This study has been transitioned to CTIS with ID 2024-510778-26-00 check the CTIS register for the current data. Primary Objective:To evaluate the efficacy of LN-145 measured by objective response rate (ORR) usingResponse Evaluation Criteria in…
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Source
Brief title
Condition
- Miscellaneous and site unspecified neoplasms benign
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
ORR is defined as the proportion of patients who have a confirmed CR or PR as
assessed per RECIST v1.1 by the IRC (Cohorts 1 and 2) or by the Investigator
(Cohort 3, 4 and Retreatment Cohort) from the date of LN-145infusion until
disease progression or start of a new anticancer therapy.
Secondary outcome
Secondary Endpoints:
• ORR is defined as the proportion of patients who have a confirmed CR or PR as
assessed per RECIST v1.1 by the Investigator (Cohort 1 and 2) from the date of
LN-145 infusion until disease progression or start of a new anticancer therapy.
•CR rate is defined as the proportion of patients who have a confirmed CR per
RECIST v1.1 as assessed by the IRC (Cohort 1 and 2) or by the Investigator (all
cohorts) from the date of LN-145 infusion until disease progression or start of
a new anticancer therapy.
•DOR is measured from the time that criteria are met for CR or PR per RECIST
v1.1 as assessed by IRC (Cohorts 1 and 2) or by the Investigator
(all cohorts) until disease progression or death due to any cause.
•DCR is measured by the percentage of patients with a best overall confirmed
response of CR or PR at any time plus stable disease (SD) >= 6 weeks per RECIST
v1.1 as assessed by IRC (Cohorts 1 and 2) or by the Investigator (all cohorts)
from the date of LN-145 infusion until disease progression or the start of a
new anticancer therapy.
•PFS is defined as the time from the date of LN-145 infusion until disease
progression, per RECIST v1.1 as assessed by IRC (Cohorts 1 and 2) or by the
Investigator (all cohorts) or death due to any cause.
•OS is the time from the date of LN-145 infusion to death due to any cause.
•Incidence of Grade >=3 TEAEs and SAEs per CTCAE v5.0 in all patients•Percentage
of successful LN-145 product generated from core biopsies in Cohort 3
Exploratory Endpoints:
• In vivo persistence of the T cells comprising the TIL product to be assessed
by monitoring the presence of TIL product-specific T-cell receptor-beta
complementarity determining region 3 (CDR3) sequences in each patient's blood
over time; CDR3 sequences present in the product and peripheral blood samples
to be identified using deep sequencing
• Exploratory endpoints aiming at identifying predictive and pharmacodynamic
clinical biomarkers of the activity of LN-145:
o Phenotypic and functional characteristics of LN 145
o Immune profile of the tumor tissues
o Gene expression profiles of the TIL product, tumor tissues, and/or PBMCs
o Mutational landscape of the tumors
o Circulating immune factors
o Immune composition of PBMCs
• HRQoL as assessed per the European Organization for Research and Treatment of
Cancer (EORTC) quality of life questionnaire (QLQ) C30 and QLQ LC13
Background summary
Lung cancer is the leading cause of cancer deaths worldwide, with approximately
1.7 million deaths reported in 2015. Of the lung cancer deaths, >80% were
attributed to non-small-cell lung cancer (NSCLC). In 2020, there will be an
estimated 228,820 new cases and 135,720 deaths attributed to lung and bronchus
cancer in the United States. Thus, despite the approval of checkpoint
inhibitors (CPIs), which revolutionized NSCLC treatment and outcomes, there
remains a significant unmet medical need in NSCLC for patients who progress on
CPIs.
Once a patient has disease progression on CPI + chemotherapy, treatment options
are limited and suffer from low efficacy (ORR ~ 10% and short duration of
response [DOR] and high toxicity). The most commonly used agent is docetaxol,
although other single-agent cytotoxic drugs or cytotoxic drugs combined with
vascular endothelial growth factor (VEGF) inhibitors are sometimes employed,
but all have similarly poor outcomes. Thus, there is an urgent need for better
therapeutic options for patients with NSCLC in second-line treatment following
CPI + chemotherapy.
From a safety perspective, TIL therapy was found to have a manageable toxicity
profile comprised of expected adverse events (AEs), which included cytopenia,
hypophosphatemia, hypoalbuminemia, and nausea. The AEs occurred early, within
the first 14 days of the lymphodepleting regimen, and had largely resolved
within 2 weeks of onset. No unexpected serious adverse reactions were reported.
TIL clonotypes persisted through Day 100 and correlated with clinical benefit,
and CCR7+ CD95+ CD45RA+ memory cells were increased at post infusion time
points. The frequency of T cells with specificity for tumor antigens was
assessed to be 10% to 15%. Of the 2 patients with CRs, it was found that both
had T cells that recognized multiple antigens.
Preliminary data demonstrates that TIL therapy elicits clinically meaningful
responses in NSCLC patients who had disease progression on prior lines of
therapy, including CPIs. That TIL treatment generated objective tumor response,
including CR and/or decrease in tumor size after failure to respond to a CPI,
which suggests that TIL therapy in metastatic NSCLC following CPI could be an
important addition to the treatment options. Due to the high unmet medical need
and clinical evidence of benefit of TIL in the study by Creelan et al. (2020),
continued evaluation of TIL in NSCLC is warranted.
Study objective
This study has been transitioned to CTIS with ID 2024-510778-26-00 check the CTIS register for the current data.
Primary Objective:
To evaluate the efficacy of LN-145 measured by objective response rate (ORR)
usingResponse Evaluation Criteria in Solid Tumors (RECIST) v1.1 assessed by
theIndependent Review Committee (IRC) for Cohorts 1 and 2 and by the
Investigator for Cohorts 3 and 4 and the Retreatment Cohort
Secondary Objectives:
• To evaluate the efficacy of LN-145 measured by ORR using RECIST v1.1assessed
by the Investigator for Cohorts 1 and 2
• To further evaluate the efficacy of LN-145 measured by complete response(CR)
rate, duration of response (DOR), disease control rate (DCR),
andprogression-free survival (PFS) using RECIST v1.1 assessed by the
IRC(Cohorts 1 and 2) and the Investigator (all cohorts); and overall
survival(OS)
• To characterize the safety profile of LN-145 in patients with non-small-cell
lung cancer (NSCLC) measured by the incidence of Grade >=3 treatment emergent
adverse events (TEAEs)
• Cohort 3 only: To determine the feasibility of LN-145 production using tumor
tissue obtained via image-guided core biopsy of tumor
Study design
A prospective, open-label, multi-cohort, non-randomized, multicenter phase 2
study evaluating adoptive cell therapy (ACT) with LN-145.
All patients will receive autologous TIL regimen, consisting of the following
steps, regardless of tumor harvest timing (pre-progression or post-progression):
1. Tumor harvest by surgical resection or image-guided core biopsy to obtain
the autologous tissue that is the source of the TIL cellular product.
2. TIL production at a Good Manufacturing Practice (GMP) facility
3. Optional continuation of previously ongoing clinical management (no new
therapy) in the interval from tumor harvest to the start of nonmyeloablative
lymphodepletion (NMA-LD).
4. Baseline assessments including imaging within 28 days prior to NMA-LD to
confirm the patient's health status is acceptable to receive autologous TIL
therapy.
5. A 5-day NMA-LD preconditioning regimen
4. TIL infusion (Day 0)
5. Iinterleukin-2 (IL-2) administration (up to 6 doses)
The following general sequential periods will occur in all cohorts, unless
otherwise specified:
1. Screening Period: Up to 28 days after the patient signs the informed consent
form (ICF) and prior to tumor harvest (i.e., enrollment)
2. Pre-treatment Period: From enrollment (i.e., tumor harvest) to initiation of
preconditioning NMA-LD regimen.
3. Treatment Period: From initiation of preconditioning NMA-LD (Day -5) to
End-of-Treatment (EOT) Visit.
• NMA-LD: Days -5 to -1
• TIL infusion: Day 0
• IL-2: Days 0 to 3 (may be Days 1 to 4)
• EOT visit: Day 30 ±3 days
4. Post-treatment Period
• Assessment Period: From completion of the EOT visit (Day 30 ±3 days) to the
End of Assessment (EOA) visit
• EOA visit: Occurs after complete or partial withdrawal of consent, at disease
progression, prior to initiation of a new anticancer therapy (if possible),
after failure to receive TIL infusion for any reason, or at 5 years (Month
60/Day 1680) from Day 0, whichever occurs first.
• Long-term Follow-up (LTFU) Period: From EOA visit to End-of-Study (EOS)
• EOS: Occurs due to death, patient lost to follow-up, withdrawal of consent,
study termination by Sponsor, or 4 years (Month 60/Day 1680) after Day 0,
whichever occurs first.
Intervention
Patients will undergo a 5-day preconditioning NMA-LD regimen that will be
initiated prior to the planned LN-145 infusion on Day 0 (i.e., Days -5 through
1. The NMA-LD regimen consists of 2 days of intravenous (IV) cyclophosphamide
(60 mg/kg) with mesna (per site standard of care or USPI/SmPC) on Days -5 and
4, and 5 days of fludarabine IV (25 mg/m2, Days -5 through 1).
IL-2 IV administrations at a dose of 600,000 IU/kg may begin as soon as 3 hours
after, but no later than 24 hours after, completion of the LN-145 infusion on
Day 0. Additional IL-2 doses will be given approximately every 8 to 12 hours
for up to 6 total doses.
Study burden and risks
Burden:
- Up to 28 visits to the investigator + a hospitalization of 12 days
- Physical examination (at most visits)
- Blood draws (at every visit)
- Collection of urine samples (2x or at the indication of the investigator)
- ECHO or MUGA scan (1x)
- Cardiac stress test & Lung function tests (1x)
- Skin test (1x)
- CT / MRI scans (19x)
- Assessment of daily activities (during screening, baseline and daily during
the treatment period)
- Questionnaires, including questions about quality of life (15x)
- Surgery and collection of tumor sample (1x and 2 possible optional biopsies).
- Long-term follow up with contact every 3 months by phone or other means (e.g.
e-mail) for up to 5 years to confirm the status of the disease and whether
another anti-cancer treatment is started.
Risks of LN-145:
LN-145 is a new investigational product that we know has potentially serious or
life-threatening side effects. Subjects are asked to inform their research
doctor and / or study staff immediately if they experience problems with:
- Fever, chills, cough
- Rash
- Increased heart rate
- Low blood pressure which can make you feel dizzy or faint
- Chest tightness and / or wheezing, shortness of breath
- Swelling of the face or throat swelling
The risks associated with TIL therapy include a delay in treatment due to the
need to harvest and grow the cells (this manufacturing process takes
approximately 16 to 22 days); an interventional harvesting procedure to obtain
tumor tissue for the cell product; the possibility that a cell product cannot
be generated; and the toxicities known to be associated with the NMA-LD
preparatory regimen and IL-2 administration.
Risks associated with the approved agents IL-2, cyclophosphamide, fludarabine
and mesna are detailed in the subject information, section 6 and the provided
SPC's.
825 Industrial Road Suite 400
San Carlos, California 94070
US
825 Industrial Road Suite 400
San Carlos, California 94070
US
Listed location countries
Age
Inclusion criteria
1. Provide written informed consent and written authorization for use and
disclosure of protected health information.
2. Be 18 to 70 years of age at the time of signing of informed consent form.
Patients who are >70 years of age may be allowed to enroll after consultation
with the Medical Monitor.
3. Have histologically or pathologically confirmed diagnosis of metastatic
Stage IV NSCLC (squamous, nonsquamous, adenocarcinoma, large cell, or mixed
histologies) without EGFR, ALK, or ROS genomic alterations.
4. Meet prior therapy criteria:
-post-progression tumor harvest: Patient must have documented radiographic
disease progression on or after the first-line therapy, inclusive of prior ICI
and platinum-based chemotherapy ± bevacizumab or targeted therapy.
-pre-progression tumor harvest and TIL production: Patient must have residual
resectable disease after completion of the platinum-based chemotherapy
component of either concurrent or sequential ICI and platinum-based
chemotherapy, meet all eligibility criteria except documented disease
progression, and intend to receive TIL therapy after disease progression on
current therapy.
5. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0
or 1 and an estimated life expectancy of >6 months, in the Investigator*s
opinion.
6. Cohorts 1, 2 and 4: Have at least 1 resectable lesion (or aggregate lesions)
with an expected minimum 1.5 cm diameter for TIL production. Cohort 3: Have a
single, measurable lesion (RECIST v1.1) and/or are unable to undergo a surgical
tumor resection, but able to undergo tumor harvest for TIL generation via
image-guided core biopsy. Retreatment Cohort: Meet any tumor requirement listed
above. All Cohorts: If the lesion considered for harvest is within a previously
irradiated field, the lesion must have demonstrated radiographic progression
prior to harvest, and the irradiation must have been completed at least 3
months prior to enrollment. Patients must have an adequate histopathology
specimen for protocol-required testing
7. Have at least 1 remaining measurable lesion as defined by RECIST v1.1
following tumor harvest for TIL manufacturing that is documented at Screening
for post disease progression tumor harvest and at Baseline forpre- and
post-progression tumor harvest
8.Required hematologic parameters:
•Absolute neutrophil count >=1000/mm3.
•Hemoglobin >=8.0 g/dL.
•Platelet count >=100,000/mm3
9. Have adequate organ function with the following laboratory test values:
•ALT and AST <=3times the upper limit of normal (<=3 × ULN); for patients with
liver metastases <=5 × ULN.
•Total bilirubin <=2 mg/dL; patients with Gilbert*s Syndrome <=3mg/dL.
•Estimated creatinine clearance >=40 mL/min using the Cockcroft-Gault formula at
Screening
10. Have a left ventricular ejection fraction (LVEF) >45% and be New York Heart
Association (NYHA) Class 1. A cardiac stress test is required for patients over
>=60 years of age or who have a history of ischemic heart disease, cardiac chest
pain, or clinically significant atrial and/or ventricular arrhythmias; the
cardiac stress test must demonstrate no irreversible wall movement abnormality.
Patients with an abnormal cardiac stress test may be enrolled if they have
adequate ejection fraction and cardiology clearance after discussion with the
Medical Monitor.
11. Have adequate pulmonary function.
If a patient is unable to perform reliable spirometry due to abnormal upper
airway anatomy, a 6-minute walk test may be used to assess pulmonary function.
Patients must be able to walk a distance at least 80% of predicted for age and
sex with no evidence of hypoxia at any point during the test (i.e., saturation
of peripheral oxygen [SpO2] must remain >=90%).
12. Have completed/discontinued chemotherapy >=21 days prior to tumor harvest.
13. Must have recovered from all prior anticancer treatment-related adverse
events to Grade<=1 (per CTCAE v5.0). Patients with irreversible toxicity (eg,
alopecia, vitiligo) after prior anticancer therapies that are not considered by
the Investigator to be a likely safety risk may qualify for the study after
discussion with the Medical Monitor.
14. Patients of childbearing potential or those with partners of childbearing
potential must be willing to practice an approved method of highly effective
birth control during treatment and for 12 months after receiving all
protocol-related therapy. Approved methods of birth control:
•Combined (estrogen- and progesterone-containing) hormonal birth control
associated with inhibition of ovulation: oral, intravaginal, transdermal
•Progesterone-only hormonal birth control associated with inhibition of
ovulation: oral, injectable, implantable
•Intrauterine device
•Intrauterine hormone-releasing system
•Bilateral tubal occlusion
•Vasectomy
•Absolute sexual abstinence if in line with the preferred/usual lifestyle of
the patient. Periodic abstinence (eg, calendar ovulation) is unacceptable.
Exclusion criteria
1. Have a history of allogeneic organ transplant or any form of cell therapy
involving a prior nonmyeloablative or myeloablative chemotherapy regimen within
the past 20 years. Patients being retreated with LN-145 are not excluded due to
prior NMA-LD during this study.
2. Have known actionable EGFR, ALK, or ROS driver mutations.
3. Have symptomatic untreated brain metastasis. Patients with brain metastases
may be enrolled with the following considerations and only after discussion
with the Medical Monitor:
a.Patients with asymptomatic brain metastases who do not clinically require
treatment may be enrolled.
b.Patients with historically treated brain metastases (i.e., treatment of brain
metastases was completed >28 days prior to date of informed consent) will be
considered for enrollment if the patient is clinically stable for >=2 weeks,
there are no new or worsening brain lesions via screening magnetic resonance
imaging (MRI), and the patient does not require ongoing corticosteroid
treatment (>10 mg/day prednisone or equivalent).
c.Patients with recently treated brain metastases (i.e., treatment of brain
metastases was completed <=28 days prior to date of informed consent) may be
considered for enrollment if the patient is asymptomatic, clinically stable for
>=2 weeks, and does not require corticosteroids (>10 mg/day prednisone or
equivalent)
d.Patients with progressive or new brain metastases on screening magnetic
resonance imaging (MRI) should suspend screening procedures and receive
appropriate treatment of brain metastases. Screening can resume after
completion of brain metastases treatment, when the patient is asymptomatic,
clinically stable for >=2 weeks, and does not require corticosteroids (>10
mg/day prednisone or equivalent) at the start of NMA-LD (Day -5). Note:
Patients who develop symptomatic brain metastases at any time after signing the
ICF until starting NMA-LD should receive appropriate treatment of brain
metastases prior to NMA-LD. Such patients must be asymptomatic, clinically
stable for >=2 weeks, and not require corticosteroids (>10 mg/day prednisone or
equivalent) at the start of NMA-LD (Day -5)
4. Require systemic steroid therapy >10 mg/day prednisone or equivalent.
Patients receiving steroids as replacement therapy for adrenocortical
insufficiency at <=10 mg/day prednisone or equivalent are not excluded.
5. Have evidence of any active viral, bacterial, or fungal infection requiring
ongoing systemic treatment or as per required screening tests.
6. Are pregnant or breastfeeding. Female patients of childbearing potential
must have a negative beta-human chorionic gonadotropin (β-HCG) test with
minimum sensitivity of 25 IU/L β-HCG (or equivalent) at Screening.
7. Have an active medical illness(es) that in the opinion of the Investigator
would pose increased risks for study participation, such as systemic
infections, coagulation disorders, or other active major medical illnesses of
the cardiovascular, respiratory, or immune systems.
8. Have received a live or attenuated vaccination within 28 days prior to the
start of NMA-LD.
9. Have any form of primary immunodeficiency (eg, severe combined
immunodeficiency disease [SCID] or acquired immune deficiency syndrome [AIDS]).
10. Have a history of hypersensitivity to any component of the study drugs.
LN-145 should not be administered to patients with a known hypersensitivity to
any component of the autologous TIL product formulation, including, but not
limited to, any of the following:
•NMA-LD (cyclophosphamide, mesna, and fludarabine)
•Proleukin®, aldesleukin, IL-2
•Antibiotics of the aminoglycoside group (i.e., streptomycin, gentamicin).
These patients may be eligible if current hypersensitivity has been excluded.
•Any component of the TIL product formulation, including dimethyl sulfoxide
(DMSO), human serum albumin (HSA), IL-2, or dextran-40
11. Have had another primary malignancy within the previous 3 years (except for
malignancies that do not require treatment or have been curatively treated >1
year ago, and in the judgment of the Investigator do not pose a significant
risk of recurrence including, but not limited to: in situ carcinoma of the
cervix; early stage skin cancer, including non-melanoma skin cancer; ductal
carcinoma in situ (DCIS) or lobular carcinoma in situ (LCIS) of the breast;
prostate cancer with Gleason score <=6; or superficial bladder cancer).
12. Participated in another clinical study with an investigational product
within 21 days prior to enrollment with the exception of investigational
programmed cell death-1 (PD-1)/PD-L1 inhibitors or tyrosine kinase inhibitors
(TKIs), which may be continued until 7 days prior to initiation of NMA-LD
13. Have any condition or characteristic (e.g., known psychiatric
diagnosis/symptoms, alcohol abuse, or substance abuse) that, in the opinion of
the Investigator, could interfere with the evaluation or interpretation of
study treatment, patient safety, or study results
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EU-CTR | CTIS2024-510778-26-00 |
| EudraCT | EUCTR2020-003629-45-NL |
| ClinicalTrials.gov | NCT04614103 |
| CCMO | NL76099.000.20 |