E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Advanced breast cancer (metastatic or locally recurrent) |
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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 | 19.0 |
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 evaluate the safety and tolerability of pertuzumab in combination with trastuzumab and a taxane. |
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E.2.2 | Secondary objectives of the trial |
To evaluate pertuzumab in combination with trastuzumab and a taxane with respect to:
•Progression-free survival (PFS)
•Overall survival (OS)
•Overall response rate (ORR)
•Clinical benefit rate (CBR)
•Duration of response
•Time to response
•Quality of life (Functional Assessment of Cancer Therapy- Breast [FACT-B] questionnaire for female patients only).
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Signed written informed consent approved by the relevant Institutional Review Board (IRB), or Independent Ethics Committee (IEC).
2. Male or female patients aged 18 years or over.
3. Histologically or cytologically confirmed and documented adenocarcinoma of the breast with metastatic or locally recurrent disease not amenable to curative resection.
4. HER2-positive (defined as either IHC 3+ or in situ hybridization [ISH] positive) as assessed by local laboratory on primary tumor and/or metastatic site if primary tumor not available (ISH positivity is defined as a ratio of 2.0 or greater for the number of HER2 gene copies to the number of signals for CEP17, or for single probe tests, a HER2 gene count greater than 4).
5. At least one measurable lesion and/or non-measurable disease evaluable according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 (Appendix 5).
6. Eastern Cooperative Oncology Group (ECOG) performance status 0, 1 or 2 (Appendix 3).
7. LVEF of at least 50%.
8. Negative serum pregnancy test in women of childbearing potential (WOCBP; premenopausal or less than 12 months of amenorrhea post-menopause, and who have not undergone surgical sterilization).
9. For WOCBP and male patients with partners of CBP who are sexually active, agreement to use a highly effective, non-hormonal form of contraception (such as surgical sterilization) or two effective forms of non-hormonal contraception (such as a barrier method of contraception in conjunction with spermicidal jelly) during and for at least 7 months post-study treatment (refer to Section 4.5.2.1 for details).
10. Life expectancy of at least 12 weeks. |
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E.4 | Principal exclusion criteria |
1. Previous systemic non-hormonal anticancer therapy for the metastatic or locally recurrent disease. Note: Prior to study entry, up to two lines of hormonal therapy for metastatic or locally recurrent disease are permitted, one of which may be in combination with Everolimus.
2. Disease-free interval from completion of adjuvant or neoadjuvant systemic non-hormonal treatment to recurrence within 6 months.
3. Previous approved or investigative anti-HER2 agents in any breast cancer treatment setting, except trastuzumab and/or lapatinib in the adjuvant or neoadjuvant setting.
4. Disease progression while receiving trastuzumab and/or lapatinib in the adjuvant or neoadjuvant setting.
5. History of persistent Grade 2 or higher (National Cancer Institute [NCI]-Common Toxicity Criteria [CTC], Version 4.0) hematological toxicity resulting from previous adjuvant or neoadjuvant therapy.
6. Patients with radiographic evidence of central nervous system (CNS) metastases as assessed by computed tomography (CT) or magnetic resonance imaging (MRI) that are not well controlled (symptomatic or requiring control with continuous corticosteroid therapy (eg dexamethasone)). Note: Patients with CNS metastases are permitted to participate in the study if they are stable in the 3 months prior to screening (as assessed by the investigator) after receiving local therapy (irradiation, surgery etc) but without anti-HER2 therapy.
7. Current peripheral neuropathy of Grade 3 or greater (NCI-CTC, Version 4.0).
8. History of other malignancy within the last 5 years prior to 1st study drug administration (dosing), except for carcinoma in situ of the cervix or basal cell carcinoma.
9. Serious uncontrolled concomitant disease that would contraindicate the use of any of the investigational drugs used in this study or that would put the patient at high risk for treatment-related complications.
10. Inadequate organ function, evidenced by the following laboratory results:
•Absolute neutrophil count <1,500 cells/mm3
•Platelet count <100,000 cells/mm3
•Hemoglobin <9 g/dL
•Total bilirubin greater than the upper limit of normal (ULN; unless the patient has documented Gilbert’s syndrome)
•Aspartate aminotransferase (AST [SGOT]) or alanine aminotransferase (ALT [SGPT]) >2.5 × ULN (> 5 × ULN in patients with liver metastases)
•Alkaline phosphatase levels > 2.5 × the ULN (> 5 × ULN in patients with liver metastases, or >10 × ULN in patients with bone metastases)
•Serum creatinine >2.0 mg/dL or 177 μmol/L
•International normalized ratio (INR) and activated partial thromboplastin time (aPTT) or partial thromboplastin time (PTT) >1.5 × ULN (unless on therapeutic anti-coagulation).
11. Uncontrolled hypertension (systolic >150 m m Hg and/or
diastolic >100 mm Hg) or clinically significant (i.e. active) cardiovascular disease: cerebrovascular accident/stroke or myocardial infarction within 6 months prior to first study medication, unstable angina, congestive heart failure (CHF) of New York Heart Association (NYHA) Grade II or higher, or serious cardiac arrhythmia requiring medication.
12. Current known infection with HIV, Hepatitis B virus, or Hepatitis C virus.
13. Dyspnea at rest due to complications of advanced malignancy, or other disease requiring continuous oxygen therapy.
14. Major surgical procedure or significant traumatic injury within 14 days prior to 1st study drug administration (dosing) or anticipation of need for major surgery during the course of study treatment. Note: Should surgery be necessary during the course of the study, patients should be allowed to recover for a minimum of 14 days prior to subsequent pertuzumab and trastuzumab treatment.
15. Receipt of intravenous antibiotics for infection within 7 days prior to enrolment.
16. Current chronic daily treatment (continuous for >3 months) with corticosteroids (dose equivalent to or greater than 10 mg/day methylprednisolone), excluding inhaled steroids.
17. Known hypersensitivity to any of the study medications or to excipients of recombinant human or humanized antibodies.
18. History of receiving any investigational treatment within 28 days prior to 1st study drug administration (dosing).
19. Assessed by the Investigator to be unable or unwilling to comply with the requirements of the protocol.
20. Concurrent participation in any interventional clinical trial. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Assessment of safety and tolerability |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
The final analysis will be done at least 60 months after the last patient has been enrolled into the study or all patients in the study have withdrawn consent, or died, or if the study is prematurely terminated by the Sponsor, whichever occurs first.
In addition to the final analysis, there will be five interim safety analyses for review by the IDMC, after approximately 100, 350, 700, 1100 and 1500 patients have been enrolled. There will also be an annual review of safety data by the IDMC following completion of enrollment. |
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E.5.2 | Secondary end point(s) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
The final analysis will be done at least 60 months after the last patient has been enrolled into the study or all patients in the study have withdrawn consent, or died, or if the study is prematurely terminated by the Sponsor, whichever occurs first.
In addition to the final analysis, there will be five interim safety analyses for review by the IDMC, after approximately 100, 350, 700, 1100 and 1500 patients have been enrolled. There will also be an annual review of safety data by the IDMC following completion of enrollment. |
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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 | No |
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 |
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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 | No |
E.8.1.1 | Randomised | No |
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 | No |
E.8.2.4 | Number of treatment arms in the trial | 1 |
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 | 6 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 231 |
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 |
Algeria |
Argentina |
Australia |
Brazil |
Canada |
China |
Ecuador |
Egypt |
European Union |
Hong Kong |
Israel |
Lebanon |
Mexico |
Morocco |
Pakistan |
Peru |
Saudi Arabia |
Serbia |
Turkey |
Ukraine |
United Arab Emirates |
Uruguay |
Venezuela, Bolivarian Republic of |
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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 is defined as at least 60 months after the last patient has been enrolled into the study or all patients in the study have withdrawn consent, or died, or if the study is prematurely 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 | 6 |
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 | 6 |
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 |