| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| HER2-positive advanced (metastatic or locally advanced) breast cancer |
|
| E.1.1.1 | Medical condition in easily understood language |
| HER2-positive advanced breast cancer |
|
| 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) |
|
| 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 |
| Investigator assessed objective overall response rates (ORR) of pertuzumab given in combination with trastuzumab together in a single infusion bag (followed by vinorelbine) and conventional sequential administration of pertuzumab and trastuzumab in separate infusion bags, followed by vinorelbine. |
|
| E.2.2 | Secondary objectives of the trial |
o Time to response
o Duration of response
o Progression free survival (PFS)
o Time to progression (TTP)
o Overall survival (OS)
o Safety and tolerability
o Quality of life (EQ-5D and FACT-B questionnaires) |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Signed written informed consent approved by the relevant Institutional Ethical Review Board (IRB).
2. Female or male patients aged 18 years or older.
3. Histologically or cytologically confirmed and documented adenocarcinoma of the breast with metastatic or locally advanced disease not amenable to curative resection.
4. HER2-positive (defined as either immunohistochemistry
[IHC] 3+ or in situ hybridization [ISH] positive) as assessed by local laboratory on primary or metastatic tumor (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 (Eisenhauer et al. 2009).
6. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.
7. Left ventricular ejection fraction (LVEF) of at least 55%.
8. Negative pregnancy test in women of childbearing potential (premenopausal or less than 12 months of amenorrhea post-menopause, and who have not undergone surgical sterilization).
9. For women of childbearing potential who are sexually active, agreement to use a highly effective, nonhormonal form of contraception or two effective forms of non-hormonal contraception during and for at least 6 months post-study treatment.
10. Fertile males willing and able to use effective nonhormonal
means of contraception (barrier method of contraception in conjunction with spermicidal jelly, or surgical sterilization) during and for at least 6 months post-study treatment.
11. Life expectancy of at least 12 weeks. |
|
| E.4 | Principal exclusion criteria |
1. Previous systemic non-hormonal anticancer therapy in the
metastatic or locally advanced breast cancer setting. (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. Previous approved or investigative anti-HER2 agents in any breast cancer treatment setting, except trastuzumab and/or
lapatinib in the adjuvant or neoadjuvant setting.
3. Disease progression while receiving trastuzumab and/or
lapatinib in the adjuvant or neoadjuvant setting.
4. Disease-free interval from completion of adjuvant or neo-adjuvant systemic non-hormonal treatment to recurrent disease of less than 6 months.
5. History of persistent Grade 2 or higher (NCI-CTC, Version
4.0) hematological toxicity resulting from previous adjuvant
or neoadjuvant therapy.
6. Patient 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 the CNS metastases are medically well controlled 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 (other than bilateral or previously diagnosed HER2-positive mBC) within the last 5 years, except for carcinoma in situ of the cervix, non-melanoma skin carcinoma, Stage 1 uterine cancer, or cancers with a similar curative outcome as those mentioned above.
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 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 × ULN (>5 × ULN in patients with liver metastases, or >10 × ULN in patients with bone metastases)
• AST (SGOT) or ALT (SGPT) >1.5 × ULN with concurrent serum alkaline phosphatase >2.5 × ULN
• 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 coagulation)
11. Uncontrolled hypertension (systolic >150 mm Hg and/or diastolic >100 mm Hg) or clinically significant (i.e. active) cardiovascular disease: including but not limited to cerebrovascular accident (CVA)/stroke or myocardial infarction within 6 months prior to first study treatment, unstable angina, congestive heart failure (CHF) of New York Heart Association (NYHA) Grade II or higher, serious cardiac arrhythmia requiring medication or other cardiovascular problem that is uncontrolled or is currently controlled with medication.
12. Current known infection with HIV, HBV, or HCV.
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 enrollment into the study 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 (IV) antibiotics for infection within 14 days prior to enrollment into the study.
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 treatments or to
excipients of recombinant human or humanized antibodies.
18. History of receiving any investigational treatment within 28 days prior to enrollment into the study.
19. Concurrent participation in any other therapeutic clinical trial.
20. Assessed by the investigator to be unable or unwilling to comply with the requirements of the protocol. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
ORR assessed by investigator according to RECIST version 1.1, based on the best (confirmed) overall response (BOR; defined as the best response recorded from the start of trial treatment until disease
progression/recurrence or death). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Analysis of the primary endpoint will be performed at the end of study for each cohort. |
|
| E.5.2 | Secondary end point(s) |
• Time to and duration (in responders)
• PFS
• TTP
• OS |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| The end of study is defined for each cohort as the time when all patients have been followed up for at least 24 months after the last patient is enrolled into the corresponding cohort unless they have been lost to follow-up, withdrawn consent, or died, or if the study is prematurely terminated by the Sponsor, whichever occurs first. Final analysis of PFS, and TTP and OS will also be performed at this time. |
|
| 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 |
| Quality of life, tolerability, optional translational research |
|
| 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 | 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 | 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) | 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.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 80 |
| 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 |
| Brazil |
| United States |
|
| 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
|
| The study will end for each cohort when all patients have been followed up for at least 24 months after the last patient is enrolled into the corresponding cohort, unless they have been lost to follow-up, withdrawn consent, or died, or if the study is prematurely terminated by the Sponsor, whichever occurs first. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 8 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| 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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