| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
HER2 positive metastatic breast cancer which has progressed after one line of trastuzumab-based therapy in the metastatic setting
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| E.1.1.1 | Medical condition in easily understood language |
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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 | 16.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10065430 |
| E.1.2 | Term | HER-2 positive breast 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 progression-free survival (PFS) between the two treatment arms based on assessments by an independent review facility (IRF).
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| E.2.2 | Secondary objectives of the trial |
To evaluate:
-Overall survival (OS)
-OS based on a 2-year truncated analysis
-PFS based on tumor assessments by the Investigators
-Time to progression (TTP) based on IRF assessment
-Time to treatment failure (TTF) based on IRF assessment
-Overall objective response rate (ORR) clinical benefit rate (CBR), based on Investigator and IRF assessments
-Duration of objective response (DR) based on IRF assessment
-Safety and tolerability of trastuzumab plus capecitabine in combination with pertuzumab
-Correlation between biomarkers from tumor tissues and clinical outcomes
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Disease-Specific:
1. Pathologically confirmed breast cancer and documented metastatic disease.
2. HER2-positive (FISH/CISH-positive and/or IHC 3+) MBC confirmed by a Sponsor-designated central laboratory. It is recommended that a formalin-fixed paraffin embedded (FFPE) tumor tissue block from the primary tumor (and/or metastatic site, if primary tumor not available) or a minimum of 6 unstained and freshly cut slides required for HER2 testing are provided. For subsequent biomarker investigations only in consenting patients, it is advised that a maximum of 25 slides from the tumor tissue material will be provided.
3. Disease progression during or following a trastuzumab-based treatment for first-line metastatic breast cancer.
4. Trastuzumab must have been part of the last prior treatment regimen.
5. Prior treatment with a taxane-containing regimen.
General:
6. Female patients, age ≥18 years.
7. LVEF ≥ 50% at baseline (assessed within 42 days prior to randomization) as determined by either 2D echocardiogram (ECHO) or MUGA (ECHO is the preferred method). If the patient is randomized, the same method of LVEF assessment, ECHO or MUGA, must be used throughout the study, and to the extent possible, be obtained at the same institution.
8. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.
9. For women of childbearing potential, agreement to use highly effective non-hormonal form of contraception or two effective forms of non-hormonal contraception by the patient and/or partner. Contraception use must continue for the duration of study treatment and for at least 6 months after the last dose of study treatment.
10. Written and signed informed consent (approved by the Independent Ethics Committee) obtained prior to beginning any protocol-specific procedures.
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| E.4 | Principal exclusion criteria |
Cancer-Related:
1. Prior therapy with pertuzumab or capecitabine.
2. Concurrent immunotherapy or anticancer hormonal therapy.
3. Existing acute reversible effects of prior treatment. This generally means at least 3 weeks should have elapsed since prior chemotherapy and at least 4 weeks since prior (radical) radiotherapy or major surgery with full recovery.
4. History of another malignancy which could affect compliance with the protocol or interpretation of results. Patients treated with curative intent who have been disease-free for at least 5 years are generally eligible, as are patients treated curatively for carcinoma in situ of the cervix or non-melanomatous skin cancer.
5. CNS metastases which are not well controlled. Eligible patients must be asymptomatic, can not be receiving steroids or anticancer treatment, and must be enrolled at least 1 month after the end of the radiotherapy treatment. Note: CT or MRI scan of the brain is mandatory (within 4 weeks prior to randomization) in case of clinical suspicion of CNS metastases.
6. History of exposure to at least one of the following cumulative doses of anthracyclines
Hematological, Biochemical and Organ Function:
7. Current uncontrolled hypertension (systolic > 150 mm Hg and/or diastolic > 100 mmHg) or unstable angina.
8. History of CHF of any New York Heart Association (NYHA) criteria, or serious cardiac arrhythmia requiring treatment (except for atrial fibrillation and/or paroxysmal supraventricular tachycardia).
9. History of myocardial infarction within 6 months prior to randomization.
10. History of LVEF decline to below 50% during or after prior trastuzumab therapy or other cardiac toxicity during previous trastuzumab treatment that necessitated discontinuation of trastuzumab.
11. Current dyspnoea at rest requiring supportive oxygen therapy or with significant pleural effusions.
General Exclusion Criteria
12. Inadequate organ function, evidenced by the following laboratory results within 28 days prior to randomization.
13. Current severe, uncontrolled systemic disease (e.g. clinical significant cardiovascular, pulmonary, or metabolic disease; wound healing disorders; ulcers; or bone fractures).
14. Evidence of any other disease, metabolic or psychological dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug, or that may affect patient compliance with study routines, or place the patient at high risk from treatment complications.
15. Patients with insulin-dependent diabetes
16. Major surgical procedure or significant traumatic injury within 28 days prior to study treatment start without full recovery, or anticipation of the need for major surgery during the course of study treatment.
17. Pregnant or lactating females.
18. Concurrent treatment with other experimental drugs. Participation in another clinical trial with any investigational drug within 30 days prior to randomization.
19. Current known infection with HIV, HBV, or HCV (active infection or carriers).
20. Active infection requiring antibiotics within 14 days prior to randomization.
21. Current chronic daily treatment with corticosteroids (dose of >10 mg/day methylprednisolone equivalent) (excluding inhaled steroids).
22. Known hypersensitivity to any of the study drugs. History of severe and unexpected reactions to fluoropyrimidine therapy.
23. Malabsorption syndrome, disease significantly affecting gastrointestinal function, resection of the stomach or small bowel, or ulcerative colitis.
24. Psychiatric disability judged by the Investigator to be interfering with compliance for oral drug intake.
25. Known deficiency or family history of deficiency of dihydropyrimidine dehydrogenase.
26. Requirement for concurrent use of the antiviral agent sorivudine (antiviral) or chemically related analogues, such as brivudine.
27. Life expectancy <12 weeks.
28. Inaccessible for treatment and/or follow-up or unwilling to comply with the requirements of the protocol.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint is PFS based on IRF evaluation. PFS is defined as the time from randomization to the first documented progressive disease (PD) as determined by IRF using RECIST version 1.0, or death from any cause, whichever occurs first. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| After approximately 337 IRF-assessed PFS events have been observed. For patients with no IRF-assessed events, surrogating death at any time as a progressive event can artificially prolong the PFS time because of a much longer life expectancy in this patient population compared with PFS. Therefore data for patients who do not have documented progressive disease or who have not died within 18 weeks of the last tumor assessment will be censored at the time of the last IRF-evaluable tumor assessment (or at the date of randomization plus 1 day for patients with no tumor assessments performed after the baseline visit). |
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| E.5.2 | Secondary end point(s) |
-Overall survival (OS) as key secondary efficacy variable
-OS based on a 2-year truncated analysis
-PFS based on Investigator assessments
-Time to Progression (TTP)
-Time to treatment failure (TTF)
-Objective response rate (ORR)
-Clinical Benefit Rate (CBR)
-Duration of objective response (DR)
-Safety and tolerability of trastuzumab plus capecitabine in combination with pertuzumab
-Correlation between biomarkers from tumour tissues and clinical outcomes
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
-Overall survival (OS): An interim analysis of OS will be performed at the time of the analysis of the primary endpoint. The event-driven final OS analysis will take place at the end of study when 67% of patients have died or withdrawn from survival follow up.
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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 | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| 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 |
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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 | Yes |
| E.8.1.6 | Cross over | Yes |
| 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 | 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 | 111 |
| 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 |
| Canada |
| Croatia |
| European Union |
| Argentina |
| Brazil |
| Hong Kong |
| Korea, Republic of |
| Thailand |
| Mexico |
| Peru |
| Russian Federation |
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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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| See protocol section 3.1.2 |
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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 | 6 |
| 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 | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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