A study to find out if an investigational product, called LN-145 (also called tumor infiltrating lymphocytes) is an effective and safe treatment in patients with recurrent, metastatic or persistent cervical carcinoma

• Register: EUCTR
• Last refreshed on: 4 May 2020
• Main ID: EUCTR2016-003447-11-GB
• Date of registration: 04/08/2017
• Prospective Registration: Yes
• Primary sponsor: Iovance Biotherapeutics, Inc.
• Public title: A study to find out if an investigational product, called LN-145 (also called tumor infiltrating lymphocytes) is an effective and safe treatment in patients with recurrent, metastatic or persistent cervical carcinoma
• Scientific title: 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 - Study of LN-145 in the treatment of Patients with cervical cancer
• Date of first enrolment: 27/10/2017
• Target sample size: 138
• Recruitment status: Authorised-recruitment may be ongoing or finished
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2016-003447-11
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: no Randomised: no Open: yes Single blind: no Double blind: no Parallel group: no Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: no Other: no Number of treatment arms in the trial: 1
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): yes Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): no

Countries of recruitment

France, Germany, Italy, Netherlands, Spain, Switzerland, United Kingdom

Contacts

• Name: Susie Tanamly
• Affiliation: Iovance Biotherapeutics, Inc.

• Name: Susie Tanamly
• Affiliation: Iovance Biotherapeutics, Inc.

Key inclusion & exclusion criteria

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
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 disese 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 multipleagent 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 locoregional 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 must 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) = 9.0 g/dL; Platelet count = 100,000/mm3
Note: Transfusions or growth factors are not allowed 28 days prior to signing the ICF and continuing through the Screening Period
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 may have Liver Function Tests (LFTs) < 5.0 times the ULN)
Total bilirubin = 2.0 mg/dL
Patients with Gilbert’s syndr
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 v4.03; 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 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 preconditioning 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 the beginning the NMA-LD preparative regimen.
8. Patients who have any form of primary or acquired immunodeficiency syndrome (such as severe combined immunodeficiency disease 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 history of ischemic heart disease, chest pain, or clinically significant atrial 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 irreversi

Age minimum:
Age maximum:
Gender:
Female: yes
Male: no

Health Condition(s) or Problem(s) studied

Recurrent, metastatic, or persistent Cervical Carcinoma
MedDRA version: 21.1 Level: LLT Classification code 10008229 Term: Cervical cancer System Organ Class: 100000004864

Therapeutic area: Diseases [C] - Cancer [C04]

Intervention(s)

Product Name: Fludarabine
Pharmaceutical Form: Concentrate for solution for injection/infusion
INN or Proposed INN: FLUDARABINE PHOSPHATE
CAS Number: 75607-67-9
Current Sponsor code: FLUDARABINE PHOSPHATE
Other descriptive name: FLUDARABINE PHOSPHATE
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 25-

Trade Name: Cyclophosphamide
Product Name: Cyclophosphamide Injection
Pharmaceutical Form: Powder for solution for injection
INN or Proposed INN: CYCLOPHOSPHAMIDE
CAS Number: 6055-19-2
Current Sponsor code: CYCLOPHOSPHAMIDE
Other descriptive name: CYCLOPHOSPHAMIDE MONOHYDRATE
Concentration unit: g gram(s)
Concentration type: equal
Concentration number: 1-

Trade Name: Proleukin
Product Name: Aldesleukin
Pharmaceutical Form: Powder for solution for injection/infusion
INN or Proposed INN: Proleukin
CAS Number: 110942-02-4
Other descriptive name: ALDESLEUKIN
Concentration unit: IU international unit(s)
Concentration type: equal
Concentration number: 22000000-

Product Name: Cryopreserved LN-145
Product Code: LN-145
Pharmaceutical Form: Solution for infusion
INN or Proposed INN: LN-145
CAS Number: Not avail.
Current Sponsor code: LN-145
Other descriptive name: LN-145
Concentration unit: Other
Concentration type: range
Concentration number: 1000000000-150000000000

Product Name: Fludarabine
Pharmaceutical Form: Lyophilisate for solution for injection
INN or Proposed INN: FLUDARABINE PHOSPHATE
CAS Number: 75607-67-9
Current Sponsor code: FLUDARABINE PHOSPHATE
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 50-

Primary Outcome(s)

Main Objective: Cohort 1 – To evaluate the efficacy of LN-145 in patients with 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 2 – To evaluate the efficacy of LN-145 in patients with cervical carcinoma who have previously received a PD-1/PD-L1 checkpoint inhibitor by assessing the objective response rate (ORR) as assessed by the Investigator 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 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

Timepoint(s) of evaluation of this end point: Every 6 weeks for 6 months, then every 3 months for a maximum of 54
months

Primary end point(s): • Cohort 1: ORR as assessed by the IRC per RECIST v1.1
• Cohort 2: ORR as assessed by the Investigator 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.

Secondary Objective: Cohort 1: To evaluate the efficacy parameters of LN-145 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 2: To evaluate the efficacy of LN-145 in patients with cervical carcinoma who have previously received a PD-1/PD-L1 checkpoint inhibitor by assessing duration of response, disease control rate, and progression-free survival as assessed by the Investigator per RECIST v1.1; to evaluate overall survival (OS) in patients; to characterize the safety profile of LN-145 in patients after the use of a PD-1/PD-L1 checkpoint inhibitor
Cohort 3: To evaluate the efficacy of LN-145 in combination with pembrolizumab in patients by assessing ORR, DOR, DCR, and PFS per RECIST 1.1, as assessed by the Investigator; to evaluate OS in patients

Secondary Outcome(s)

Secondary end point(s): Cohort 1
• 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 2
• 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 TEAEs, including SAEs, therapy-related 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.

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

Secondary ID(s)

NCT03108495

C-145-04

Source(s) of Monetary Support

Iovance Biotherapeutics Inc.

Ethics review

Status: Approved
Approval date: 27/10/2017
Contact: