A Phase 2, Multicenter Study to Evaluate the Efficacy and Safety Using Autologous Tumor Infiltrating Lymphocytes (LN-145) in Patients with Recurrent, Metastatic, or Persistent Cervical Carcinoma

To be eligible for the study, patients must meet ALL of the following criteria
prior to participation:
1. 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.
2. 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, including the OS Follow-up Period
3. Must be able and willing to comply to the study visit schedule and protocol
requirements
4. Must have recurrent, metastatic, or persistent squamous cell carcinoma
(SCC), adenosquamous carcinoma (ASC), or adenocarcinoma (AC) of the cervix that
is not amenable to curative treatment with surgery and/or radiation therapy
5. 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)
6. 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
Enrollment, 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
7. Cohort 1 and Cohort 2: Progression during or following at least one, but no
more than three, prior systemic chemotherapeutic treatments for recurrent,
metastatic, or persistent cervical carcinoma
• A line of systemic therapy is defined as any chemotherapy or multiple-agent
chemotherapy regimen that was administered for recurrent, metastatic, or
persistent SCC, ASC, or AC of the cervix.
• A bevacizumab and chemotherapy combination is encouraged as a prior line of
treatment.
• Neither chemoradiation, nor chemotherapy in the neoadjuvant or adjuvant
settings are considered as a prior line of systemic therapy.
Cohort 2: Must also have previously received treatment with a checkpoint
inhibitor (ie, PD-1, PD-L1]) in the setting of recurrent, metastatic, or
persistent disease either as monotherapy or in combination (eg, in combination
with chemotherapy or another immune agent).
Cohort 3: This cohort will enroll patients from the United States only.
8. Any prior therapy directed at the malignant tumor, including chemotherapy,
biologic/targeted agents, and immunologic agents must be discontinued at least
28 days prior to tumor resection. Radiation therapy is permitted as long as
the lesions irradiated are not expected to be used for TIL generation or as
target lesions and any toxicities have resolved to Grade <= 1 at least 2 weeks
prior to NMA-LD.
9. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or
1
10. Must meet the following laboratory criteria:
• Absolute neutrophil count (ANC) >= 1000/mm3
• Hemoglobin (Hb) >= 8 g/dL or >= 4.96 mmol/L
• Platelet count >= 100,000/mm3
• Serum alanine transaminase (ALT)/serum glutamic-pyruvic transaminase (SGPT)
and aspartate transaminase (AST)/serum glutamic-oxaloacetic transaminase (SGOT)
< 3.0 times the upper limit of normal (ULN)
Patients with liver metastasis must have liver function tests (LFTs) < 5.0
times the ULN
• Total bilirubin <= 2.0 mg/dL
Patients with Gilbert*s syndrome must have a total bilirubin <= 3.0 mg/dL
• Serum creatinine must be <= 1.5 mg/dL
• Measured creatinine clearance (CrCl) >= 40 mL/min calculated from a 24-hour
urine collection
11. Patient has no evidence of any active viral, bacterial, or fungal infection
requiring ongoing systemic treatment. Patients must be seronegative for the
human immunodeficiency virus (HIV). Patients with acute or chronic hepatitis
infections may be enrolled if the viral load by nucleic acid amplification test
(NAAT) is undetectable with/without active treatment
12. Patients of childbearing potential must be willing to take the appropriate
precaution to avoid pregnancy 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:
• 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 (IUD)
• Intrauterine hormone-releasing system (IUS)
• Bilateral tubal occlusion
• Vasectomized partner
• 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
13. Prior to study Enrollment (tumor resection), patient must have
documentation of radiological disease progression after the most recent therapy
14. Patients have provided written authorization for use and disclosure of
protected health information

Patients who meet any of the following criteria are not eligible for
participation in this study:
1. Patients who have received an organ allograft or prior cell transfer therapy
except for prior LN-145 therapy in the setting of re-treatment only
2. Patients who require systemic steroid therapy (> 10 mg/day of prednisone or
other steroid equivalent dose).
Patients receiving steroids as replacement therapy for adrenocortical
insufficiency at <= 10 mg/day of prednisone or other steroid equivalent may be
eligible.
3. Patients who currently have prior therapy-related toxicities Grade > 1
according to National Cancer Institute (NCI) Common Terminology Criteria for
Adverse Events (CTCAE) v5.0 (eg, uveitis); except for peripheral neuropathy,
alopecia, or vitiligo prior to Enrollment (tumor resection)
• Patients with a history of uveitis must have an eye examination performed by
a trained eye specialist at Screening to rule out active uveitis that requires
treatment. Patients who have active uveitis that requires active treatment will
be excluded.
• If toxicities have resolved to Grade <= 1, a minimum of 2 weeks must elapse
prior to Enrollment (tumor resection)
• Patients may not have any pre-planned procedures within 2 weeks prior to the
start of NMA-LD preparative regimen
Cohort 2: Patients with documented Grade >= 2 diarrhea or colitis as a result of
previous treatment with a PD-1/PD-L1 checkpoint inhibitor(s) must have been
asymptomatic for at least 6 months or had a normal colonoscopy post-checkpoint
inhibitor treatment, by visual assessment, prior to tumor resection.
Cohort 2: Patients with immunotherapy-related endocrinopathies stable for at
least 6 weeks (eg, hypothyroidism, stable on hormonal substitution) and
controlled with hormonal replacement, are allowed.
4. No longer applicable
5. Patients who have a history of hypersensitivity to any component or
excipient of LN-145 or other study drugs:
• NMA-LD preparative 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-145 infusion product formulation including dimethyl
sulfoxide (DMSO), human serum albumin (HSA), IL-2, and dextran-40
6. Patients who have active systemic infections, coagulation disorders, or
other active major medical illness(es) of the cardiovascular, respiratory, or
immune system, including evidence in the medical history of urinary tract
obstruction, a positive cardiac stress test, myocardial infarction, cardiac
arrhythmia, obstructive or restrictive pulmonary disease, or other conditions
that in the opinion of the Investigator would increase the risk of
participation
• Patients with corrected (ie, percutaneous nephrostomy tubes) urinary tract
obstruction must have negative surveillance cultures from externalized tubes
within 7 days prior to the start of NMA-LD preparative regimen. Asymptomatic
patients with chronic colonization of indwelling urinary diversion tubes may be
eligible after active urinary infection is ruled out and discussion with the
Medical Monitor.
• Patients with evidence of any uncontrolled or active systemic infection
requiring ongoing treatment cannot proceed to NMA-LD. Prophylactic
anti-infection therapy is acceptable.
7. 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
preparative regimen
8. Patients who have any form of primary immunodeficiency (such as severe
combined immunodeficiency [SCID] or acquired immunodeficiency syndrome [AIDS])
9. Patients who have a diagnosis of end-stage renal disorder requiring
hemodialysis
10. Patients who have a left ventricular ejection fraction (LVEF) < 45% or who
are New York Heart Association (NYHA) Class 2 or higher. Patients >= 60 years of
age or who have a history of ischemic heart disease, chest pain, or clinically
significant atrial and/or ventricular arrhythmias must have a cardiac stress
test (or equivalent local standard stress test):
• Patients with an abnormal cardiac stress test may be Enrolled if they have
adequate ejection fraction (>= 45%) and cardiology clearance after consultation
with the Medical Monitor
• Patients with any irreversible wall movement abnormalities are excluded
11. Patients who have a documented forced expiratory volume in 1 second (FEV1)
of <= 60%
12. Patients who have had another primary malignancy within the previous 3
years (except for curatively treated localized malignancy that has not required
treatment for > 1 year, and in the judgement of the Investigator, does not pose
a significant risk of recurrence including, but not limited to, non-melanoma
skin cancer or bladder cancer)
13. Patients who are of the following protected classes will be excluded,
including:
• Pregnant, parturient, or breastfeeding women
• Persons who are hospitalized without consent or those deprived of liberty
because of a judiciary or administrative decision
• Patients with a legal protection measure or a person who cannot express
his/her consent
• Patients in emergency situations who cannot consent to the study
14. Patients who have received a live or attenuated vaccine within 28 days
prior to beginning the NMA-LD preparative regimen
15. Patients whose cancer requires immediate attention or who would otherwise
suffer a disadvantage by participating in this study
16. Cohort 1 and Cohort 3: Patients who have received prior treatment with
immunotherapy (eg, PD-1, PD-L1, or anti-cytotoxic T lymphocyte-associated
antigen-4 [CTLA-4] antibodies)
17. Patients who have Grade >= 2 hemorrhage within 14 days prior to Enrollment
(tumor resection)
18. Cohort 3: Patients may not have active or prior documented autoimmune or
inflammatory disorders (including pneumonitis, inflammatory bowel disease [eg,
colitis or Crohn*s disease], diverticulitis [with the exception of
diverticulosis], systemic lupus erythematosus, sarcoidosis syndrome, or Wegener
syndrome [granulomatosis with polyangiitis, Graves* disease, rheumatoid
arthritis, hypophysitis, uveitis, etc.]). The following are exceptions to this
criterion:
• Patients with vitiligo or alopecia
• Patients with hypothyroidism (eg, following Hashimoto syndrome) stable on
hormone replacement
• Patients with any chronic skin condition that does not require systemic
therapy
• Patients with celiac disease controlled by diet alone