| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Claudin (CLDN)18.2-Positive, HER2-Negative, Locally Advanced Unresectable or Metastatic Gastric or Gastroesophageal Junction (GEJ) Adenocarcinoma |
| Adénocarcinome de l’estomac ou de la jonction œsogastrique (JOG) Claudine (CLDN)18.2-positif, HER2-négatif, localement avancé inopérable ou métastatique |
|
| E.1.1.1 | Medical condition in easily understood language |
| Metastatic Gastric or Gastroesophageal Junction (GEJ) Adenocarcinoma |
| Adénocarcinome de l’estomac ou de la jonction œsogastrique (JOG) métastatique |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10001150 |
| E.1.2 | Term | Adenocarcinoma gastric |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| to evaluate the efficacy of IMAB362 plus mFOLFOX6 compared with placebo plus mFOLFOX6 (as first-line treatment) as measured by PFS in subjects with Claudin (CLDN)18.2 positive, HER2–negative locally advanced unresectable or metastatic gastric and GEJ adenocarcinoma |
| ·Évaluer l’efficacité de l’association d’IMAB362 plus mFOLFOX6 par rapport à l’association de placebo plus mFOLFOX6 (en traitement de première ligne), mesurée d’après la survie sans progression (SSP) chez des patients présentant un adénocarcinome de l’estomac ou de la jonction œsogastrique (JOG) Claudine (CLDN)18.2-positif, HER2 (récepteur 2 du facteur de croissance épithélial humain)-négatif, localement avancé inopérable ou métastatique |
|
| E.2.2 | Secondary objectives of the trial |
-To evaluate efficacy as measured by Overall Survival (OS) as a key secondary objective
-To evaluate efficacy as measured by Objective Response Rate (ORR)
-To evaluate efficacy as measured by Duration of Response (DOR)
-To evaluate safety and tolerability of IMAB362
-To evaluate health related quality of life (HRQoL) using the parameters as measured by European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30, QLQ-OG25, Global Pain (GP) and the EuroQOL Five Dimensions Questionnaire 5L (EQ5D-5L) questionnaires
-To evaluate the pharmacokinetics of IMAB362
-To evaluate the immunogenicity profile of IMAB362 |
-Évaluer l’efficacité, mesurée d’après la survie globale (SG) comme objectif secondaire fondamental
-Évaluer l’efficacité, mesurée d’après le taux de réponse objective (TRG)
-Évaluer l’efficacité, mesurée d’après le taux de réponse objective (TRO)
-Évaluer la tolérance et la sécurité d’emploi de l’IMAB362
-Évaluer la qualité de vie (QdV) liée à la santé à l’aide des paramètres mesurés par les questionnaires QLQ-C30, QLQ-OG25, Douleur globale (GP, Global Pain) de l’Organisation européenne de recherche et de traitement du cancer (EORTC, European Organization for Research and Treatment of Cancer) et le questionnaire EQ5D-5L à 5 dimensions et 5 niveaux (EuroQOL Five Dimensions Questionnaire 5L)
-Évaluer la pharmacocinétique de l’IMAB362
-Évaluer le profil d’immunogénicité de l’IMAB362 |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
General Criteria:
1.Institutional Review Board (IRB)/Independent Ethics Committee (IEC) approved written informed consent and privacy language as per national regulations (e.g., HIPAA Authorization for US sites) must be obtained from the subject or legally authorized representative (if applicable) prior to any study-related procedures.
2.Subject is considered an adult (e.g., ≥ 18 years of age in the US) according to local regulation at the time of signing the informed consent.
3.Subject agrees not to participate in another interventional study while on study treatment.
4.Female subject must either:
Be of non-childbearing potential:
-postmenopausal (defined as at least 1 year without any menses for which there is no other obvious pathological or physiological cause) prior to Screening, or
-documented surgically sterile (e.g., hysterectomy, bilateral salpingectomy,
bilateral oophorectomy)
Or, if of childbearing potential:
-agree not to try to become pregnant during the study and for 6 months after the final study treatment administration,
and, have a negative serum pregnancy test at Screening, (Note: Subjects with elevated serum beta human chorionic gonadotropin (βhCG) and a demonstrated non-pregnant status through additional testing are eligible), and if heterosexually active, agree to consistently use 1 form of highly effective birth control* starting at Screening and throughout the study period and for 6 months after the final study drug administration.
5.Female subject must agree not to breastfeed starting at Screening and throughout the study period, and for 6 months after the final study treatment administration.
6.Female subject must not donate ova starting at Screening and throughout the study period, and for 6 months after the final study drug administration.
7.A sexually active male subject with female partner(s) who are of childbearing potential is eligible if:
-Agree to use a male condom starting at screening and continue throughout study treatment and for 6 months after the final study drug administration.
-If he has not had a vasectomy or is not sterile as defined below, his female partner(s) is utilizing 1 form of highly effective birth control starting at Screening and continue throughout study treatment and for 6 months after the he receives his final study drug administration.
8.Male subject must not donate sperm starting at Screening and throughout the study period and for 6 months after the final study drug administration.
9.Male subject with a pregnant or breastfeeding partner(s) must agree to remain abstinent or use a condom for the duration of the pregnancy or for the time partner is breastfeeding throughout the study period and for 6 months after the final study drug administration.
Disease Specific Criteria:
10.Subject has histologically confirmed diagnosis of Gastric or GEJ adenocarcinoma.
11.Subject has radiologically confirmed locally advanced unresectable or metastatic disease within 28 days prior to the first dose of study treatment.
12.Subject has measurable disease according to RECIST 1.1 within 28 days prior to the first dose of study treatment. For subjects with only 1 measurable lesion and prior radiotherapy, the lesion must be outside the field of prior radiotherapy or must have documented progression following radiation therapy.
13.Subject’s tumor expresses CLDN18.2 in ? 75% of tumor cells demonstrating moderate to strong membranous staining as determined by central IHC testing.
14.Subject has a HER2-Negative tumor as determined by local or central testing on a gastric or GEJ tumor specimen.
Physical or Laboratory Findings
15.Subject has ECOG performance status 0 to 1.
16.Subject has predicted life expectancy 12 weeks in the opinion of the investigator.
17.Subject must meet all of the following criteria based on the centrally analyzed laboratory tests within 14 days prior to the first dose of study treatment. In case of multiple laboratory data within this period, the most recent data should be used to determine eligibility.
-Hemoglobin (Hgb) >= 9 g/dL. NOTE: subject must not have received any growth factor or blood transfusions within 14 days prior to the hematology values obtained at screening. Subjects requiring transfusions to meet eligibility criteria are not eligible.
-Absolute neutrophil count (ANC) >= 1.5 x 109/L
-Platelets >=100 x 109/L
-Albumin >= 2.5 g/dL
-Total bilirubin < 1.5 x upper limit of normal (ULN)
-Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x
ULN without liver metastases (or ≤ 5 x ULN if liver metastases are present)
-Either serum creatinine ≤ 1.5 x ULN or estimated glomerular filtration rate ? 45 mL/min/1.73 m2
-PT/international normalized ratio (INR) and PTT ≤ 1.5 x ULN (except for subjects receiving anticoagulation therapy)
|
|
| E.4 | Principal exclusion criteria |
Prohibited Treatment or Therapies
1.Subject has received prior systemic chemotherapy for locally advanced unresectable or metastatic gastric or GEJ adenocarcinoma. However, subject may have received either neo-adjuvant or adjuvant chemotherapy as long as it was completed at least 6 months prior to the first dose of study treatment.
2.Subject has received radiotherapy for locally advanced unresectable or metastatic gastric or GEJ adenocarcinoma unless the radiotherapy was completed within28 days prior to start of study treatment. Subject who received palliative radiotherapy to peripheral bone metastases >=14 days prior to start of study treatment and has recovered from all acute toxicities is allowed.
3.Subject has received systemic immunosuppressive therapy, including systemic corticosteroids within 14 days prior to first dose of study treatment. Subjects using a physiologic replacement dose of hydrocortisone or its equivalent (defined as up to 30 mg per day of hydrocortisone or up to 10 mg per day of prednisone) are allowed.
4.Subject has received other investigational agents or devices within 28 days prior to first dose of study treatment.
Medical History or Concurrent Disease
5.Subject has prior severe allergic reaction or intolerance to a monoclonal antibody, including humanized or chimeric antibodies.
6.Subject has known immediate or delayed hypersensitivity, intolerance or contraindication to any component of study treatment.
7.Subject has prior severe allergic reaction or intolerance to any component of mFOLFOX6.
8.Subject has known dihydropyrimidine dehydrogenase deficiency.
9.Subject has gastric outlet syndrome or persistent/recurrent vomiting.
10.Subject with recent gastric bleeding or symptomatic subjects with proven gastric ulcers that would exclude the subject from participation per investigator judgment.
11.Subject has a known history of a positive test for human immunodeficiency virus (HIV) infection or known active hepatitis B (positive HBs Ag) or C infection. For subjects who are negative for HBs Ag, but HBc Ab positive, an HB DNA test will be performed and if positive the subject will be excluded. Subjects with positive serology but negative HCV RNA test results are eligible.
12.Subject has an active autoimmune disease that has required systemic treatment within the past 2 years.
13.Subject has active infection requiring systemic therapy that has not completely resolved within 14 days prior to start of study treatment.
14.Subject has significant cardiovascular disease, including:
-Congestive heart failure (defined as New York Heart Association Class III or IV), myocardial infarction, unstable angina, coronary angioplasty, stenting, coronary artery bypass graft, cerebrovascular accident or hypertensive crisis within 6 months prior to administration of first dose of study drug.
-History of clinically significant ventricular arrhythmias (i.e., sustained ventricular tachycardia, ventricular fibrillation or Torsades de Pointes);
-QTc interval > 450 msec
-Cardiac arrhythmias requiring anti-arrhythmic medications (Subject with rate controlled atrial fibrillation for > 1 month prior to first dose of study drugs are eligible)
15.Subject has known active central nervous system metastases and/or carcinomatous meningitis.
16.Subject has known peripheral sensory neuropathy > Grade 1 unless the absence of deep tendon reflexes is the sole neurological abnormality.
17.Subject has had a major surgical procedure and has not completely recovered within 28 days prior to the start of study treatment.
18.Subject has psychiatric illness or social situations that would preclude study compliance, per investigator judgment.
19.Subject has another malignancy for which treatment is required per investigator’s clinical judgment.
20.Subject has any concurrent disease, infection or comorbid condition that interferes with the ability of the subject to participate in the study, which places the subject at undue risk or complicates the interpretation of data in the opinion of the investigator.
|
Traitement ou thérapies interdit(e)s:
1.Antécédents de chimiothérapie systémique pour un cancer de l’estomac ou de la JOG localement avancé inopérable ou métastatique. Cependant, le (la) patient(e) peut avoir reçu une chimiothérapie néoadjuvante ou adjuvante s’il (si elle) a terminé ce traitement au moins 6 mois avant la première dose de traitement à l’étude.
2.Antécédents de radiothérapie pour un cancer de l’estomac ou de la JOG localement avancé inopérable ou métastatique dans les 28 jours précédant le début du traitement à l’étude. Les patients ayant reçu une radiothérapie palliative sur des métastases osseuses périphériques ? 14 jours avant le début du traitement à l’étude et ayant récupéré de toutes les toxicités aiguës sont autorisés à participer.
3.Antécédents de traitement immunosuppresseur systémique, y compris corticoïdes systémiques dans les 14 jours précédant la première dose de traitement à l’étude. Les patients sous traitement de substitution à dose physiologique d’hydrocortisone ou de son équivalent (définie comme jusqu’à 30 mg par jour d’hydrocortisone ou jusqu’à 10 mg par jour de prednisone) sont autorisés à participer.
4.Antécédents d’administration d’autres agents ou dispositifs à l’étude, dans les 28 jours précédant la première dose de traitement à l’étude.
Antécédents médicaux/anamnèse et maladies concomitants:
5.Antécédents de réaction allergique sévère ou d’intolérance à un anticorps monoclonal, y compris des anticorps humanisés ou chimériques.
6.Antécédents connus d’hypersensibilité immédiate ou retardée, intolérance ou contre-indication à un des composants du traitement à l’étude.
7.Antécédents de réaction allergique sévère ou d’intolérance à un des composants de mFOLFOX6.
8.Déficit connu en dihydropyrimidine déshydrogénase.
9.Sténose pylorique ou vomissements persistants/récurrents
10.Hémorragie gastrique récente ou présence de symptômes chez des patients ayant des ulcères gastriques prouvés, pouvant exclure toute participation à l’étude, d’après le jugement de l’investigateur.
11.Antécédents connus de résultat positif au dépistage de l’infection par le virus de l’immunodéficience humaine (VIH) ou présence connue d’une hépatite B active (AgHBs positif) ou d’une hépatite C active. Pour les patients ayant un résultat négatif pour l’AgHBs mais un résultat positif pour les AC anti-HBc, une analyse de l’ADN du VHB sera effectuée et si le résultat de cette analyse est positif, la participation du patient (de la patiente) ne sera pas autorisée. Les patients ayant une sérologie positive mais une analyse d’ARN du VHC négative sont éligibles.
12.Maladie auto-immune active ayant nécessité un traitement systémique dans les 2 années précédentes.
13.Infection active nécessitant un traitement systémique qui n’est pas complètement terminée dans les 14 jours précédant le début du traitement à l’étude.
14.Maladie cardiovasculaire significative, incluant :
·Insuffisance cardiaque congestive (définie comme de Classe III ou IV selon la classification de la New York Heart Association), infarctus du myocarde, angor instable, angioplastie coronaire, pose d’endoprothèses coronaires (stents), pontage coronaire, accident vasculaire cérébral ou crise hypertensive dans les 6 mois précédant l’administration de la première dose de médicament à l’étude.
·Antécédents d’arythmies ventriculaires cliniquement significatives (c’est-à-dire, tachycardie ventriculaire prolongée, fibrillation ventriculaire ou torsades de pointes).
·Intervalle QTc > 450 msec.
·Arythmies cardiaques nécessitant des médicaments anti-arythmiques (les patients ayant une fibrillation auriculaire de fréquence contrôlée depuis > 1 mois avant la première dose de médicaments à l’étude sont éligibles)
15.Présence connue de métastases actives du système nerveux central et/ou d’une méningite carcinomateuse.
16.Neuropathie sensitive périphérique connue > grade 1, sauf si l’absence de réflexes ostéo-tendineux est la seule anomalie neurologique.
17.Antécédents d’intervention chirurgicale majeure n’ayant pas totalement récupéré dans les 28 jours précédant le début du traitement à l’étude.
18.Pathologie psychiatrique ou situation sociales susceptible d’interférer sur l’observance de l’étude, d’après le jugement de l’investigateur.
19.Présence d’un autre cancer nécessitant un traitement, d’après le jugement clinique de l’investigateur.
20.Présence concomitante d’une pathologie, infection ou comorbidité interférant sur la capacité du patient (de la patiente) à participer à l’étude, présentant un risque inutile pour le patient (la patiente) ou compliquant l’interprétation des données, d’après l’avis de l’investigateur. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary endpoint is PFS, which is defined as the time from the date of randomization until the date of radiological PD (per Response Evaluation Criteria In Solid Tumors [RECIST] 1.1 by independent review committee [IRC]) or death from any cause, whichever is earliest.
|
| SSP, définie comme le temps écoulé entre la date de la randomisation et la date d’une PM radiologique (d’après l’évaluation du CEI selon les critères RECIST 1.1) ou du décès de quelque cause que ce soit, selon l’événement survenant en premier. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The primary analysis will be performed when the protocol-defined number of PFS events have been observed. |
| L'analyse primaire sera effectuée lorsque le nombre d'événements SSP défini par le protocole aura été observé. |
|
| E.5.2 | Secondary end point(s) |
The secondary endpoints are:
-OS, defined as the time from the date of randomization until the date of death from any cause
-ORR, defined as the proportion of subjects who have a best overall response (BOR) of CR or PR as assessed by IRC per RECIST 1.1
-DOR, defined as the time from the date of the first response (CR/PR) until the date of PD as assessed by IRC per RECIST 1.1 or date of death from any cause, whichever is earliest
-Safety and tolerability, as measured by AEs, laboratory test results, vital signs, electrocardiograms (ECGs) and Eastern Cooperative Oncology Group (ECOG) performance status
-HRQoL, as collected via EORTC QLQ-C30, QLQ-OG25, GP and EQ5D-5L questionnaires
-Pharmacokinetics of IMAB362, Cmax and Ctrough
-Immunogenicity of IMAB362 as measured by the frequency of anti-drug antibody (ADA) positive subjects.
The exploratory endpoints are:
-TTP, defined as the time from the date of randomization until the date of PD as assessed by IRC per RECIST 1.1.
-PFS2, defined as the time from the date of randomization until the date of PD (per investigator) following subsequent anti-cancer therapy, death from any cause or start of any other anti-cancer therapy, whichever is earliest.
-DCR, defined as the proportion of subjects who have a BOR of SD, CR or PR as assessed by IRC per RECIST 1.1.
-Potential genomic and/or other exploratory biomarkers that may be related to treatment outcome of IMAB362
-HRU |
Les critères d'évaluation secondaires:
·SG, définie comme le temps écoulé entre la date de la randomisation jusqu’à la date du décès, de quelque cause que ce soit.
·TRO, défini comme la proportion de patients ayant une meilleure réponse globale (MRG) ou une RC ou une RP, d’après l’évaluation du CEI selon les critères RECIST 1.1
·DdR, définie comme le temps écoulé entre la date de la première réponse (RC/RP) et la date d’une PM d’après l’évaluation du CEI selon les critères RECIST 1.1 ou la date du décès de quelque cause que ce soit, selon l’événement survenant en premier
·Tolérance et sécurité d’emploi, mesurées d’après les EI, les résultats des analyses biologiques, les signes vitaux, les ECG et le bilan de performances ECOG
·QdV liée à la santé (HRQoL), d’après les réponses aux questionnaires EORTC QLQ-C30, QLQ-OG25, GP et EQ5D-5L
·Pharmacocinétique de l’IMAB362, Cmax et Cmin
·Immunogénicité de l’IMAB362 d’après la mesure de la fréquence des patients ayant des anticorps anti-médicaments (AAM-positifs).
Les critères d'évaluation exploratoires:
·TAP, défini comme le temps écoulé entre la date de la randomisation jusqu’à la date de la PM d’après l’évaluation du CEI selon les critères RECIST 1.1.
·Survie sans progression 2 (SSP2), définie comme le temps écoulé entre la date de la randomisation jusqu’à la date de la PM (d’après l’évaluation de l’investigateur) après un traitement anticancéreux ultérieur, la date du décès, de quelque cause que ce soit, ou l’instauration d’un autre traitement anticancéreux, selon l’événement survenant en premier.
·TCM, défini comme la proportion de patients ayant une MRG) de maladie stable (MS), RC ou une RP, d’après l’évaluation du CEI selon les critères RECIST 1.1
·Biomarqueurs génomiques et/ou autres potentiels susceptibles d’être corrélés au résultat du traitement par IMAB362
·HRU |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| The secondary endpoint analysis will be performed at the protocol defined primary PFS analysis and at the final OS analysis after 100% of the planned death events have been observed. |
| L'analyse d'évaluation secondaire sera effectuée à l'analyse SSP primaire définie par le protocole et à l'analyse finale SG après que 100% des événements de décès prévus ont été observés. |
|
| 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 | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| 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 | Yes |
| E.6.12 | Pharmacoeconomic | Yes |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Immunogenicity |
| Immunogénicité |
|
| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| 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 | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| 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) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.3.1 | Comparator description |
| Chlorure de sodium à 0,9 % solution injectable |
| 0.9% Sodium Chloride Injection |
|
| 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 | 12 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 60 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Belgium |
| Brazil |
| Canada |
| Chile |
| China |
| Colombia |
| Costa Rica |
| France |
| Germany |
| Israel |
| Italy |
| Japan |
| Korea, Republic of |
| Mexico |
| Peru |
| Poland |
| Spain |
| Taiwan |
| United Kingdom |
| United States |
|
| 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
|
| The end of study in all participating countries is defined as the last subject's last visit, or last contact. |
| La fin des études dans tous les pays participants est définie comme la dernière visite du dernier sujet, ou dernier contact. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | 14 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 8 |
| E.8.9.2 | In all countries concerned by the trial days | 14 |
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