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    Summary
    EudraCT Number:2016-003447-11
    Sponsor's Protocol Code Number:C-145-04
    National Competent Authority:Germany - PEI
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2017-08-14
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedGermany - PEI
    A.2EudraCT number2016-003447-11
    A.3Full title of the trial
    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
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    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
    A.3.2Name or abbreviated title of the trial where available
    Study of LN-145 in the treatment of Patients with cervical cancer
    A.4.1Sponsor's protocol code numberC-145-04
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT03108495
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorIovance Biotherapeutics, Inc.
    B.1.3.4CountryUnited States
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportIovance Biotherapeutics Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationIovance Biotherapeutics, Inc.
    B.5.2Functional name of contact pointSusie Tanamly
    B.5.3 Address:
    B.5.3.1Street Address999 Skyway Road, Suite 150
    B.5.3.2Town/ citySan Carlos
    B.5.3.3Post code94070
    B.5.3.4CountryUnited States
    B.5.4Telephone number+1650260 7120240
    B.5.5Fax number+16502607126
    B.5.6E-mailc14504.cervical@iovance.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameFludarabine
    D.3.4Pharmaceutical form Concentrate for solution for injection/infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNFLUDARABINE PHOSPHATE
    D.3.9.1CAS number 75607-67-9
    D.3.9.2Current sponsor codeFLUDARABINE PHOSPHATE
    D.3.9.3Other descriptive nameFLUDARABINE PHOSPHATE
    D.3.9.4EV Substance CodeSUB13897MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number25
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Cyclophosphamide
    D.2.1.1.2Name of the Marketing Authorisation holderBaxter Healthcare Ltd.
    D.2.1.2Country which granted the Marketing AuthorisationUnited Kingdom
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameCyclophosphamide Injection
    D.3.4Pharmaceutical form Powder for solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNCYCLOPHOSPHAMIDE
    D.3.9.1CAS number 6055-19-2
    D.3.9.2Current sponsor codeCYCLOPHOSPHAMIDE
    D.3.9.3Other descriptive nameCYCLOPHOSPHAMIDE MONOHYDRATE
    D.3.9.4EV Substance CodeSUB16414MIG
    D.3.10 Strength
    D.3.10.1Concentration unit g gram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 3
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Proleukin
    D.2.1.1.2Name of the Marketing Authorisation holderNovartis Pharmaceuticals UK Limited
    D.2.1.2Country which granted the Marketing AuthorisationUnited Kingdom
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameAldesleukin
    D.3.4Pharmaceutical form Powder for solution for injection/infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNProleukin
    D.3.9.1CAS number 110942-02-4
    D.3.9.3Other descriptive nameALDESLEUKIN
    D.3.9.4EV Substance CodeSUB05303MIG
    D.3.10 Strength
    D.3.10.1Concentration unit IU international unit(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number22000000
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 4
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameLN-145
    D.3.2Product code LN-145
    D.3.4Pharmaceutical form Solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNLN-145
    D.3.9.1CAS number Not avail.
    D.3.9.2Current sponsor codeLN-145
    D.3.9.3Other descriptive nameLN-145
    D.3.9.4EV Substance CodeSUB187994
    D.3.10 Strength
    D.3.10.1Concentration unit Other
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number1x10^9 to 150x10^9
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) Yes
    D.3.11.3.1Somatic cell therapy medicinal product Yes
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 5
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameFludarabine
    D.3.4Pharmaceutical form Lyophilisate for solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNFLUDARABINE PHOSPHATE
    D.3.9.1CAS number 75607-67-9
    D.3.9.2Current sponsor codeFLUDARABINE PHOSPHATE
    D.3.9.4EV Substance CodeSUB13897MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number50
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 6
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Proleukin
    D.2.1.1.2Name of the Marketing Authorisation holderClinigen Healthcare Ltd.
    D.2.1.2Country which granted the Marketing AuthorisationUnited Kingdom
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameAldesleukin
    D.3.4Pharmaceutical form Powder and solvent for solution for injection/infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNProleukin
    D.3.9.1CAS number 110942-02-4
    D.3.9.3Other descriptive nameALDESLEUKIN
    D.3.9.4EV Substance CodeSUB05303MIG
    D.3.10 Strength
    D.3.10.1Concentration unit IU international unit(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number22000000
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Recurrent, metastatic, or persistent Cervical Carcinoma
    E.1.1.1Medical condition in easily understood language
    Cervical cancer that has come back, spread to other places in the body, or has not improved
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level LLT
    E.1.2Classification code 10008229
    E.1.2Term Cervical cancer
    E.1.2System Organ Class 100000004864
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    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
    E.2.2Secondary objectives of the trial
    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
    E.2.3Trial contains a sub-study No
    E.3Principal 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) ≥ 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 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.4Principal 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 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.5.1Primary 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.
    E.5.1.1Timepoint(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.5.2Secondary 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.
    E.5.2.1Timepoint(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.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial1
    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.8.4.1Number of sites anticipated in Member State concerned3
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA20
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If 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
    United Kingdom
    E.8.7Trial 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.8.9.1In the Member State concerned years5
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years5
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 122
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 16
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male No
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state3
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 69
    F.4.2.2In the whole clinical trial 138
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    This is a one-time therapy, and there is no post-study treatment. There will be a five year follow-up for overall survival (OS) from Enrollment (tumor resection) or until discontinuation of the patient from the study
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2018-11-29
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-11-01
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2018-12-27
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