| 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 | 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 |
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, in Germany and Switzerland only, 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]) 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 (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 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) ≥ 40mL/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 positive serology for hepatitis B virus surface antigen (HBsAg), hepatitis B core antibody (anti-HBc), or hepatitis C virus antibody (HCV Ab) indicating acute or chronic infection hepatitis infections may be enrolled if the viral load by polymerase chain reaction (PCRnucleic acid
amplification test (NAAT) 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, highly effective method of birth control during treatment and for 12 months after receiving the last protocol-related therapy.
Please refer to the protocol for the exhaustive list of criteria |
|
| 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 require systemic steroid therapy (> 10 mg/day of prednisone or other steroid equivalent dose). Patients receiving steroids as replacement therapy for any reason 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 NCI-Common Terminology Criteria for Adverse Events v5.0 (eg. uveitis); except for peripheral neuropathy, alopecia or vitiligo prior to enrollment. 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 (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 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. 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 (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 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).
Please refer to the protocol for the exhaustive list of criteria |
|
| 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 |
| Every 6 weeks for 6 months, then every 3 months for a maximum of 54 months |
|
| 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 |
Every 6 weeks for 6 months, then every 3 months for a maximum of 54 months;
OS: Time Frame: Unitl 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 | 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 | 14 |
| 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 |
| Switzerland |
| United Kingdom |
| United States |
| France |
| Germany |
| Italy |
| Netherlands |
| Spain |
|
| 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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