E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Metastatic HER2-positive adenocarcinoma of the stomach or gastro-esophageal junction. |
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E.1.1.1 | Medical condition in easily understood language |
Metastatic HER2-positive adenocarcinoma of the stomach or gastro-esophageal junction. |
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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 | 14.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10071114 |
E.1.2 | Term | Metastatic gastric adenocarcinoma |
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 | 14.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10063916 |
E.1.2 | Term | Metastatic gastric cancer |
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 | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To compare the duration of overall survival in patients who are randomized at enrollment to treatment with one of two trastuzumab dosing regimens (loading dose of 8mg/kg) followed by either 6mg/kg or 10mg/kg maintenance doses given every 3 weeks, plus cisplatin and capecitabine. |
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E.2.2 | Secondary objectives of the trial |
• To compare the duration of overall survival (OS) in patients on the two trastuzumab treatment arms who are found to have trastuzumab Cmin values < 12 μg/mL on Cycle 1 Day 21.
• To assess trastuzumab concentrations during treatment Cycle 1 and trastuzumab Cmin(Day 21) values in additional treatment cycles through Cycle 11 (ie, pre-dose concentration before Cycle 12 = Cycle 11 Day 21 concentration) or until disease progression (whatever occurs first) for the two dosing regimens.
• To evaluate the safety and tolerability of trastuzumab for the two dosing regimens.
• To compare the duration of progression-free survival (PFS) and the overall objective response rate (ORR) in patients on the two trastuzumab treatment arms who are found to have trastuzumab Cmin values < 12 μg/mL on treatment Cycle 1 Day 21. |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Evaluation of the pharmacokinetics of trastuzumab administered every three weeks at two different maintenance dose levels to patients with metastatic HER2-positive gastric or gastro-esophageal junction adenocarcinoma. Protocol BO27798PK version B dated 12-Mar-2012.
Objectives of the PK sub-study:
• To characterize the serum trastuzumab concentration-vs-time (C-vs-T) profiles in the study population following the initial loading dose (8 mg/kg) at Cycle 1, and the maintenance doses (6 mg/kg or 10 mg/kg q3W) at Cycles 2 and 4.
• To evaluate the accumulation of peak and trough serum trastuzumab concentrations following selected sequential doses given every three weeks, up to the projected steady-state (refer to Section 5.1.1, Table 1).
• To describe the pharmacokinetic (PK) of trastuzumab in patients with metastatic gastric/GEJ cancer and compare to previous observations in patients with metastatic breast cancer and gastric cancer.
• To support development and refinement of an integrated population-based model for the PK disposition of trastuzumab in cancer patients, using data from multiple dosing regimens and disease types.
• To measure the HER2/Neu serum extracellular domain (ECD) concentrations pre-dose at Cycles 2, 3, 4, and 5 and to investigate the impact of HER2/Neu serum ECD on trastuzumab pharmacokinetics. |
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E.3 | Principal inclusion criteria |
1. Male or female. Age ≥ 18 years.
4. Histologically confirmed adenocarcinoma of the stomach or gastro-esophageal junction with metastatic disease documented to involve at least lung or liver or both
5. Measurable disease according to RECIST 1.1. or non-measurable evaluable disease
6. At least 2 organs involved by metastatic gastric tumor (including at least lung or liver or both) in addition to the site of the primary tumor. Metastasis in distant lymph nodes, peritoneal metastasis, malignant pleural effusion, etc. count as ‘organs’ in this
context.
7. HER2 positive (defined as either IHC3+ or IHC2+/ISH+, with ISH positivity defined as a ratio of >=2.0 of HER2 gene copy number/number of signals for CEP 17) primary or metastatic tumor, as assessed by central laboratory
8. CCR >=45 ml/min
9. ECOG PS = 2
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E.4 | Principal exclusion criteria |
1. Previous chemotherapy for locally advanced or metastatic disease
2. Prior gastrectomy
3. Prior therapy with an anti-HER2 agent and/or platinum-based chemotherapeutic agent
4. Lack of physical integrity of the upper gastrointestinal tract or malabsorption syndrome (e.g., patients with a jejunostomy probe, gastric or jejunostomy tubes) which may impair the ability to administer or absorb capecitabine, as capecitabine is an orally administered drug.
6. Residual relevant toxicity resulting from previous therapy
11. History of documented congestive heart failure; angina pectoris requiring medication; electrocardiogram (ECG) evidence of trans-mural myocardial infarction; poorly controlled hypertension (systolic blood pressure (BP) > 180 mmHg or diastolic BP>100 mm Hg); clinically significant valvular heart disease; or high risk uncontrollable arrhythmias
12. Baseline LVEF< 50%, documented by echocardiography, MUGA scan, or cardiac MRI.
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E.5 End points |
E.5.1 | Primary end point(s) |
The study primary endpoint will be OS duration in all randomized patients. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
This is event driven, when approximately 379 deaths have occurred. |
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E.5.2 | Secondary end point(s) |
The secondary endpoints will be OS in patients with Cycle 1 Cmin <12 ug/ml, Pharmacokinetic analyses , safety and tolerability in the two dosing regimens; duration of progression-free survival (PFS) and the overall objective response rate (ORR) in patients who are found to have trastuzumab Cmin values < 12 μg/mL on treatment Cycle 1 Day 21. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
This is event driven, when approximately 379 deaths have occurred. |
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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 | No |
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 |
overall survival (OS); progression-free survival (PFS) and the overall objective response rate (ORR) |
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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) | 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 | 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) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
Standard of care (cisplatin/capecitabine chemotherapy) |
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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
| Information not present in EudraCT |
E.8.4 | The trial involves multiple sites in the Member State concerned | Information not present in EudraCT |
E.8.4.1 | Number of sites anticipated in Member State concerned | 6 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 32 |
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 |
Serbia |
Australia |
Bosnia and Herzegovina |
Brazil |
Canada |
Chile |
China |
Czech Republic |
Germany |
Hungary |
Italy |
Korea, Republic of |
New Zealand |
Portugal |
Spain |
Mexico |
Panama |
Peru |
Philippines |
Poland |
Russian Federation |
South Africa |
Turkey |
Ukraine |
United Kingdom |
United States |
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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
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The end of the study will be when the targeted number of death events for the final analysis of the primary endpoint of OS (~379/400) is reached and the last patient has completed 24 months of cardiac safety follow-up from last administration of trastuzumab, or when the study is terminated by the Sponsor, whichever occurs first. Patients still receiving trastuzumab at the time of study end and who do not have PD will be provided with commercial product. |
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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 | |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 9 |
E.8.9.2 | In all countries concerned by the trial months | 1 |
E.8.9.2 | In all countries concerned by the trial days | 0 |