E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
HER2-positive adenocarcinoma of the stomach or gastroesophageal junction |
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E.1.1.1 | Medical condition in easily understood language |
HER2-positive advanced 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 | 14.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10066896 |
E.1.2 | Term | HER-2 positive gastric cancer |
E.1.2 | System Organ Class | 100000004864 |
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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 estimate the minimum (trough) pertuzumab concentration
(Cmin) at Day 43 for two dose levels of pertuzumab in order to
identify a dose that produces a steady-state Cmin of ≥ 20 μg/mL in 90% of patients receiving pertuzumab and trastuzumab plus chemotherapy as first-line treatment for HER2-positive inoperable locally advanced or recurrent and/or metastatic adenocarcinoma of the stomach or gastroesophageal junction
• To evaluate the safety and tolerability of two dose levels of pertuzumab in combination with trastuzumab and chemotherapy administered every 3 weeks to patients with HER2-positive inoperable locally advanced or recurrent and/or metastatic adenocarcinoma of the stomach or gastroesophageal junction |
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E.2.2 | Secondary objectives of the trial |
To make an exploratory assessment of the anti-tumor activity of pertuzumab in combination with trastuzumab and chemotherapy in patients with HER2 positive inoperable locally advanced or recurrent and/or metastatic adenocarcinoma of the stomach or gastroesophageal junction |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Disease-Specific Inclusion Criteria
• Histologically confirmed adenocarcinoma of the stomach or gastroesophageal junction with inoperable locally advanced or metastatic disease, not amenable to curative therapy. Patients with advanced disease who present with a recurrence post operatively (when intent of surgery was cure) are also eligible for entry.
• Measurable disease, according to the Response Evaluation Criteria in Solid Tumors (RECIST), v1.1, assessed using imaging techniques (CT or MRI), or non-measurable disease that can be followed
• HER2 positive tumor defined as either IHC 3+ or IHC 2+ in combination with ISH +, as assessed by central laboratory on primary or metastatic tumor ISH positivity is defined as a ratio of >= 2.0 for the number of HER2 gene copies to the number of signals for CEP17.
Availability of formalin-fixed paraffin-embedded (FFPE) tissue with at least 5 mm of invasive tumor for central confirmation of HER2 eligibility is mandatory.
• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1
• Baseline LVEF >= 55% (measured by ECHO or MUGA)
• Life expectancy of at least 3 months.
General Inclusion Criteria
• Male or female
• Age >= 18 years
• Signed informed consent
• For women of childbearing potential and male participants with partners of childbearing potential: agreement to use a highly effective non-hormonal form of contraception or two effective forms of non-hormonal contraception by the patient and/or partner (see Section 7.2.6 for details). Contraception use must continue for the duration of study treatment and for at least 6 months after the last dose of study medication. |
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E.4 | Principal exclusion criteria |
Cancer-Related Exclusion Criteria
• Previous chemotherapy for advanced or metastatic disease, except that prior adjuvant or neoadjuvant therapy is allowed if at least 6 months has elapsed between completion of adjuvant or neoadjuvant therapy and enrollment in the study. Adjuvant or neoadjuvant treatment with platinum-based therapy is not allowed.
• Lack of physical integrity of the upper gastrointestinal tract or malabsorption syndrome (e.g., patients with partial or total gastrectomy can enter the study, but not those with a jejunostomy probe)
• Active (significant or uncontrolled) gastrointestinal bleeding
• Residual relevant toxicity resulting from previous therapy (e.g., neurological toxicity of >= Grade >= 2 [NCI CTCAE]), with the exception of alopecia
• Other malignancy within the last 5 years, except for carcinoma in situ of the cervix, or basal cell carcinoma.
Exclusion Criteria Related to Hematological, Biochemical, and Organ Function
• Any of the following abnormal laboratory tests immediately prior to randomization:
Serum total bilirubin > 1.5 times the upper limit of normal (ULN) or, for patients with known Gilberts syndrome, serum total bilirubin > 2 × ULN
For patients with no liver and no bone metastases:
AST or ALT > 2.5 × ULN, and alkaline phosphatase (ALP) > 2.5 × ULN
In patients with liver metastases and no bone metastases:
AST or ALT > 5 × ULN, and ALP > 2.5 × ULN
In patients with liver metastases and bone metastases:
AST or ALT > 5 × ULN, and ALP > 10 × ULN;
In patients with bone metastases and no liver metastases:
AST or ALT > 2.5 × ULN, and ALP > 10 × ULN
Albumin < 25 g/L
Creatinine clearance < 60 mL/min
Total WBC count < 2500/μL (< 2.5 × 109/L)
Absolute neutrophil count (ANC) < 1500/μL (<1.5 × 109/L)
Platelets < 100,000/μL (<100 × 109/L).
Other Study Drug–Related Exclusion Criteria
• Serious cardiac illness or medical conditions including but not confined to:
History of documented heart failure or systolic dysfunction (LVEF < 50%)
High-risk uncontrolled arrhythmias, such as atrial tachycardia with a heart rate >= 100/min at rest, significant ventricular arrhythmia (ventricular tachycardia) or higher-grade AV block (second-degree AV block Type 2 [Mobitz II] or third-degree AV block)
Angina pectoris requiring anti-anginal medication
Clinically significant valvular heart disease
Evidence of transmural infarction on ECG
Poorly controlled hypertension (e.g., systolic blood pressure > 180 mmHg or diastolic blood pressure > 100 mmHg)
• Dyspnea at rest due to complications of advanced malignancy or other disease, or requirement for supportive oxygen therapy
• Treatment with chronic or high-dose corticosteroid therapy.
Inhaled steroids and short courses of oral steroids for anti-emesis or as an appetite stimulant are allowed.
• Clinically significant hearing abnormality
• Known dihydropyrimidine dehydrogenase deficiency.
General Exclusion Criteria
• History or clinical evidence of brain metastases
• Serious uncontrolled systemic intercurrent illness (e.g., infections or poorly controlled diabetes)
• Pregnant or lactating. Women of childbearing potential must have a negative serum pregnancy test within 7 days prior to randomization, irrespective of the method of contraception used.
• Radiotherapy within 4 weeks prior to start of study treatment, or within 2 weeks prior to start of study treatment if palliative radiotherapy is given to bone metastatic site peripherally and patient recovers from any acute toxicity
• Major surgery within 4 weeks prior to start of study treatment, without complete recovery
• Known active infection with HIV, hepatitis B virus, or hepatitis C virus
• Known hypersensitivity to any of the study drugs
• Inability to comply with follow-up testing or procedures, as determined by the investigator. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Minimum (trough) serum concentration (Cmin) for pertuzumab |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
This study is not designed or powered to provide an accurate evaluation of efficacy. Thus, efficacy analyses are exploratory and no comparisons between dose levels will be made. Investigator-assessed tumor response will be used to summarize best overall response at the end of Cycles 3 and 6 for each treatment arm, defined as patients with a complete or partial response as determined by RECIST. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | No |
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 | 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 | 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 | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
Two different dosing schemes of pertuzumab will be compared to each other |
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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
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 20 |
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 |
European Union |
Korea, Republic of |
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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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The end of study will be when progressive disease has occurred in all patients and the last patient has completed cardiac safety follow-up thereafter, or all patients have died,
withdrawn, or discontinued from the study, whichever is earlier. |
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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 | 4 |
E.8.9.1 | In the Member State concerned months | 7 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 7 |
E.8.9.2 | In all countries concerned by the trial days | 0 |