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    Summary
    EudraCT Number:2019-003396-19
    Sponsor's Protocol Code Number:EOADR1-19
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2021-01-22
    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 ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2019-003396-19
    A.3Full title of the trial
    A phase 1/2 trial of EO2401, a novel microbial-derived peptide therapeutic vaccine, in combination with PD-1 check point blockade, for treatment of patients with locally advanced or metastatic adrenocortical carcinoma, or malignant pheochromocytoma/paraganglioma.
    Studio di fase 1/2 su EO2401, vaccino terapeutico Peptidico innovativo di origine microbiomica, in associazione con blocco del chEckpoint PD-1 per il trattamento di pazienti con carcinoma adrenocorticale localmente avaNzato o metastatiCo o fEocromocitoma/paRaganglioma maligno.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    An Early Phase Clinical Trial to investigate EO2401, a Novel Cancer Vaccine Therapy, with an Immune-Checkpoint Blocker, in Patients with unresectable, previously treated and previously untreated, locally advanced or metastatic adrenocortical carcinoma or malignant pheochromocytoma/paraganglioma, a Certain Form of adrenals cancer.
    Una sperimentazione clinica precoce su EO2401, una nuova terapia vaccinale contro il cancro, in associazione con blocco del chEckpoint immunitario, in pazienti con carcinoma surrenale non resecabile, precedentemente trattato e non trattato, localmente avanzato o metastatico o feocromocitoma/paraganglioma maligno.
    A.3.2Name or abbreviated title of the trial where available
    Spencer study
    Spencer study
    A.4.1Sponsor's protocol code numberEOADR1-19
    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 SponsorENTEROME
    B.1.3.4CountryFrance
    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 supportEnterome
    B.4.2CountryFrance
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationENTEROME
    B.5.2Functional name of contact pointJean-Michel Paillarse
    B.5.3 Address:
    B.5.3.1Street Address94/96 Avenue Ledru-Rollin
    B.5.3.2Town/ cityParis
    B.5.3.3Post code75011
    B.5.3.4CountryFrance
    B.5.4Telephone number+33185761062
    B.5.5Fax number000000
    B.5.6E-mailjmpaillarse@enterome.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 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 namend
    D.3.2Product code [EO2401]
    D.3.4Pharmaceutical form Emulsion for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.9.2Current sponsor codeEO2316
    D.3.9.3Other descriptive nameEO2316
    D.3.10 Strength
    D.3.10.1Concentration unit µg microgram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number300
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.9.2Current sponsor codeEO2317
    D.3.9.3Other descriptive nameEO2317
    D.3.10 Strength
    D.3.10.1Concentration unit µg microgram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number300
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.9.2Current sponsor codeEO2318
    D.3.9.3Other descriptive nameEO2318
    D.3.10 Strength
    D.3.10.1Concentration unit µg microgram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number300
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.9.2Current sponsor codeUCP2
    D.3.9.3Other descriptive nameUCP2
    D.3.10 Strength
    D.3.10.1Concentration unit µg microgram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number300
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.9.1CAS number 190396-06-6
    D.3.9.2Current sponsor codeMONTANIDE ISA51
    D.3.9.3Other descriptive nameMONTANIDE ISA51
    D.3.9.4EV Substance CodeSUB33722
    D.3.10 Strength
    D.3.10.1Concentration unit µl/ml microlitre(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number500
    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 Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    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 OPDIVO (10 mg/mL)
    D.2.1.1.2Name of the Marketing Authorisation holderBristol-Myers Squibb Pharma EEIG
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    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 nameNivolumab
    D.3.2Product code [nd]
    D.3.4Pharmaceutical form Concentrate for 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 INNNivolumab
    D.3.9.1CAS number 946414-94-4
    D.3.9.2Current sponsor codend
    D.3.9.4EV Substance CodeSUB122750
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    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) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    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 Yes
    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
    - locally advanced or metastatic adrenocortical carcinoma (ACC)
    - malignant pheochromocytoma/paraganglioma (MPP)
    - carcinoma adrenocorticale localizzato avanzato o metastatico (ACC)
    - feocromocitoma/paraganglioma maligno (MPP)
    E.1.1.1Medical condition in easily understood language
    - locally advanced or metastatic adrenocortical carcinoma (ACC)
    - malignant pheochromocytoma/paraganglioma (MPP)
    - carcinoma adrenocorticale localizzato avanzato o metastatico (ACC)
    - feocromocitoma/paraganglioma maligno (MPP)
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10001388
    E.1.2Term Adrenocortical carcinoma
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.1
    E.1.2Level LLT
    E.1.2Classification code 10034876
    E.1.2Term Pheochromocytoma
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10075444
    E.1.2Term Malignant paraganglioma
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary objective of this trial is to evaluate safety and tolerability of EO2401 in combination with nivolumab in patients with unresectable, previously treated, and previously untreated, locally advanced or metastatic ACC, and progressive MPP.
    L’obiettivo primario dello studio è la valutazione della sicurezza e della tollerabilità di EO2401 in associazione con nivolumab in pazienti con ACC non resecabile, trattato in precedenza e non trattato in precedenza, localmente avanzato o metastatico e MPP in progressione.
    E.2.2Secondary objectives of the trial
    The secondary objectives include assessment of:
    - immunogenicity in relation to T cells of EO2316, EO2317, EO2318, and UCP2 that compose EO2401; T cell cross-reactivity with the human TAAs IL13Ra2, FOXM1, and BIRC5/surviving will also be evaluated,
    - objective response rate (ORR) and duration of response (DOR), and
    - progression-free survival (PFS) and overall survival (OS).
    Gli obiettivi secondari comprendono la valutazione di:
    • immunogenicità in relazione ai linfociti T di EO2316, EO2317, EO2318 e UCP2, che costituiscono EO2401; sarà inoltre valutata la reattività crociata dei linfociti T con i TAA umani IL13Ra2, FOXM1 e BIRC5/survivina
    • tasso di risposta obiettiva (ORR, objective response rate) e durata della risposta (DOR, duration of response) e
    • sopravvivenza libera da progressione (PFS, progression-free survival) e sopravvivenza complessiva (OS, overall survival).
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. For inclusion in Cohort 1 patients should have adrenocortical carcinoma, or malignant pheochromocytoma/paraganglioma, as defined below for Cohorts 2A and 3A.
    2. For inclusion in Cohorts 2A and 2B patients should have histologically confirmed (at primary diagnosis) unresectable locally advanced or metastatic (ENSAT/AJCC] stage 3 = tumor has spread into nearby tissues or lymph nodes, or stage 4 = metastatic disease) adrenocortical carcinoma.
    a. In addition, for inclusion in Cohort 2 A patients should also have received treatment with at least one line, but not more than two prior lines, of systemic therapy including mitotane and/or chemotherapy (other groups of systemic therapies utilized in e.g. clinical trials will also be assessed and counted if appropriate).
    b. In addition, for inclusion in Cohort 2B patients should not have received prior systemic therapy for their adrenocortical carcinoma.
    Note, adjuvant therapy for patients with complete resections should not be counted in the definitions above.
    3. For inclusion in Cohorts 3A and 3B patients should have histologically confirmed (at primary diagnosis) unresectable malignant (defined as metastatic disease, i.e. presence of chromaffin tissue in non-chromaffin organs pheochromocytoma/paraganglioma, and RECIST defined progression should have been documented during a maximum of an 18months period.
    a. In addition, for inclusion in Cohort 3A patients should also have received treatment with at least two prior lines of systemic therapy including radionuclide therapy and/or chemotherapy (other groups of systemic therapies utilized in e.g. clinical trials will also be assessed and counted if appropriate).
    b. In addition, for inclusion in Cohort 3B patients should not have received prior systemic therapy for their malignant pheochromocytoma/paraganglioma.
    4. Patients with an age = 18 years old.
    5. Patients who are human leukocyte antigen (HLA)-A2 positive.
    6. Patients with an Eastern Cooperative Oncology Group (ECOG) performance status = 2 (see Section 12.2 [39]).
    7. Patients with a life expectancy > 4 months as judged by their treating physician.
    8. Patients with at least one measurable lesion according to RECIST 1.1 (see Section 12.1).
    9. Males or non-pregnant, non-lactating, females who are:
    e) female, post-menopausal (serum follicle-stimulating hormone (FSH) level > 40 mIU/mL >),
    f) female and male, surgically sterile (e.g. bilaterally blocked or removed fallopian tubes, vas deferens),
    g) female of childbearing potential with a negative highly sensitive serum pregnancy test within 72 hours prior to first administration of study treatment and use of a highly effective contraception from signing the Informed Consent Form (ICF) through 5 months after the last study treatment dose administered; note, the male partner should in addition to the use of highly effective contraception by the female patient also use condoms,
    h) male patient with female partners of childbearing potential must use condoms from signing the ICF through 5 months after the last study treatment dose administered; in addition, male patients must ensure that their partners of childbearing potential also use highly effective contraception.
    Highly effective barrier and non-barrier contraception include:
    i) combined (estrogen and progesterone containing) hormonal contraception associated with inhibition of ovulation: oral, intravaginal, transdermal,
    ii) progestogen-only hormonal contraception associated with inhibition of ovulation: oral, injectable, implantable, intrauterine device, and
    iii) sexual abstinence when in line with the preferred and usual lifestyle of the patient (e.g. periodic abstinence is not considered a highly effective method).
    10. Patients willing and able to comply with the scheduled visits, treatment plan, laboratory tests, and other study procedures indicated in the protocol.
    11. see Protocol
    1. Per essere inclusi nella coorte 1, i pazienti devono essere affetti da carcinoma adrenocorticale o feocromocitoma/paraganglioma maligno, come definito di seguito per le coorti 2A e 3A.
    2. Per essere inclusi nelle coorti 2A e 2B, i pazienti devono essere affetti da carcinoma adrenocorticale istologicamente confermato (alla diagnosi primaria), non resecabile, localmente avanzato o metastatico (stadio 3 ENSAT/AJCC = tumore diffuso ai tessuti adiacenti o ai linfonodi oppure stadio 4 = malattia metastatica).
    a. Inoltre, per essere inclusi nella coorte 2A, i pazienti devono anche essere stati trattati con almeno una linea, ma non più di due linee precedenti, di terapia sistemica contenente mitotano e/o chemioterapia (se opportuno, saranno valutati e calcolati anche altri gruppi di terapie sistemiche utilizzate per esempio negli studi clinici).
    b. Inoltre, per essere inclusi nella coorte 2B, i pazienti non devono essere stati sottoposti in precedenza a terapia sistemica per il carcinoma adrenocorticale.
    La terapia adiuvante per i pazienti con resezioni complete non va calcolata nelle definizioni riportate sopra.
    3. Per essere inclusi nelle coorti 3A e 3B, i pazienti devono essere affetti da feocromocitoma/paraganglioma maligno, istologicamente confermato (alla diagnosi primaria), non resecabile (definito come malattia metastatica, ovvero presenza di tessuto cromaffine in organi non cromaffini) e deve essere stata documentata progressione secondo i criteri RECIST in un periodo massimo di 18 mesi.
    a. Inoltre, per essere inclusi nella coorte 3A, i pazienti devono anche essere stati trattati con almeno due linee precedenti di terapia sistemica contenente radionuclidi e/o chemioterapia (se opportuno, saranno valutati e calcolati anche altri gruppi di terapie sistemiche utilizzate per esempio negli studi clinici).
    b. Inoltre, per essere inclusi nella coorte 3B, i pazienti non devono essere stati sottoposti in precedenza a terapia sistemica per il feocromocitoma/paraganglioma maligno.
    4. Pazienti di età = 18 anni.
    5. Pazienti positivi all’antigene leucocitario umano (HLA, human leukocyte antigen)-A2.
    6. Pazienti con performance status secondo l’Eastern Cooperative Oncology Group (ECOG) = 2.
    7. Pazienti con aspettativa di vita > 4 mesi secondo il giudizio del medico curante.
    8. Pazienti con almeno una lesione misurabile secondo i criteri RECIST 1.1.
    9. vedi Protocollo
    10. vedi Protocollo
    11. vedi Protocollo
    E.4Principal exclusion criteria
    1. Patients treated with dexamethasone > 2 mg/day or equivalent (i.e. 13 mg/day of prednisone, or 53 mg/day of hydrocortisone) within 14 days before the first EO2401 administration, unless required to treat an adverse event. Note, inhaled steroids and adrenal replacement steroid doses > 13 mg daily prednisone equivalents are permitted. Thus, patients needing hydrocortisone replacement therapy due to prior or
    ongoing mitotane therapy can receive hydrocortisone doses > 53 mg/day, i.e. also in the normally used range of 60-80 mg/day, and still be included in the trial.
    2. Patients with prior treatment with compounds targeting PD-1, PD-L1, CTLA-4, or similar compounds where general resistance against therapeutic vaccination approaches might have developed (e.g. defects to the cellular antigen processing/presentation machinery, including mutations in Janus kinas [JAK] 1, JAK2, and ß-2-microglobulin [B2M]) allowing tumor cells to avoid recognition and attack by immune cells.
    3. Patients with prior exposure to EO2401, e.g. patients treated in Cohorts 2B or 3B of the current trial cannot be re-enrolled for treatment also in Cohorts 2A or 3A.
    4. Patients treated with immunotherapy (meaning immunostimulatory or immunosuppressive therapy; beside excluded, or allowed, compounds per other inclusion/exclusion criteria specifications), radionuclide therapy, radiotherapy, cytoreductive therapy, or received treatment with any other investigational agent within 28 days before the first EO2401 administration. Note, for patients with ACC continued treatment with mitotane during this trail is allowed provided tumor progression on this therapy has been demonstrated under therapeutic plasma level or at maximum individual tolerated dose and mitotane plasma level monitoring is maintained during the trial (mitotane might have been given in the adjuvant and/or established disease settings as long as progression on this therapy before trial inclusion has been documented). For patients with MPP, concurrent therapy with octreotide is allowed provided tumor progression on this therapy has been demonstrated; concurrent therapy with bisphosphonates (e.g. zoledronic acid) or denosumab is also allowed.
    5. Patients with ACC with more than three organs involved by disease, combined with high ki-67 expression in tumor (= 20%), and unresectable primary tumor.
    6. Patients with ACC and uncontrolled cortisol secretion (according to the judgement of the treating physician).
    7. Patients with MPP and uncontrolled blood pressure (according to the judgement of the treating physician).
    8. Patients with abnormal laboratory values according to the following list (note, lab ranges according to the performing laboratory's reference ranges):
    a. hemoglobin < 10 g/dL (6.2 mmol/L) (transfusion to correct the value is acceptable),
    b. white blood cell count decrease (< 3.0 × 109/L),
    c. absolute neutrophil count decrease (< 1.5 × 109/L),
    d. platelet count decrease (< 75 × 109/L),
    e. bilirubin > 1.5 x upper limit of normal (ULN) (note, benign hereditary hyperbilirubinemia, e.g. Gilbert's syndrome is permitted),
    f. alanine aminotransferase (ALT) > 3 x ULN; if disease metastatic to the liver > 5 x ULN,
    g. aspartate aminotransferase (AST) > 3 x ULN; if disease metastatic to the liver > 5 x ULN,
    h. serum creatinine increase (> 1.5 x ULN); however, if creatinine clearance (measured, or calculated according to the Cockcroft/Gault [40] formula; CCr={((l40–age) x weight)/(72xSCr)} x 0.85 (if female); CCr (creatinine clearance) = mL/minute, age = years, weight = kg, SCr (serum creatinine) = mg/dL) is > 40 mL/minute the patient can be enrolled, and
    i. abnormal thyroid function per local laboratory levels (note, patients with hypothyroidism only requiring hormone replacement therapy are permitted to enroll).
    9. see Protocol
    10. see Protocol
    11. see Protocol
    1. Pazienti trattati con desametasone > 2 mg/giorno o equivalente (13 mg/giorno di prednisone o 53 mg/giorno di idrocortisone) nei 14 giorni precedenti alla prima somministrazione di EO2401, a meno che non sia necessario per trattare un evento avverso. Sono ammessi steroidi per inalazione e dosi di terapia steroidea di sostituzione surrenalica > 13 mg al giorno di equivalenti del prednisone. Quindi, i pazienti che hanno necessità di una terapia di sostituzione dell’idrocortisone a causa della terapia con mitano precedente o in corso possono ricevere dosi di idrocortisone > 53 mg/giorno, anche nell’intervallo usato normalmente di 60-80 mg/giorno, ed essere comunque inclusi nello studio.
    2. Pazienti trattati in precedenza con composti mirati a PD-1, PD-L1, CTLA-4 o composti simili che possono aver indotto lo sviluppo di resistenza generale verso gli approcci terapeutici di vaccinazione (per es. difetti cellulari di processazione/
    presentazione dell’antigene, comprese mutazioni di Janus chinasi [JAK] 1, JAK2 e ß-2-microglobulina [B2M]), che permettano alle cellule tumorali di evitare il riconoscimento e l’attacco da parte delle cellule immunitarie.
    3. Pazienti esposti in precedenza a EO2401, per es. i pazienti trattati nelle coorti 2B o 3B del presente studio non possono essere nuovamente arruolati per il trattamento anche nelle coorti 2A o 3A.
    4. Pazienti trattati con immunoterapia (ovvero terapia immunostimolatoria o immunosoppressiva; oltre i composti esclusi, o ammessi, in base ad altri criteri di inclusione/esclusione), terapia con radionuclidi, radioterapia, terapia di citoriduzione o trattamento con qualsiasi altro farmaco sperimentale nei 28 giorni precedenti alla prima somministrazione di EO2401. Per i pazienti con ACC è ammessa la continuazione del trattamento con mitotano durante il presente studio, purché sia stata dimostrata progressione del tumore durante questa terapia a livello plasmatico terapeutico o alla dose massima tollerata individuale e il monitoraggio del livello plasmatico di mitotano sia continuato durante lo studio (il mitotano può essere stato somministrato nel contesto adiuvante e/o di malattia conclamata purché sia stata documentata la progressione durante questa terapia prima dell’inclusione nello studio). Per i pazienti con MPP è ammessa la terapia concomitante con octreotide purché sia stata dimostrata progressione del tumore con questa terapia; è ammessa anche la terapia concomitante con bifosfonati (per es. acido zoledronico) o denosumab.
    5. Pazienti con ACC con più di tre organi interessati dalla malattia, in combinazione con espressione elevata di ki-67 nel tumore (= 20%) e tumore primitivo non resecabile.
    6. Pazienti con ACC e secrezione non controllata di cortisolo (secondo il giudizio del medico curante).
    7. Pazienti con MPP e pressione arteriosa non controllata (secondo il giudizio del medico curante).
    8-23. vedi Protocollo
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint regarding safety and tolerability of EO2401 in combination with nivolumab is a descriptive medical assessment of the combined profile of incidences of adverse events (AEs), treatmentemergent AEs (TEAEs), serious AEs (SAEs), deaths, reasons for treatment discontinuation/delays, and laboratory abnormalities using the NCICTCAE v5.0 grading system.
    L’endpoint primario relativo alla sicurezza e alla tollerabilità di EO2401 in associazione con nivolumab è una valutazione medica descrittiva del profilo combinato delle incidenze di eventi avversi (AE, adverse event), AE emergenti dal trattamento (TEAE, treatment-emergent AE), AE gravi (SAE, serious AE), decessi, motivi di interruzione/ritardo del trattamento e anomalie di laboratorio utilizzando il sistema di classificazione NCI-CTCAE v5.0.
    E.5.1.1Timepoint(s) of evaluation of this end point
    AEs will be monitored throughout the study. AEs are collected from the date of the patient's signing the ICF until 30 days after the final administration of study drug. SAEs with a plausible causal relationship to study drug will be reported from the date of the patient's signing the ICF until indefinitely (regardless of time elapse from the final study drug administration). An AE causally not related to study drug will be monitored (followed-up) until resolution, stabilization, or end of the clinical trial. Clinically relevant laboratory abnormalities will be followed up until they return to normal or become stabilized (permanent condition). Any AE with a plausible causal relationship to study drug as well as all SAEs will be followed up until the event has resolved or stabilized.
    AEs will be monitored throughout the study. AEs are collected from the date of the patient's signing the ICF until 30 days after the final administration of study drug. SAEs with a plausible causal relationship to study drug will be reported from the date of the patient's signing the ICF until indefinitely (regardless of time elapse from the final study drug administration). An AE causally not related to study drug will be monitored (followed-up) until resolution, stabilization, or end of the clinical trial. Clinically relevant laboratory abnormalities will be followed up until they return to normal or become stabilized (permanent condition). Any AE with a plausible causal relationship to study drug as well as all SAEs will be followed up until the event has resolved or stabilized.
    E.5.2Secondary end point(s)
    • Percentage of patients with shown immunogenicity (expansion of specific T cells comparing samples taken at baseline versus on treatment n an individual patient determining if the patient has a positive response to the immunization, or not) in relation to EO2316, EO2317, EO2318, and UCP2 that compose EO2401 by interferon-gamma (IFN-¿) enzyme-linked immunospot (ELISpot), and if needed by intracellular cytokines staining, or multimers staining assays. Cross reactivities with the human TAAs IL13Ra2, FOXM1, and BIRC5/survivin will also be evaluated by the same methods.
    • ORR and DOR as described by RECIST 1.1 and iRECIST criteria.
    • PFS as described by RECIST 1.1 and iRECIST criteria, defined as the time interval from the date of first study treatment administration to the date of progression (by RECIST 1.1 or iRECIST criteria) or death due to any cause, whichever is earlier. Patients without progression or death are to be censored at the time of the last tumor assessment.
    • OS defined as the time interval from the date of first study treatment administration to the date of death due to any cause. Patients alive will be censored at the date of the last documented follow-up.
    • Percentuale di pazienti con evidenza di immunogenicità (espansione di linfociti T specifici mediante il confronto di campioni prelevati al basale rispetto a quelli prelevati durante il trattamento in un singolo paziente, per determinare se il paziente ha o meno una risposta positiva all’immunizzazione) in relazione a EO2316, EO2317, EO2318 e UCP2, che costituiscono EO2401, valutata mediante tecnica immunospot enzimatica (ELISpot, enzyme-linked immunospot) per la rilevazione di interferone-gamma (IFN-¿) e, se necessario, mediante colorazione delle citochine intracellulari o test di colorazione dei multimeri. Anche le reattività crociate con i TAA umani IL13Ra2, FOXM1 e BIRC5/survivina saranno valutate con gli stessi metodi.
    • ORR e DOR come descritto dai criteri RECIST 1.1 e iRECIST.
    • PFS come descritto dai criteri RECIST 1.1 e iRECIST, definita come il tempo trascorso dalla data della prima somministrazione del trattamento dello studio alla data della progressione (in base ai criteri RECIST 1.1 o iRECIST) o del decesso dovuto a qualsiasi causa, a seconda di quale evento si verifichi per primo. I pazienti senza progressione o ancora in vita saranno censurati alla data dell’ultima valutazione del tumore.
    • OS definita come il tempo trascorso dalla data della prima somministrazione del trattamento dello studio alla data del decesso dovuto a qualsiasi causa. I pazienti in vita saranno censurati alla data dell’ultimo follow-up documentato.
    E.5.2.1Timepoint(s) of evaluation of this end point
    • Percentage of patients with shown immunogenicity is evaluated on Week 1, 5 , 7 , 11, 15 and 19, then every 4 weeks of treatment onwards. Post treatment is evaluated on Day 30 and every 8 weeks before disease
    progression.
    • Objective Response Rate (ORR) and Duration of Response (DOR) as described by RECIST 1.1 and iRECIST criteria.
    • PFS as described by RECIST 1.1 and iRECIST criteria, defined as the time interval from the date of first study treatment administration to the date of progression (by RECIST 1.1 or iRECIST criteria) or death due to any cause, whichever is earlier. Patients without progression or death are to be censored at the time of the last tumor assessment.
    • Percentage of patients with shown immunogenicity is evaluated on Week 1, 5 , 7 , 11, 15 and 19, then every 4 weeks of treatment onwards. Post treatment is evaluated on Day 30 and every 8 weeks before disease
    progression.
    • Objective Response Rate (ORR) and Duration of Response (DOR) as described by RECIST 1.1 and iRECIST criteria.
    • PFS as described by RECIST 1.1 and iRECIST criteria, defined as the time interval from the date of first study treatment administration to the date of progression (by RECIST 1.1 or iRECIST criteria) or death due to any cause, whichever is earlier. Patients without progression or death are to be censored at the time of the last tumor assessment.
    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 Yes
    E.6.13.1Other scope of the trial description
    Immunogenicity
    Immunogenicità
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) Yes
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other Yes
    E.7.1.3.1Other trial type description
    A phase Ib/II trial but another trial is the First in Human.
    Fase Ib/II
    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 No
    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 Yes
    E.8.1.7.1Other trial design description
    La sperimentazione è uno studio con 5 coorti.
    The trial is a 5-cohort study.
    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 Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.4.1Number of sites anticipated in Member State concerned1
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA8
    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 Information not present in EudraCT
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    United States
    Denmark
    France
    Germany
    Italy
    Netherlands
    Spain
    Sweden
    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
    LVLS
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months6
    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: 47
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 25
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    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 state14
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 64
    F.4.2.2In the whole clinical trial 72
    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)
    The investigator will ensure that patients receive appropriate standard of care to treat the condition under the study.
    Lo sperimentatore si assicurerà che i pazienti ricevano standard adeguati di cura per trattare la condizione clinica nel corso dello studio.
    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 Decision2020-03-03
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-01-07
    P. End of Trial
    P.End of Trial StatusOngoing
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