patients with symptomatic and/or untreated brain metastases (of any size and any number) - Patients with definitively treated brain metastases, will be considered for enrollment after discussion with Medical Monitor, and must be stable for 2-4 weeks prior to the start of treatment nonmyeloablative lymphodepletion)
d. Patients who are pregnant or breastfeeding
e. 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
f. Patients who have active medical illness(es) that in the opinion of the Investigator would pose increased risk for study participation, such as systemic infections requiring antibiotics, coagulation disorders or other active major medical illnesses of the cardiovascular, respiratory or immune system
g. Patients who have any form of primary immunodeficiency (such as Severe Combined Immunodeficiency Disease and AIDS)
h. Patients who have a history of severe immediate hypersensitivity reaction to cyclophosphamide, fludarabine, or IL-2
i. Patients who have a left ventricular ejection fraction (LVEF) < 45% at Screening
j. Patients who have obstructive or restrictive pulmonary disease and have a documented FEV1 (forced expiratory volume in 1 second) of ≤ 60%
k. 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 non-melanoma skin cancer that has been adequately treated)
l. Patients with known allergic reaction to antibiotics of aminoglycoside group (i.e. streptomycin, gentamicin)
m. Patients who have been shown to be BRAF mutation positive (V600), but have not received prior systemic therapy with a BRAF-directed kinase inhibitor |
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E.5 End points |
E.5.1 | Primary end point(s) |
Objective response rate (ORR) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
After last patient in Cohort 2 reach the 6-month tumor assessment, and final analysis at end of 2-year post-treatment follow up. |
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E.5.2 | Secondary end point(s) |
Complete response (CR) rate, duration of response (DOR), disease control rate (DCR), progression free survival (PFS) and overall survival (OS) per RECIST 1.1 criteria 2 by independent and Investigator review
Incidence, severity, seriousness, relationship to study treatment, and characteristics of treatment-emergent AEs (TEAEs), including AEs leading to early discontinuation from treatment or withdrawal from the study, and AEs resulting in deaths |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
After last patient in Cohort 2 reach the 6-month tumor assessment, and final analysis at end of 2-year post-treatment follow up. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 24 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
France |
Germany |
Hungary |
Italy |
Spain |
Switzerland |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
Three years from last patient receiving last dose of adjuvant IL-2 or end of study (EOS) visit |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 5 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 5 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |