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EUCTR2016-003447-11 | SNCTP000002862

Étude multicentrique de phase 2 visant à évaluer l’efficacité et la sécurité d’emploi de lymphocytes autologues infiltrant la tumeur (LN-145) chez des patientes atteintes d’un carcinome cervical récurrent, métastatique ou persistant

Data source: BASEC (Imported from 10.12.2019), WHO (Imported from 01.12.2019)
Changed: 03.12.2019
Disease category: Gebärmutterkrebs

Brief description of trial (Source of data: BASEC)

Cette étude est menée dans le but de déterminer si le LN-145, lorsqu’il est administré en monothérapie, est sûr et bénéfique dans le traitement de patientes atteintes d’un carcinome cervical.

Le LN-145 est un médicament expérimental. Le terme «expérimental» signifie que le médicament n’a pas été approuvé par l’agence américaine des produits alimentaires et médicamenteux (Food and Drug Administration, FDA) ou toute autre autorité sanitaire comme Swissmedic. Le LN-145, également appelé «lymphocytes infiltrant les tumeurs» (LIT), est constitué de globules blancs (GB) obtenus à partir de la tumeur de la patiente. Pour produire le LN-145, la propre tumeur du patient est transférée dans un centre de production afin d’isoler et de mettre en culture les cellules T qui peuvent attaquer la tumeur lorsque le LN-145 est réintroduit dans le corps du patient à l’aide d’une perfusion (perfusion de lymphocytes autologues infiltrant la tumeur).

Dans cette étude, environ 138 patientes atteintes d’un carcinome cervical récurrent, métastatique ou persistant seront traitées par le LN-145 dans plusieurs centres situés en Suisse et en-dehors.


Une procédure de sélection nécessitant certains examens médicaux sera effectuée pour vérifier l’éligibilité pour cette étude.

Les patientes qui ont complété le traitement seront évaluées pour l’efficacité et la sécurité du traitement par LN-145 à la semaine 6 après la perfusion de LN-145 et ensuite toutes les 6 semaines jusqu’au mois 6 (Jour 183 ; Visite 21). La réponse des patientes continuera d’être évaluée tous les 3 mois (12 semaines) pendant 5 ans maximum à compter du Jour 0 ou jusqu’à :
• Une progression de la maladie,
• Début d’un nouveau traitement anticancéreux

La période de suivi de la survie globale commencera après la dernière évaluation de l’étude et se poursuivra jusqu’à 5 ans après la résection de la tumeur ou jusqu’à l’arrêt de l'étude, avec un contact par téléphone tous les 3 mois pour obtenir le statut de survie.

Health conditions investigated (Source of data: BASEC)

Patientes atteintes d’un carcinome cervical récurrent, métastatique ou persistant

Health conditions (Source of data: WHO)

Recurrent, metastatic, or persistent Cervical Carcinoma
MedDRA version: 20.0Level: LLTClassification code 10008229Term: Cervical cancerSystem Organ Class: 100000004864;Therapeutic area: Diseases [C] - Cancer [C04]

Rare disease (Source of data: BASEC)

No

Intervention investigated (e.g. drug, therapy or campaign) (Source of data: BASEC)

Il s’agit d’une étude de phase 2, multicentrique, multicohorte, en ouvert, interventionnelle, utilisant la perfusion de LIT autologues (LN-145). Avant traitement par le LN-145, les patients auront leur nombre de lymphocytes/GB existants diminué par traitement de Cyclophosphamide et Fludarabine. Ce procédé est appelé schéma thérapeutique de préparation par la lymphodéplétion non myéloablative (NMA-LD).
L’IL-2 (Interleukine-2) est administrée suite au traitement par le LN-145 dans le but d’aider le LN-145 à mieux agir.

Interventions (Source of data: WHO)


Product Name: Non-cryopreserved LN-145
Product Code: Non-cryopreserved 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: up to
Concentration number: 150000000000-

Trade Name: Fludarabine Phosphate
Product Name: Fludarabine Phosphate
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: Cryopreserved 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: up to
Concentration number: 150000000000-

Criteria for participation in trial (Source of data: BASEC)

Pour être éligible à l’étude, les patientes doivent satisfaire à TOUS les critères suivants avant leur participation :
- Être âgée de plus de 18 ans au moment du consentement.
- Être atteinte d’un carcinome épidermoïde, d’un carcinome adénosquameux ou d’un adénocarcinome du col de l’utérus récurrent, métastatique ou persistant qui n’est pas adapté à un traitement curatif par chirurgie et/ou par radiothérapie et pour lequel aucun autre traitement ne devrait avoir de bénéfice significatif, de l’avis de l’investigateur..
- Au moins une lésion résécable (ou agrégat de lésions réséquées) ayant un diamètre d’au moins 1,5 cm après résection pour la génération de LIT
- doivent présenter une progression pendant ou après au moins un, mais pas plus de trois traitements chimiothérapeutiques systémiques antérieurs pour un cancer du col de l’utérus récurrent, métastatique ou persistant
Il existe des critères supplémentaires qui doivent être remplis pour participer à cette étude clinique. L’investigateur les examinera en détails jusqu’à l’inclusion des patients dans cette étude.

Exclusion criteria (Source of data: BASEC)

Les patientes qui remplissent L’UN OU L’AUTRE des critères suivants ne sont pas éligibles pour participer à l’étude :
- Patientes ayant présenté une autre tumeur maligne primaire dans les 3 années précédentes (sauf pour une tumeur maligne localisée traitée de manière curative n’ayant pas nécessité de traitement pendant > 1 an et qui, de l’avis de l’investigateur, ne présente pas un risque significatif de récidive, notamment, le cancer de la peau non mélanome ou le cancer de la vessie)
- Patientes présentant des métastases cérébrales symptomatiques et/ou non traitées (quelle que soit la taille et quel que soit le nombre). Les patientes présentant des métastases cérébrales définitivement traitées seront prises en compte pour l’inclusion et doivent être stables pendant ≥ 14 jours avant le début du schéma thérapeutique de préparation par NMA-LD.
- Patientes présentant toute forme d’immunodéficience primaire (comme le déficit immunitaire combiné sévère [DICS] ou le syndrome de l’immunodéficience acquise [SIDA]).

Il existe des critères supplémentaires qui peuvent empêcher de participer à cette étude clinique. L’investigateur les examinera en détails jusqu’à l’inclusion des patients dans cette étude.

Inclusion/Exclusion Criteria (Source of data: WHO)

Inclusion criteria:
1. Must be =18 years of age at the time of consent.
2. Must understand and voluntarily sign an informed consent document prior to any study related assessments/procedures being conducted.
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, adenosquamous carcinoma or adenocarcinoma 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. Must have at least 1 lesion that is resectable for TIL generation. The resected TIL generating lesion(s) should be least 1.5 cm in diameter post-resection, and can be surgically removed with minimal morbidity (typically defined as any operation for which expected hospitalization is = 3 days). If the lesion is within a previously irradiated field, the irradiation must have occurred at least 3 months prior to planned tumor resection. An aggregate of = 1.5 cm in diameter from multiple lesions is permitted.
6. Following resection for TIL generation, must have a remaining measurable target lesion as defined by RECIST v1.1. If measurable target lesion(s) are in previously irradiated areas, irradiation must have occurred at least 3 months prior to tumor resection, and the lesions must have demonstrated evidence of progression since radiation.
7. Must have had at least 1 and no more than 3 prior systemic chemotherapeutic treatments (such as carboplatin/cisplatin, paclitaxel, and bevacizumab except where there are contraindications) for cervical carcinoma. Patients must have progressive disease while receiving or after the completion of the most recent prior treatment.
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.
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 > 9.0 g/dL
• Platelet count > 100,000/mm3
• ALT/SGPT and AST/SGOT < 3.0 x the upper limit of normal (ULN)
o Patients with liver metastases may have LFT = 3.0 x ULN)
• Total bilirubin = 2.0 mg/dL
o 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 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 (anti-HCV) indicating acute or chronic infection may be enrolled if the viral load by polymerase chain reaction (PCR) is undetectable with/without active treatment.
12. Patients of childbearing potential must be willing to practice an approved method of birth control starting at the time of informed consent and for 1 year after the completion of all study treatment regimen. Approved methods of birth control are as follows:
• combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (e.g. oral, intravaginal, transdermal)
• progestogen-only hormon
Exclusion criteria:
1. Patients who have received an organ allograft or prior cell transfer therapy except for prior LN-145 therapy.
2. Patients who are on a systemic steroid therapy > 10 mg of prednisone daily or other steroid equivalent.
A short course of higher dose steroid therapy is allowed in cases of exacerbation of known disease or for treatments of new acute symptoms.
3. Patients who currently have prior therapy-related toxicities greater than Grade 1 according to NCI-CTCAE v4.03; except for peripheral neuropathy, alopecia or vitiligo prior to enrollment/resection.
• If toxicities have resolved to Grade 1 or less, a minimum of 4 weeks must elapse prior to enrollment (tumor resection).
• Patients may not have any pre-planned procedures within 2 weeks of the start of NMA-LD.
4. No longer applicable
5. Patients who have a contraindication to or hypersensitivity reaction to any component or excipients of the TIL therapy and the other study drugs:
• NMA-LD (cyclophosphamide, mesna and fludarabine)
• IL-2
• antibiotics of the aminoglycoside group (i.e. streptomycin, gentamicin)
• any component of the the TIl infusion product formulation including dimethyl sulfoxide (DMSO), human serum albumin (HSA), IL-2, and dextran-40
6. Patients with active systemic infections, coagulation disorders or other active major medical illnesses 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 of the start of NMA-LD.
• Patients with an intercurrent infection following tumor resection must be infection-free and off antibiotics for at least 14 days prior to the initiation of NMA-LD.
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 after discussion with the Sponsor’s Medical Monitor/Designee, and must be stable for at least 2–4 weeks, and asymptomatic prior to the start of treatment (NMA-LD).
8. Patients who have any form of primary or acquired immunodeficiency syndrome, such as severe combined immunodeficiency disease or acquired immune deficiency 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. A cardiac stress test demonstrating any irreversible wall movement abnormality in any patients > 60 years of age or in patients who have a history of ischemic heart disease, chest pain, or clinically significant atrial or ventricular arrhythmias.
• 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.
11. Patients who have a FEV1 (forced expiratory volume in 1 second) of less than or equal to 60% of predicted normal.
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 greater than 1 y

Further information on the trial in WHO primary registry

https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2016-003447-11

Further information on the trial from WHO database (ICTRP)

http://apps.who.int/trialsearch/Trial2.aspx?TrialID=EUCTR2016-003447-11-DE

Further information on trial

Date trial registered

14.08.2017

Incorporation of the first participant

29.11.2018

Recruitment status

Authorised-recruitment may be ongoing or finished

Academic title (Source of data: WHO)

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

Type of trial (Source of data: WHO)

Interventional clinical trial of medicinal product

Design of the trial (Source of data: WHO)

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 (Source of data: WHO)

Human pharmacology (Phase I): noTherapeutic exploratory (Phase II): yesTherapeutic confirmatory - (Phase III): noTherapeutic use (Phase IV): no

Primary end point (Source of data: WHO)

Main Objective: To evaluate the efficacy of LN-145 in patients with recurrent, metastatic, or persistent cervical carcinoma based on the objective response rate (ORR) using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 as assessed by the investigator.;Secondary Objective: - To characterize the safety profile of LN-145 in patients with recurrent, metastatic, or persistent cervical carcinoma
- To evaluate the efficacy parameters of LN-145 in patients with recurrent, metastatic, or persistent cervical carcinoma such as duration of response (DOR), disease control rate (DCR) and progression-free survival (PFS) using RECIST v1.1 as assessed by the investigator
- To evaluate overall survival (OS) in patients with recurrent, metastatic, or persistent cervical carcinoma;Primary end point(s): ORR using RECIST v1.1 as assessed by the Investigator;Timepoint(s) of evaluation of this end point: After last patient complete treatment and reach the 6-month tumor assessment, and final analysis at end of 2-year post-treatment follow up.

Secundary end point (Source of data: WHO)

Secondary end point(s): • Incidence of treatment-emergent AEs (TEAEs), including serious adverse events (SAEs),, therapy-related AEs, adverse events (AEs) leading to early discontinuation of treatment or withdrawal from Efficacy Follow-Up or death
• Complete Response (CR) rate using RECIST v1.1 as assessed by the Investigator
• Duration of Response (DOR) using RECIST v1.1 as assessed by the Investigator
• Disease Control Rate (DCR) using RECIST v1.1 as assessed by the Investigator
• Progression-Free Survival (PFS) using RECIST v1.1 as assessed by the Investigator
• Overall Survival (OS);Timepoint(s) of evaluation of this end point: After last patient complete treatment and reach the 6-month tumor assessment, and final analysis at end of 2-year post-treatment follow up.

Contact information (Source of data: WHO)

Iovance Biotherapeutics Inc.

Trial sites

Trial sites in Switzerland (Source of data: BASEC)

Bern, Lausanne

Countries (Source of data: WHO)

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

Contact for further information on the trial

Details of contact in Switzerland (Source of data: BASEC)

Dr. Angela Orcurto
+41 79 556 7517
angela.orcurto@chuv.ch

Contact for general information (Source of data: WHO)

Susie Tanamly
999 Skyway Road, Suite 150
Iovance Biotherapeutics, Inc.
+1650260 7120240
c14504.cervical@iovance.com

Contact for scientific information (Source of data: WHO)

Susie Tanamly
999 Skyway Road, Suite 150
Iovance Biotherapeutics, Inc.
+1650260 7120240
c14504.cervical@iovance.com

Principal Sponsor/Investigator

Principal sponsor (Source of data: WHO)

Iovance Biotherapeutics, Inc.

Further trial identification numbers

BASEC ID (Source of data: BASEC)

2017-02024

Secondary ID (Source of data: WHO)

C-145-04;NCT03108495