| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Recurrent, metastatic, or persistent Cervical Carcinoma |
|
| E.1.1.1 | Medical condition in easily understood language |
| Cervical cancer that has come back, spread to other places in the body, or has not improved |
|
| 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 | LLT |
| E.1.2 | Classification code | 10008229 |
| E.1.2 | Term | Cervical cancer |
| E.1.2 | System Organ Class | 100000004864 |
|
| 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 |
Cohort 1 and 2 – To evaluate the efficacy of LN-145 in patients with
recurrent, metastatic, or persistent cervical carcinoma based on the
objective response rate as assessed by the Independent Review
Committee per Response Evaluation Criteria in Solid Tumors v1.1
Cohort 3 (US only) – To characterize the safety profile of LN-145 in
combination with pembrolizumab in patients with recurrent, metastatic,
or persistent cervical carcinoma
Cohort 4 – To explore the efficacy and safety profile for previously
enrolled patients with recurrent, metastatic, or persistent cervical
carcinoma treated with LN-145
Cohort 5 – To explore the efficacy and safety profile for re-treated
patients with recurrent,
metastatic, or persistent cervical carcinoma treated with LN-145 in
Cohorts 1 and 2 |
|
| E.2.2 | Secondary objectives of the trial |
Cohort 1 and 2: To evaluate the efficacy parameters of LN-145 in
patients with recurrent,
metastatic, or persistent cervical carcinoma by assessing duration of
response, disease control rate and progression-free survival as assessed
by the IRC per RECIST v1.1; to evaluate ORR, DOR, DCR, and PFS as
assessed by the Investigator per RECIST v1.1; to evaluate overall
survival (OS) in patients; to characterize the safety profile of LN-145
Cohort 3: To evaluate the efficacy of LN-145 in combination with
pembrolizumab in patients with recurrent,
metastatic, or persistent cervical carcinoma by assessing ORR, DOR,
DCR, and PFS per RECIST 1.1, as assessed by the Investigator; to
evaluate OS in patients |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
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 (or legally authorized representative) must have the ability to understand the requirements of the study, have provided written informed consent as evidenced by signature on an ICF approved by an Institutional Review Board/Independent Ethics Committee, 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 SCC, ASC, or AC of the cervix that is not amenable to curative treatment with surgery and/or radiation therapy and for which no other therapies are expected to have significant benefit, in the opinion of the Investigator.
5. At least one resectable lesion (or aggregate of leasions 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 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, or 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]). Cohort 3 (United States only): Must have not received any therapies other than prior chemoradiation or surgery for loco-regional disease
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 may have been received up to 28 days prior to tumor resection for lesions not expected to be used for TIL generation or target lesions. Radiation therapy may have been received up to 28 days prior to tumor resection for lesions not expected to be used for TIL generation or target lesions.
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 ≥ 5.6 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) ≥ 40mL/min
11. Patients must be seronegative for the HIV. Patients with positive serology for HBsAg, anti-HBc or HCV Ab indicating acute or chronic infection may be enrolled if the viral load by PCR is undetectable with/without active treatment.
12. Patients of childbearing potential must be willing to take appropriate precaution to avoid pregnancy for the duration of the study and practice an approved method of birth control during treatment and for 12 months after receiving the last protocol-related therapy.Approved methods are outlined in the protocol.
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 |
|
| E.4 | Principal exclusion criteria |
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 are on chronic systemic steroid therapy for any reason.
3. Patients who currently have prior therapy-related toxicities Grade > 1 according to NCI-Common Terminology Criteria for Adverse Events v5.0; except for peripheral neuropathy, alopecia or vitiligo prior to enrollment. If toxicities have resolved to Grade ≤ 1, a minimum of 4 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 (i.e. streptomycin, gentamicin); except those who are skin-test negative for gentamycin hypersensitivity; any component of the LN-145 infusion product formulation including DMSO, 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 14 days prior to the start of NMA-LD preparative regimen.
Patients with an intercurrent infection following tumor resection must be infection-free and off ABX for at least 14 days prior to the initiation of NMA-LD preparative regimen.
7. Patients with symptomatic and/or untreated brain metastases. 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 or acquired immunodeficiency syndrome).
9. Patients who have a diagnosis of end-stage renal disorder requiring hemodialysis.
10. Patients who have a left ventricular ejection fraction < 45% or who are New York Heart Association Class 2 or higher. Patients ≥ 60 years of age or in patients 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 an abnormal cardiac stress test may be enrolled if they have adequate ejection fraction and cardiology clearance with approval of 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) ≤ 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 judgment 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
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 e.g. PD-1, PD-L1, or anti-cytotoxic T lymphocytes-associated antigen-4 [CTLA-4] antibodies).
17. Patients who have Grade ≥ 2 hemorrhage within 14 days prior to Enrollment
18. Cohort 3: Patients may not have active or prior documented autoimmune or inflammatory disorders, including some exceptions to this criterion |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
• Cohort 1 and 2: ORR as assessed by the IRC per RECIST v1.1;
• Cohort 3: Incidence of Grade ≥ 3 treatment-emergent adverse events
(TEAEs);
• Cohorts 4 and 5: Because of the small sample size, results will be
reported as appropriate by descriptive statistics. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Patients will be evaluated at week 6 after LN-145 infusion, then every 6 weeks till Month 6, and then every 3 months for up to 5 years from Day 0 (LN-145 infusion). |
|
| E.5.2 | Secondary end point(s) |
Cohort 1 and 2:
• DOR, DCR, and PFS as assessed by the IRC per RECIST v1.1
• ORR, DOR, DCR, and PFS as assessed by the Investigator per RECIST
v1.1
• OS
• Incidence of severity, seriousness, relationship to study treatment,
and characteristics of treatment-emergent adverse events (TEAEs),
including serious AEs (SAEs), therapyrelated AEs, and AEs leading to
early discontinuation from treatment or withdrawal from the Assessment
Period or death
Cohort 3
• ORR, DOR, DCR, and PFS as assessed by the Investigator per RECIST
v1.1
• OS
Cohorts 4 and 5
• Because of the small sample size, results will be reported as
appropriate by descriptive statistics. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Patients will be evaluated at week 6 after LN-145 infusion, then every 6 weeks till Month 6, and then every 3 months for up to 5 years from Day 0 (LN-145 infusion);
OS: Time Frame: Unitl death or up to 5 years from study enrollment;
Adverse Events: Time Frame: Up to 5 years from study enrollment |
|
| 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 | No |
| 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.8.2.4 | Number of treatment arms in the trial | 1 |
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 20 |
| 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 |
| Italy |
| Netherlands |
| Spain |
| Switzerland |
| 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
|
| 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 |
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