E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
HER2-positive advanced gastroesophageal junction/gastric cancer |
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E.1.1.1 | Medical condition in easily understood language |
HER2-positive advanced gastroesophageal junction/gastric cancer |
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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 | PT |
E.1.2 | Classification code | 10066896 |
E.1.2 | Term | HER-2 positive 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 overall survival (OS) in patients treated with pertuzumab in addition to Herceptin® (trastuzumab) plus fluoropyrimidine plus cisplatin (TFP) versus patients treated with placebo in addition to TFP
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E.2.2 | Secondary objectives of the trial |
• To compare investigator-assessed PFS, ORR, duration of objective response (DoR), and clinical benefit rate (CBR) between the two treatment arms
• To compare the safety profile between the two treatment arms
• To assess the pharmacokinetics of pertuzumab
• To compare the patient-reported outcomes (PROs) of health-related quality of life (HRQoL), GC, and treatment-related symptoms as measured by the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 scale and
its GC module, the QLQ-STO22, for patients in each treatment arm |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Disease-Specific Inclusion Criteria
1. Histologically confirmed (by enrolling center) metastatic adenocarcinoma of the stomach or GEJ
2. HER2-positive tumor defined as either IHC 3+ or IHC 2+, the latter in combination with ISH+, as assessed by a sponsor-designated central laboratory on a primary or metastatic tumor
Note: ISH positivity is defined as a ratio of ≥ 2.0 for the number of HER2 gene copies to the number of signals for chromosome 17 centromere (CEP17). For IHC scoring, the cutoffs as approved by the Food and Drug Administration (FDA) in the context of ToGA apply. Availability of formalin-fixed paraffin-embedded (FFPE)
representative tumor tissue for central confirmation of HER2 is mandatory. (See Section 4.5.1.1 for further details.)
3. Measurable or evaluable non-measurable disease as assessed by the investigator, according to RECIST v1.1; see Appendix 3.
4. Eastern Cooperative Oncology Group (ECOG) PS 0 or 1
5. Life expectancy ≥ 3 months
General Inclusion Criteria
6. Age≥ 18 years
7. Ability to comply with requirements of the protocol, as assessed by the investigator
8. Signed Informed Consent document |
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E.4 | Principal exclusion criteria |
Cancer-Related Exclusion Criteria
1. Previous systemic cytotoxic chemotherapy for advanced (metastatic) disease
2. History of exposure to the following cumulative doses of anthracyclines:
a. Epirubicin > 720 mg/m2
b. Doxorubicin or liposomal doxorubicin > 360 mg/m2
c. Mitoxantrone > 120 mg/m2 or idarubicin > 90 mg/m2
d. Other (e.g., liposomal doxorubicin or other anthracycline greater than the equivalent of 360 mg/m2 of doxorubicin)
e. If more than one anthracycline has been used, then the cumulative dose must not exceed the equivalent of 360 mg/m2 of doxorubicin.
3. Evidence of disease progression documented within 6 months after completion of prior neoadjuvant or adjuvant cytotoxic chemotherapy, or both, or radiotherapy for gastric or GEJ adenocarcinoma
4. Previous treatment with any HER2-directed therapy, at any time, for any duration
5. Previous exposure to any investigational treatment within 30 days before the first dose of study treatment
6. Radiotherapy within 30 days before the first dose of study treatment (within 2 weeks if given as palliation to bone metastases, if recovered from all toxicities)
7. History or evidence of brain metastasis
8. Clinically significant active GI bleeding (Grade ≥ 2 according to NCI CTCAE v4.03)
9. Residual toxicity resulting from previous therapy (e.g., hematologic, cardiovascular, or neurologic toxicity that is Grade ≥ 2). Alopecia is permitted.
10. Other malignancy (in addition to GC) occurring within 5 years before enrollment, except for carcinoma in situ of the uterine cervix or squamous or basal cell carcinoma of the skin that has been previously treated with curative intent Clinical Laboratory Exclusion Criteria (must be confirmed within 7 days before first dose of study treatment)
11. Absolute neutrophil count (ANC) < 1.5 × 109/L
12. Platelet count < 75 × 109/L
13. Hemoglobin < 9.0 g/dL
14. Creatinine CL< 60 mL/min (Cockcroft-Gault Formula, see Appendix 6)
15. Serum bilirubin (total) > 1.5 × upper limit of normal (ULN) of laboratory normal range; in case of known Gilbert disease a total bilirubin of up to 2 × ULN is permitted.
16. AST, ALT, and alkaline phosphatase (ALP) parameters:
a) In patients with no liver and no bone metastases
i. AST or ALT > 1.5 × ULN, and ALP > 2.5 ×ULN
ii. AST or ALT > 2.5 ×ULN
b) In patients with liver metastases and no bone metastases
i. AST or ALT > 5 × ULN, and ALP > 2.5 ×ULN
c) In patients with liver metastases and bone metastases
i. AST or ALT > 5 × ULN, and ALP > 10×ULN
d) In patients with bone metastases and no liver metastases
i. AST or ALT > 1.5 × ULN, and ALP > 10 ×ULN
17. Serum albumin < 25 g/L
18. Serum pregnancy test positive in a female patient of childbearing potential
General Exclusion Criteria
19. Documented history of congestive heart failure (CHF) of any New York Heart Association (NYHA) criteria (see Appendix 5)
20. Angina pectoris requiring treatment
21. Myocardial infarction within the past 6 months before the first dose of study treatment
22. Clinically significant valvular heart disease or uncontrollable high-risk cardiac arrhythmia (i.e., atrial tachycardia with a heart rate >100/min at rest), significant ventricular arrhythmia (ventricular tachycardia) or higher-grade atrioventricular-block
(second degree AV-block Type 2 [Mobitz 2] or third degree AV-block)
23. History or evidence of poorly controlled arterial hypertension (systolic blood pressure > 180 mmHg or diastolic blood pressure >100 mmHg)
24. Baseline LVEF value < 55%, assessed by echocardiogram [ECHO], multigated acquisition (MUGA) scan, or cardiac magnetic resonance imaging (MRI) scan
25. Dyspnea at rest due to complications of advanced malignancy or other disease or requirement of supportive oxygen therapy
26. Any significant uncontrolled intercurrent systemic illness (e.g., active infection, poorly controlled diabetes mellitus)
27. Previous major surgery within 30 days before the first dose of study treatment, unless completely recovered
28. Known infection with HIV, hepatitis B virus, or hepatitis C virus that requires active treatment
29. Ongoing chronic treatment or high-dose treatment with corticosteroids. Inhaled steroids, topical steroids and clinically indicated short courses of oral steroids are permitted.
30. Known dihydropyrimidine dehydrogenase (DPD) deficiency
31. Known hypersensitivity to any component of study treatment
32. Current use of antiviral drug sorivudine or its chemically related analogs, such as brivudine
33. Lactating female patient
34. Any patient unwilling or unable to use adequate contraceptive measures (as described in Section 5.2.3) during study treatment and for at least 7 months after the last dose of pertuzumab or trastuzumab, except for a patient with documented surgical sterilization or a postmenopausal female |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy variable, OS, is the time from the date of randomization to the date of death from any cause. For patients who are still alive on the date of clinical data cutoff for the OS analysis, the last date when the patient is known to be alive on or prior to the clinical cut-off date will be used to determine the censoring date. Patients who do not have any postbaseline data (e.g., dosing records, imaging dates, visit dates) will be censored at the date of randomization plus 1 day. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
The primary endpoint will be assessed approx. 50 months after FPI when 502 deaths will have occurred – which is expected to happen in approx. JUL2017. However, if the interim efficacy analysis (351 deaths) provided significant and meaningful treatment benefit and an acceptable safety profile can be seen, then the study could be stopped early. The interim analysis is expected to take place in approx. AUG2016 |
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E.5.2 | Secondary end point(s) |
Investigator-assessed progression-free survival (PFS), objective response rate (ORR), duration of objective response (DoR), and clinical benefit rate (CBR). |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
These will be analysed together with the primary endpoint. |
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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 | Yes |
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 |
Quality of Life, exploratory biomarker assessments |
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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 | 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.8.2.4 | 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 | 8 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 69 |
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 |
Bosnia and Herzegovina |
Brazil |
Canada |
China |
Croatia |
El Salvador |
European Union |
Guatemala |
Hong Kong |
India |
Japan |
Kazakhstan |
Korea, Republic of |
Macedonia, the former Yugoslav Republic of |
Malaysia |
Mexico |
Panama |
Peru |
Russian Federation |
Serbia |
Switzerland |
Taiwan |
Thailand |
Turkey |
Ukraine |
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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This study will end when the targeted number of events for the final analysis of OS (n = 502) is reached and the last patient who received study treatment has completed 5 years of cardiac safety follow up thereafter or when the study is terminated by the
Sponsor, whichever occurs first. |
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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 | 8 |
E.8.9.1 | In the Member State concerned months | 10 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 8 |
E.8.9.2 | In all countries concerned by the trial months | 10 |
E.8.9.2 | In all countries concerned by the trial days | 0 |