| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| lung cancer |
| cancer du poumon |
|
| E.1.1.1 | Medical condition in easily understood language |
| lung cancer |
| Cancer du poumon |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| Evaluer l’efficacité de la combinaison UCPVax plus Nivolumab comme seconde ligne de traitement des cancers du poumon non à petites cellules avancés. |
| Evaluer l’efficacité de la combinaison UCPVax plus Nivolumab comme seconde ligne de traitement des cancers du poumon non à petites cellules avancés. |
|
| E.2.2 | Secondary objectives of the trial |
1. Evaluer le taux de réponses objectives à 6 mois selon les critères RECIST.
2. Evaluer la survie sans progression et le taux de réponses objectives selon les critères iRECIST dans le bras expérimental
3. Evaluer le taux de contrôle de la maladie (DCR) après 12 mois.
4. Evaluer les toxicités selon les critères du NCI-CTCAE version 5 à chaque visite
5. Evaluer la survie globale (SG): intervalle de temps entre la date de l’initiation du traitement et la date de décès quelle que soit la cause.
6. Evaluer l’immunogénicité de la combinaison évaluée par test ELISPOT-interféron-gamma dans le sang périphérique.
7. Evaluer la qualité de vie relative à la santé
8. Exploratoire: TMB, ctDNA, microbiote, angiogenèse tumorale, infiltrats immunitaires
|
1. Evaluer le taux de réponses objectives à 6 mois selon les critères RECIST.
2. Evaluer la survie sans progression et le taux de réponses objectives selon les critères iRECIST dans le bras expérimental
3. Evaluer le taux de contrôle de la maladie (DCR) après 12 mois.
4. Evaluer les toxicités selon les critères du NCI-CTCAE version 5 à chaque visite
5. Evaluer la survie globale (SG): intervalle de temps entre la date de l’initiation du traitement et la date de décès quelle que soit la cause.
6. Evaluer l’immunogénicité de la combinaison évaluée par test ELISPOT-interféron-gamma dans le sang périphérique.
7. Evaluer la qualité de vie relative à la santé
8. Exploratoire: TMB, ctDNA, microbiote, angiogenèse tumorale, infiltrats immunitaires
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1- Signed informed consent
2- Male or female patients, age ≥ 18 years
3- Histologically or cytologically confirmed NSCLC (adenocarcinoma, squamous cell carcinoma, large cell carcinoma, undifferentiated carcinoma or other)
4- Advanced NSCLC cancer patient previously treated with a first line of combo chemotherapy plus anti-PD-1 or chemotherapy plus anti-PDL-1 combination
5- Measurable disease defined according to RECIST v1.1 guidelines (Note: Previously irradiated lesions can be considered as measurable disease only if disease progression has been unequivocally documented at that site since radiation.)
6- Patients must have a mandatory treatment-free interval of at least 21 days following previous systemic anti-cancer treatments
7- Patients who have received previous systemic anticancer treatment and/or radiotherapy should have recovered from any treatment related toxicity, to a level of ≤ grade 1 (according to National Cancer Institute [NCI] common terminology criteria for adverse events, version 5 (CTCAE v5) with the exception of Grade 2 alopecia
8- Performance status 0 or 1 on the ECOG scale
9- Females must be using highly effective contraceptive measures and have a negative pregnancy test prior to the start of dosing if of childbearing potential, or must have evidence of non-childbearing potential by fulfilling one of the following criteria at screening:
•Post-menopausal is defined as aged more than 50 years and amenorrhoeic for at least 12 months following cessation of all exogenous hormonal treatments.
•Women under the age of 50 years would be considered postmenopausal if they have been amenorrhoeic for 12 months or more following cessation of exogenous hormonal treatments and with luteinizing hormone and follicle stimulating hormone levels in the post-menopausal range for the institution.
•Women with documentation of irreversible surgical sterilisation by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation.
Male patients with a female partner of childbearing potential should be willing to use barrier contraception during the study and for 5 months following discontinuation of study drug. Patients should refrain from donating sperm from the start of dosing until 5 months after discontinuing study treatment.
10- Affiliation to French social security or receiving such a regime.
11- Ability to comply with the study protocol, in the Investigator’s judgment. |
1- Signed informed consent
2- Male or female patients, age ≥ 18 years
3- Histologically or cytologically confirmed NSCLC (adenocarcinoma, squamous cell carcinoma, large cell carcinoma, undifferentiated carcinoma or other)
4- Advanced NSCLC cancer patient previously treated with a first line of combo chemotherapy plus anti-PD-1 or chemotherapy plus anti-PDL-1 combination
5- Measurable disease defined according to RECIST v1.1 guidelines (Note: Previously irradiated lesions can be considered as measurable disease only if disease progression has been unequivocally documented at that site since radiation.)
6- Patients must have a mandatory treatment-free interval of at least 21 days following previous systemic anti-cancer treatments
7- Patients who have received previous systemic anticancer treatment and/or radiotherapy should have recovered from any treatment related toxicity, to a level of ≤ grade 1 (according to National Cancer Institute [NCI] common terminology criteria for adverse events, version 5 (CTCAE v5) with the exception of Grade 2 alopecia
8- Performance status 0 or 1 on the ECOG scale
9- Females must be using highly effective contraceptive measures and have a negative pregnancy test prior to the start of dosing if of childbearing potential, or must have evidence of non-childbearing potential by fulfilling one of the following criteria at screening:
•Post-menopausal is defined as aged more than 50 years and amenorrhoeic for at least 12 months following cessation of all exogenous hormonal treatments.
•Women under the age of 50 years would be considered postmenopausal if they have been amenorrhoeic for 12 months or more following cessation of exogenous hormonal treatments and with luteinizing hormone and follicle stimulating hormone levels in the post-menopausal range for the institution.
•Women with documentation of irreversible surgical sterilisation by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation.
Male patients with a female partner of childbearing potential should be willing to use barrier contraception during the study and for 5 months following discontinuation of study drug. Patients should refrain from donating sperm from the start of dosing until 5 months after discontinuing study treatment.
10- Affiliation to French social security or receiving such a regime.
11- Ability to comply with the study protocol, in the Investigator’s judgment. |
|
| E.4 | Principal exclusion criteria |
1- Diagnosis of additional malignancy within 2 years prior to the inclusion with the exception of curatively treated basal cell carcinoma of the skin and/or curatively resected in situ cervical or breast cancer
2- Patient with any medical or psychiatric condition or disease, which would make the patient inappropriate for entry into this study
3- Participation in a clinical study with an investigational product within 4 weeks prior to the start of the study treatment
4- Patient under guardianship, curatorship or under the protection of justice
5- Uncontrolled pleural effusion, pericardial effusion, ascites or symptomatic fistula
6- Uncontrolled tumor-related pain: Symptomatic lesions amenable to palliative radiotherapy should be treated prior to randomization. Patients should be recovered from the effects of radiation. There is no required minimum recovery period
7- Known active central nervous system metastases and/or carcinomatous meningitis. Subject with previously treated brain metastases and with radiological and clinical stability are allowed.
8- Presence of EGFR mutation, ALK or ROS1 translocation
9- Uncontrolled brain metastases. Patients with controlled brain metastases after radiation therapy or with asymptomatic brain metastases may be included.
10- Inadequate organ functions: known cardiac failure of unstable coronaropathy, respiratory failure, or uncontrolled infection or another life-risk condition
11- Active or chronic hepatitis B or C and/or HIV positive (HIV 1/2 antibodies patients), or a known history of active Tuberculosis bacillus
12- Any immunosuppressive therapy (i.e. corticosteroids >10mg of hydrocortisone or equivalent dose) within 14 days before the planned start of study therapy
13- Active autoimmune disease that has required a systemic treatment in past 2 years (i.e. corticosteroids or immunosuppressive drugs). Replacement therapy (e.g. thyroxine, insulin) is allowed
14- Active or history of autoimmune disease or immune deficiency,
15- Patients with a history of autoimmune-related hypothyroidism who are on thyroid replacement hormone are eligible for the study,
16- Patients with controlled Type 1 diabetes mellitus who are on an insulin regimen are eligible for the study,
17- Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic manifestations only (e.g., patients with psoriatic arthritis are excluded) are eligible for the study provided all of following conditions are met:
18- Prior allogeneic bone marrow transplantation or prior solid organ transplantation
19- History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins
20- Known hypersensitivity or allergy to Chinese hamster ovary cell products or any component of Nivolumab formulation
21- History of idiopathic or secondary pulmonary fibrosis (History of radiation pneumonitis in the radiation field fibrosis is permitted), or evidence of active pneumonitis requiring a systemic treatment with 28 days before the planned start of study therapy
22- Major surgical procedure other than for diagnosis within 4 weeks prior to initiation of study treatment, or anticipation of need for a major surgical procedure during the course of the study
23- Severe infection within 4 weeks prior to initiation of study treatment, including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia
24- Treatment with therapeutic oral or IV antibiotics within 4 weeks prior to initiation of study treatment. Patients receiving prophylactic antibiotics (e.g., to prevent a urinary tract infection or chronic obstructive pulmonary disease exacerbation) are eligible for the study
25- Receipt of a live, attenuated vaccine within 4 weeks prior to the initiation of treatment or anticipation that such a live, attenuated vaccine will be required during the study
Note: Patients must agree not to receive live, attenuated influenza vaccine (e.g.,FluMist®) within 28 days prior to randomisation, during treatment or within 5 months following the last dose of Nivolumab
26- Patients requiring oxygen therapy
27- Patients with LEVF<40%
28- Preexistent peripheral neuropathy or impaired audition,
29- Known hypersensitivity or contraindication to taxanes
30- Inadequate hematology function: Lymphocyte count at baseline < 800/mm3 ; neutrophil count <1500/mm3, platelets <100000/mm3, Hemoglobin<9g/dL
31- Inadequate hepatic function: bilirubin 2.5 fold ULN, AST/ALT 2.5 fold ULN or 5 fold ULN with liver metastasis, International normalized thromboplastin time ratio >1.5
32- Inadequate renal function: MDRD CrCl <40ml/min
33- Others inadequate laboratory values: serum albumin<30 g/L; troponin > ULN; BNP > ULN.
34- Active alcohol or drug abuse.
|
1- Diagnostic d'une tumeur maligne supplémentaire dans les 2 ans précédant l'inclusion à l'exception du carcinome basocellulaire de la peau traité curativement et / ou réséqué curativement in situ du cancer du col ou du sein
2- Patient souffrant de toute condition ou maladie médicale ou psychiatrique
3- Participation à une étude clinique avec un produit expérimental dans les 4 semaines précédant le début du traitement de l'étude
4- Patient sous tutelle, curatelle ou sous protection de la justice
5- Épanchement pleural incontrôlé, épanchement péricardique, ascite ou fistule symptomatique
6- Douleur incontrôlée liée à la tumeur
7- Métastases actives connues du système nerveux central et / ou méningite carcinomateuse.
8- Présence de mutation EGFR, translocation ALK ou ROS1
9- Métastases cérébrales non contrôlées. L
10- Fonctions d'organes inadéquates: insuffisance cardiaque connue de coronaropathie instable, insuffisance respiratoire, ou infection incontrôlée ou autre condition potentiellement mortelle
11- Hépatite B ou C active ou chronique et / ou séropositive (patients atteints d'anticorps VIH 1/2), ou antécédents connus de bacille actif de la tuberculose
12- Tout traitement immunosuppresseur (c'est-à-dire corticostéroïdes> 10 mg d'hydrocortisone ou dose équivalente) dans les 14 jours avant le début prévu du traitement à l'étude
13- Maladie auto-immune active qui a nécessité un traitement systémique au cours des 2 dernières années (c.-à-d. Corticostéroïdes ou médicaments immunosuppresseurs). Une thérapie de remplacement (par exemple thyroxine, insuline) est autorisée
14- Actif ou antécédent de maladie auto-immune ou de déficit immunitaire,
15- Les patients ayant des antécédents d'hypothyroïdie auto-immune liés à l'hormone de substitution thyroïdienne sont éligibles pour l'étude,
16- Les patients atteints de diabète sucré de type 1 contrôlé qui suivent un régime d'insuline sont éligibles pour l'étude,
17- Les patients atteints d'eczéma, de psoriasis, de lichen simplex chronicus ou de vitiligo présentant des manifestations dermatologiques uniquement (par exemple, les patients atteints d'arthrite psoriasique sont exclus) sont éligibles pour l'étude à condition que toutes les conditions suivantes soient remplies:
18- Transplantation allogénique antérieure de moelle osseuse ou transplantation antérieure d'organe solide
19- Antécédents de réactions allergiques graves, anaphylactiques ou autres réactions d'hypersensibilité aux anticorps chimériques ou humanisés ou aux protéines de fusion
20- Hypersensibilité ou allergie connue aux produits à base de cellules ovariennes de hamster chinois ou à tout composant de la formulation de Nivolumab
21- Antécédents de fibrose pulmonaire idiopathique ou secondaire (les antécédents de pneumopathie radique dans la fibrose radioactive sont autorisés), ou preuve d'une pneumonite active nécessitant un traitement systémique 28 jours avant le début prévu du traitement à l'étude
22- Intervention chirurgicale majeure autre que pour le diagnostic dans les 4 semaines précédant le début du traitement de l'étude, ou anticipation de la nécessité d'une intervention chirurgicale majeure au cours de l'étude
23- Infection sévère dans les 4 semaines avant le début du traitement de l'étude, y compris, mais sans s'y limiter, l'hospitalisation pour des complications d'infection, de bactériémie ou de pneumonie sévère
24- Traitement avec des antibiotiques thérapeutiques oraux ou IV dans les 4 semaines avant le début du traitement de l'étude. Les patients recevant des antibiotiques prophylactiques (par exemple, pour prévenir une infection des voies urinaires ou une exacerbation d'une maladie pulmonaire obstructive chronique) sont éligibles pour l'étude
25- Réception d'un vaccin vivant atténué dans les 4 semaines précédant le début du traitement ou anticipation qu'un tel vaccin vivant atténué sera nécessaire pendant l'étude
Remarque: Les patients doivent accepter de ne pas recevoir de vaccin antigrippal vivant atténué (par exemple, FluMist®) dans les 28 jours avant la randomisation, pendant le traitement ou dans les 5 mois suivant la dernière dose de Nivolumab
26- Patients nécessitant une oxygénothérapie
27- Patients avec LEVF <40%
28- Neuropathie périphérique préexistante ou audition altérée,
29- Hypersensibilité ou contre-indication connue aux taxanes
30- Fonction hématologique inadéquate: nombre de lymphocytes au départ <800 / mm3; numération des neutrophiles <1500 / mm3, plaquettes <100000 / mm3, hémoglobine <9g / dL
31- Fonction hépatique inadéquate: bilirubine 2,5 fois ULN, AST / ALT 2,5 fois ULN ou 5 fois ULN avec métastases hépatiques, rapport de temps de thromboplastine normalisé international> 1,5
32- Fonction rénale inadéquate: MDRD CrCl <40 ml / min
33- Autres valeurs de laboratoire inadéquates: albumine sérique <30 g / L; troponine> ULN; BNP> ULN.
34- Abus actif d'alcool ou de drogues. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Progression-free survival (PFS) rate at 6 months. PFS is defined by the duration from the date of initiation of the treatment to the disease progression (RECIST) or death from any cause whichever occurs first, censoring cases without progression at the date of last disease assessment.
|
| Taux de survie sans progression (PFS) à 6 mois. La SSP est définie par la durée à partir de la date de début du traitement jusqu'à la progression de la maladie (RECIST) ou le décès de toute cause, selon la première éventualité, censurant les cas sans progression à la date de la dernière évaluation de la maladie. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
1. Objective Response Rate (ORR) at 6 months according to RECIST criteria. ORR is defined as the addition of complete response (CR) and partial response (PR) rates.
2. PFS and ORR according to iRECIST criteria in the experimental arm
3. Disease Control Rate (DCR) by 12 months defined as the percentage of patients who have achieved complete response, partial response and stable disease to the therapeutic intervention.
4. Safety will be evaluated according to NCI CTCAE v 4.03 at each visit
5. Overall survival (OS) is defined by the duration from the date of inclusion to death from any cause.
6. Assessment of Telomerase-specific T cell responses by IFN- ELISPOT in peripheral blood.
7. Health-related quality of life (HRQoL) evaluated using EORTC QLQ-C30 and LC-13 modules specific to lung cancer
8. Exploratory: TMB, ctDNA, microbiote, tumor angiogenesis, immune infiltrates |
1. Taux de réponse objective (ORR) à 6 mois selon les critères RECIST. ORR est défini comme l'addition des taux de réponse complète (CR) et de réponse partielle (PR).
2. PFS et ORR selon les critères iRECIST dans le bras expérimental
3. Taux de contrôle des maladies (DCR) de 12 mois défini comme le pourcentage de patients qui ont obtenu une réponse complète, une réponse partielle et une maladie stable à l'intervention thérapeutique.
4. La sécurité sera évaluée selon NCI CTCAE v 4.03 à chaque visite
5. La survie globale (SG) est définie par la durée entre la date d'inclusion et le décès quelle qu'en soit la cause.
6. Évaluation des réponses des lymphocytes T spécifiques de la télomérase par IFN- ELISPOT dans le sang périphérique.
7. Qualité de vie liée à la santé (HRQoL) évaluée à l'aide des modules EORTC QLQ-C30 et LC-13 spécifiques au cancer du poumon
8. Exploratoire: TMB, ADNct, microbiote, angiogenèse tumorale, infiltrats immuns
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| 6 months / 12 months |
| 6 mois / 12 mois |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | 60 |
| E.8.9.1 | In the Member State concerned days | |
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