| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| 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 |
|
| 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 | 21.1 |
| 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) |
|
| 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 |
| Evaluate the efficacy of LN-144 in patients with unresectable or metastatic melanoma using the ORR, as assessed by the IRC per RECIST v1.1 |
|
| E.2.2 | Secondary objectives of the trial |
• Evaluate the efficacy endpoints of duration of response (DOR), disease control rate (DCR), and PFS, as assessed by the IRC per RECIST v1.1
• Further evaluate efficacy of LN-144 in patients with metastatic unresectable or melanoma by assessing ORR, DOR, DCR, and PFS, as assessed by the Investigator per RECIST v1.1
• Evaluate OS
• Characterize the safety profile of LN-144 in patients with unresectable or metastatic melanoma |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
a. Patients with unresectable metastatic or melanoma (Stage IIIc or
Stage IV)
b. Patients must have progressed following ≥ 1 prior systemic therapy including a PD-1 blocking antibody; and if BRAF V600 mutation-positive, a BRAF inhibitor or BRAF inhibitor in combination with MEK inhibitor
c. Prior to study Enrollment, documentation of radiological disease progression after the most recent therapy
d. At least one measurable target lesion, as defined by RECIST v1.1
Lesions in previously irradiated areas (or other local therapy) should not be selected as target lesions, unless treatment was ≥ 3 months prior to Screening, and there has been demonstrated disease progression in that particular lesion
If a lesion is partially resected to generate TIL, and remains visible on the Baseline scan after surgery, then the partially resected lesion can be used for RECIST v1.1 response assessment, but only as a non-target lesion
e. At least one resectable lesion (or aggregate of lesions resected) of a minimum 1.5 cm in diameter post-resection to generate TIL; surgical removal with minimal morbidity (defined as any procedure for which expected hospitalization is ≤ 3 days)
f. Patients must be ≥ 18 years of age at the time of consent. Enrollment of patients > 70 years of age may be allowed after consultation with the Medical Monitor
g. Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 (Appendix 2) and an estimated life expectancy of ≥ 3 months
h. In the opinion of the Investigator, patients must be able to complete all studyrequired procedures
i. Patients must have the following hematologic parameters:
• Absolute neutrophil count (ANC) ≥ 1000/mm3
• Hemoglobin (Hb) ≥ 9.0 g/dL
• Platelet ≥ 100,000/mm3
Note: Transfusions or growth factors are not allowed 28 days prior to signing the informed consent form (ICF) and continuing through the Screening Period
j. 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
• Estimated creatinine clearance (eCrCl) ≥ 40 mL/min using the Cockcroft- Gault formula
• Total bilirubin ≤ 2 mg/dL
• Patients with Gilbert's syndrome must have a total bilirubin ≤ 3 mg/dL
k.Patients must have recovered from all prior therapy-related AEs to ≤ Grade 1 (per Common Terminology Criteria for Adverse Events [CTCAE] v4.03), except for alopecia or vitiligo, prior to Enrollment (tumor resection)
• Patients with documented ≥ Grade 2 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 tumor resection
• Patients with immunotherapy-related endocrinopathies stable for at least 6 weeks (eg, hypothyroidism), and controlled with hormonal replacement (non-corticosteroids), are allowed
l. Patients must have a washout period of ≥ 28 days from prior anticancer therapy(ies) to the start of the planned NMA-LD preconditioning regimen:
• Targeted therapy: MEK/BRAF or other targeted agent
• Chemotherapy
• Immunotherapy: anti-CTLA-4/anti-PD-1, other mAb, or vaccine
• Palliative radiation therapy is permitted so long as it does not involve lesions being selected for TIL, or as target or non-target lesions. Washout is not required if all related toxicities have resolved to ≤ Grade 1 as per CTCAE v4.03
m. Patients of childbearing potential or their partners of childbearing potential must be willing to take the appropriate precaution to avoid pregnancy or fathering a child for the duration of the study and practice an approved, highly effective method of birth control during treatment and for 12 months after receiving the last protocol-related therapy
• Approved methods of birth control are as follows:
o Combined (estrogen and progesterone containing) hormonal birth control associated with inhibition of ovulation: oral, intravaginal, transdermal
o Progesterone-only hormonal birth control associated with inhibition of ovulation: oral, injectable, implantable
o Intrauterine device (IUD)
o Intrauterine hormone-releasing system (IUS)
o Bilateral tubal occlusion
o Vasectomized partner
o 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
|
|
| E.4 | Principal exclusion criteria |
a. Patients who have been shown to be BRAF mutation positive (V600), but have not received prior systemic therapy with a BRAF inhibitor alone or a BRAF inhibitor in combination with a MEK inhibitor
b. Patients who have received an organ allograft or prior cell transfer therapy
c. Patients with melanoma of uveal/ocular origin
d. Patients who have a history of hypersensitivity to any component or excipient of LN-144 or other study drugs:
• NMA-LD preconditioning regimen (cyclophosphamide, mesna, and fludarabine)
• Antibiotics (ABX) of the aminoglycoside group (ie, streptomycin, gentamicin); except those who are skin-test negative for gentamicin hypersensitivity
• Any component of the LN-144 infusion product formulation including DMSO, HSA, IL-2, and dextran-40
e. 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, and must be stable for ≥ 14 days prior to beginning the NMA-LD preconditioning regimen
f. Patients who are on chronic systemic steroid therapy for any reason
g. Patients who have active medical illness(es) that would pose increased risk for study participation, including: active systemic infections requiring systemic ABX, coagulation disorders, or other active major medical illnesses of the cardiovascular, respiratory, or immune system
h. Patients who have ≥ Grade 2 hemorrhage within 14 days prior to
Enrollment (tumor resection)
i. Patients who are seropositive for any of the following:
• Human immunodeficiency virus (HIV)-1 or HIV-2 antibodies
• Hepatitis B antigen (HBsAg), hepatitis B core antibody (anti-HBc antibody),or hepatitis C antibody (HCV Ab); Patients with acute or chronic hepatitis infections may be enrolled if the viral load by polymerase chain reaction (PCR) is undetectable with/without active treatment.
• Syphilis (Rapid Plasma Reagin [RPR] test or venereal disease research laboratory [VDRL] test)
• Cytomegalovirus (CMV) IgM antibody titer or PCR assay; and Epstein-Barr virus (EBV) IgM or PCR assay, indicating active infection
• Positive herpes simplex virus (HSV)-1 and HSV-2 IgM serologyor or PCR assay,
• Patients who are HSV immunoglobulin M (IgM) or PCR assay positive will need to receive appropriate treatment and become IgM or PCR assay negative prior to starting the NMA-LD preconditioning regimen
j. Patients who have any form of primary immunodeficiency (such as severe combined immunodeficiency disease [SCID] and acquired immunodeficiency syndrome [AIDS])
k. Patients who have a left ventricular ejection fraction (LVEF) < 45% or New York Heart Association (NYHA) functional classification > Class 1
• Patients ≥ 60 years of age and who have a history of ischemic heart disease, chest pain, or clinically significant atrial and/or ventricular arrhythmias must have a cardiac stress test. Patients with any irreversible wall movement abnormalities are excluded
l. Patients who have a documented forced expiratory volume in 1 second (FEV1) of ≤ 60%
m. 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)
n. Patients who have received a live or attenuated vaccine within 28 days of beginning the NMA-LD preconditioning regimen
o. Patients who are pregnant or breastfeeding
p. Patients whose cancer requires immediate attention or who would otherwise suffer a disadvantage by participating in this trial
q. 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 |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| ORR, as assessed by the IRC per RECIST v1.1 |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Every 6 weeks for 6 months, then every 3 months for a maximum of 54 months |
|
| E.5.2 | Secondary end point(s) |
• The DOR, DCR, and PFS per RECIST v1.1 as assessed by IRC
• The ORR, DOR, DCR, and PFS, per RECIST v1.1 as assessed by the Investigator
• OS
• Incidence, severity, seriousness, relationship to study treatment, and characteristics of treatment-emergent adverse events (TEAEs), including AEs leading to early discontinuation from treatment or withdrawal from the Response Assessment Period study follow-up, and AEs resulting in deaths |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Every 6 weeks for 6 months, then every 3 months for a maximum of 54 months;
OS: Time Frame: Until death or up to 60 months;
adverse events: Time Frame: Maximum 60 months |
|
| 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 | 9 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 32 |
| 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 |
| United States |
| France |
| Spain |
| Switzerland |
| Germany |
| Italy |
| Hungary |
| United Kingdom |
|
| 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
|
The study is expected to be completed approximately 5 years (60
months) from Enrollment (tumor resection) of the last patient. This is
the time point when all patients have exited the study for any reason,
or study is terminated by the Sponsor, whichever occurs first. |
|
| 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 |
Print
