E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
advanced adenocarcinoma of the stomach, the esophagus or the gastroesophageal junction |
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E.1.1.1 | Medical condition in easily understood language |
advanced cancer of the stomach or the esophagus |
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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 | LLT |
E.1.2 | Classification code | 10066354 |
E.1.2 | Term | Adenocarcinoma of the gastroesophageal junction |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10001173 |
E.1.2 | Term | Adenocarcinoma of esophagus |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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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) |
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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 |
• Progression-free survival (PFS) • Safety and tolerability of IMAB362 in combination with EOX |
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E.2.2 | Secondary objectives of the trial |
•Survival rate at 12 months • Overall survival (OS) • Time to progression (TTP) • Objective tumor response rate (ORR) • Disease control rate (DCR) • Duration of response (DOR) |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
(1) Histologically confirmed adenocarcinoma of the stomach, the esophagus or the gastroesophageal junction (2) Inoperable locally advanced disease or resections with R2 outcome or recurrent or metastatic disease. After receiving treatment cycles 2 and 4 of this study protocol, patients will be reevaluated for resectability according to institutional guidelines. (3) CLDN18.2 expression confirmed by immunohistochemistry on paraffin embedded tumor tissue sample. Tumors with a staining intensity of 2+ or 3+(the sum is decisive) in at least 40 % of the tumor cells. (4) Measurable and/or non-measurable disease as defined according to RECISTv1.1. (5) Age ≥ 18 years. (6) Written Informed Consent Form. (7) ECOG performance status (PS) 0-1. (8) Life expectancy > 3 months. (9) HER2/neu negative patients and patients with HER2/neu positive status but not eligible to trastuzumab therapy in discretion of the investigator. (10) Adequate cardiac function. Formal measurement of left cardiac ejection fraction is ≥ 55%. (11) Adequate hepatic function; bilirubin < 1.5 x ULN, AST and ALT < 2.5 x ULN (5 x ULN if liver metastases are present). (12) Adequate renal function; creatinine < 1.5 x ULN, glomerular filtration rate (GFR) ≥51 ml/minute calculated or measured. If the calculated GFR is <51 ml/min then a measured GFR based on 24h urine is required. The measured GFR should always take precedence over the calculated GFR. (13) Adequate hematological function; absolute neutrophil count (ANC) ≥1.5x10e9/l; white blood cell (WBC) count 3.5 ≥ x10e9/l; platelets ≥ 100x10e9/l; hemoglobin (Hb) ≥ 9 g/dl (can be post-transfusion). (14) Women of childbearing potential (last menstruation less than 2 years prior to enrollment): Negative blood serum pregnancy test (β-HCG) at screening phase and using a highly effective method of contraception during the treatment phase and for 4 months after the last infusion of the study drug. (15) Male patients whose sexual partners are women of childbearing potential must use condoms during the treatment phase and for 6 months after the last infusion of the study drug. (16) The partners of the patients must also apply contraceptive methods. |
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E.4 | Principal exclusion criteria |
(1) Prior severe allergic reaction or intolerance to a monoclonal antibody, including humanized or chimeric antibodies. (2) Prior severe allergic reaction or intolerance to the chemotherapeutics used in this study or any excipient in the respective formulations. (3) Previous chemotherapy for advanced disease. (4) Previous perioperative chemotherapy with curative intention within 6 months (counted from the stop date of the perioperative chemotherapy), of start of study treatment. If interval is longer than 6 months, patients are allowed. (5) Radiotherapy within 4 weeks of start of study treatment (cycle 1, day1; 2 week interval allowed if palliative RTx given to bone metastatic side peripherally and patient recovered from acute toxicity). (6) Other investigational agents or devices concurrently or within 4 weeks prior to this study (cycle 1, day 1). (7) Known HIV infection or known symptomatic hepatitis (A, B, C). (8) Symptomatic cerebral metastases. (9) Clinically significant (i.e. active) cardiac disease. History of myocardial infarction or hospitalization for congestive heart failure within 12 months of enrollment. (10) Other clinically significant disease or co-morbidity which may adversely affect the safe delivery of treatment within this trial including, but not limited to any of the following: ongoing or active infection requiring parenteral antibiotics, uncontrolled hypertension, present cardiac arrhythmia with serious hemodynamic consequences or unstable angina pectoris. (11) Psychiatric illness or social situations that would preclude study compliance. (12) Pregnancy or breastfeeding. (13) Gastric bleeding within last 2 weeks, only symptomatic peptic ulcer. (14) Concurrent systemic immunosuppressive therapy, in particular systemic corticoids should be stopped 2 weeks prior to therapy (Cycle 1, Day 1). Inhaled and topically applied steroids are the exception and allowed. Systemic steroids should be avoided as long as patient is under study medication. Exception is otherwise uncontrollable nausea/vomiting. (15) Previous treatments with maximum cumulative doses of epirubicin >500 mg/m² and/or other anthracyclines and anthracenediones. (16) Treatment with Sorivudine or analogs. (17) Known peripheral neuropathy > Grade 1 (absence of deep tendon reflexes as the sole neurological abnormality does not render the patient ineligible). (18) Malabsorption syndrome or inability to take oral medication (administration of capecitabine by naso-gastric or jejunostomy feeding tube is permitted). (19) Known dihydropyrimidine dehydrogenase (DPD) deficiency. (20) History of interstitial lung disease (e.g. pneumonitis or pulmonary fibrosis) or evidence of interstitial lung disease on baseline chest CT scan only if clinically relevant. (21) Patients should have no evidence of dyspnea at rest. (22) Prior or current active autoimmune disease (like inflammatory bowel disease, systemic vasculitis, scleroderma, psoriasis, hemolytic anemia, immune-mediated thrombocytopenia, rheumatoid arthritis, systemic lupus erythematosus, Sjogren's syndrome, sarcoidosis or other rheumatologic disease) requiring management with immunosuppression. Asthma and chronic obstructive pulmonary disease that does not require daily systemic corticosteroids is acceptable. (23) Sinusoidal obstruction syndrome, formerly known as veno-occlusive disease (VOD), if present, should be stable or improving. |
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E.5 End points |
E.5.1 | Primary end point(s) |
PFS is defined as the time from randomization to the first observation of disease progression or death from any cause. Patients without documented progression or death will be censored as of the last tumor evaluation determining lack of progression. Safety and tolerability of IMAB362 in combination with EOX. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Imaging will be performed to determine tumor burden at the following timepoints: • Baseline: ≤9 - 1 days prior to initiation of therapy (baseline) if the last assessment is older than 4 weeks • 6-weekly intervals until week 31, meaning week 7, 13, 19, 25, 31 (day 1 ± 4 days of these weeks) • every 12 weeks thereafter, meaning week 40, 49, ff (day 1± 4 days of these weeks) • anytime in between if there is clinical indication for progression
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E.5.2 | Secondary end point(s) |
• Time to Progression is defined as the time from randomization of therapy to the first observation of confirmed disease progression. For patients who have not progressed either clinically or on the last scan, they will be censured as of the last tumor evaluation. • To determine survival status at 12 months following initiation of therapy each patient will be classified as alive or dead (irrespective of cause of death). For this purpose, upon completion of the last cycle, all patients will continue to be followed until death or loss to follow up. Patients who discontinue treatment due to progression will be followed in the same manner. • Overall survival is defined as the time from randomization to death from any cause or last contact if alive. • Objective Response Rate comprises the fraction of patients with CR, PR according to RECIST v1.1. It is set in relation to the FAS set and PP population. • Disease Control Rate is defined as the fraction of patients with CR or PR or SD according to RECIST v1.1. It is set in relation to the FAS set and PP population. • Duration of response is determined as the time when criteria for CR, PR, SD are first met until the first date that recurrent or progressive disease or death occur. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Timepoints for all imaging assessments and tumor marker level evaluation to determine CR, PR, SD or PD are: • Imaging will be performed to determine tumor burden at the following timepoints: • Baseline: ≤9 - 1 days prior to initiation of therapy (baseline) if the last assessment is older than 4 weeks • 6-weekly intervals until week 31, meaning week 7, 13, 19, 25, 31 (day 1 ± 4 days of these weeks) • every 12 weeks thereafter, meaning week 40, 49, ff (day 1± 4 days of these weeks) • anytime in between if there is clinical indication for progression Follow-up at 12 months for overall survival |
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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 | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
- Immunogenicity assessement - to explore in advance the effect size and adverse event profile of IMAB362 in combination with chemotherapy -identifications of potential predictive biomarkers |
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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 | 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) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 3 |
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 | 1 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 23 |
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 |
Bulgaria |
Czech Republic |
Germany |
Latvia |
Russian Federation |
Ukraine |
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E.8.7 | Trial has a data monitoring committee | No |
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
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 5 |
E.8.9.1 | In the Member State concerned months | 5 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 5 |
E.8.9.2 | In all countries concerned by the trial months | 5 |
E.8.9.2 | In all countries concerned by the trial days | 0 |