| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| HER2 positive metastatic breast cancer |
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| E.1.1.1 | Medical condition in easily understood language |
| HER2 positive metastatic breast 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 | 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) based on tumor assessments by an independent review facility (IRF) between patients in the two treatment arms. |
|
| E.2.2 | Secondary objectives of the trial |
• To compare overall survival (OS) between the two treatment arms
• To compare PFS between the two treatment arms based upon investigator assessment of progression
• To compare the overall objective response rate between the two treatment arms
• To compare the duration of objective response between the two treatment arms
• To compare the safety profile between the two treatment arms (including crossover patients and those no longer receiving placebo)
• To compare time to symptom progression, as assessed by the FACT Trial Outcome Index - Physical Functional Breast (TOI-PFB)
• To evaluate if biomarkers from tumor tissues or blood samples (e.g., HER3 expression, Fc gamma, and serum ECD/HER2 and/or HER ligands concentrations) correlate with clinical outcomes
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| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
1. DNA REPOSITORY SUBSTUDY IN ASSOCIATION WITH PERTUZUMAB STUDY TOC4129g/WO20698. Protcocol no. TOC4129g/WO20698 (Substudy 1), dated 7-Sep-07.
The primary objective of this study is to perform exploratory analyses to generate hypotheses identifying genes associated with treatment response, toxicity, or disease risk. If such genetic hypotheses are identified, they may be tested in future clinical studies within this therapeutic area. This study is optional and a separate Informed Consent will be required.
2. A SUBSTUDY IN ASSOCIATION WITH PERTUZUMAB PROTOCOL TOC4129g/WO20698 TO EVALUATE CORRECTED QT INTERVAL, PHARMACOKINETICS, AND DRUG-DRUG INTERACTION. Protocol no. TOC4129g/WO20698 (Substudy 2), version B dated 6-Mar-08.
The objectives of this substudy are the following:
-To characterize the pharmacokinetics of pertuzumab in patients with HER2-positive MBC and to compare these data with PK data from other clinical studies.
-To Characterize of the potential of a drug-drug interaction of pertuzumab on the pharmacokinetics of docetaxel in the presence of trastuzumab and on the
pharmacokinetics of trastuzumab in the presence of docetaxel.
-To describe the effect of pertuzumab on the change from baseline in QTc interval using both Fridericia’s correction (QTcF) and Bazett’s correction (QTcB).
-To describe the proportion of patients with QTc interval prolongation and change from baseline in QTc interval using both correction formulaes.
-To describe the effect of pertuzumab on the ECG parameters of heart rate, QT interval, PR interval, and QRS Duration. |
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| E.3 | Principal inclusion criteria |
Disease specific inclusion criteria:
1. Histologically or cytologically confirmed adenocarcinoma of the breast with locally recurrent or metastatic disease, and candidate for chemotherapy. Patients with measurable and/or non-measurable disease are eligible.
Patients with only bone metastases are eligible provided that they have some bone metastases that have not been previously irradiated and tumor tissue samples from the primary tumor are available for central HER 2 testing and subsequent biomarkers analysis.
Locally recurrent disease must not be amenable to resection with curative intent.
Note: Patients with de novo Stage IV disease are eligible.
2. HER2-positive (defined as 3+ IHC or FISH amplification ratio ≥ 2.0 ) MBC confirmed by a Sponsor-designated central laboratory. It is recommended that a formalin-fixed paraffin-embedded (FFPE) tissue block from the primary tumor (or metastatic if the primary is not available) be submitted for central laboratory confirmation of HER2 eligibility; however, if that is not possible, 25 unstained and freshly cut slides will be submitted. (Tissue will subsequently be used for assessment of biomarkers.)
General inclusion criteria:
3. Age ≥ 18 years
4. Left Ventricular Ejection Fraction (LVEF) >= 50% at baseline (within 42 days of randomization) as determined by either 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) (see Section 7.4.2 of the protocol). All pre-study LVEF values during and post-trastuzumab adjuvant treatment for patients who received such adjuvant therapy prior to enrollment into the study will be collected.
5. Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1
6. For women of childbearing potential and men 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. Contraception use must continue for the duration of study treatment and for at least 7 months after the last dose of study treatment. Male patients whose partners are pregnant should use condoms for the duration of the pregnancy. For further details see Section 7.2.6.
7. Signed, written informed consent (approved by the Institutional Review Board or Independent Ethics Committee) obtained prior to any study procedure.
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|
| E.4 | Principal exclusion criteria |
Cancer Related Exclusion Criteria:
1. History of anticancer therapy for MBC (with the exception of one prior hormonal regimen for MBC which must be stopped prior to randomization). Anticancer therapy for MBC includes any EGFR or anti-HER2 agents or vaccines, cytotoxic chemotherapy, or more than one prior hormonal regimen for MBC. One prior hormonal “regimen” for MBC may include more than one hormonal therapy, for example, if the switch is not related to disease progression, such as toxicity or local standard practice, this will be counted as one “regimen”. If a patient receives hormonal therapy for MBC and is switched to a different hormonal therapy due to disease progression, this will be counted as two “regimens” and the patient is not eligible.
2. History of approved or investigative tyrosine kinase/HER inhibitors for breast cancer in any treatment setting, except trastuzumab used in the neoadjuvant or adjuvant setting
3. History of systemic breast cancer treatment in the neo-adjuvant or adjuvant setting with a disease-free interval from completion of the systemic treatment (excluding hormonal therapy) to metastatic diagnosis of < 12 months
4. History of persistent Grade ≥ 2 hematologic toxicity resulting from previous adjuvant therapy
5. Current peripheral neuropathy of NCI-CTCAE, Version 3.0, Grade ≥ 3 at randomization
6. History of other malignancy within the last 5 years, except for carcinoma in situ of the cervix or basal cell carcinoma or squamous cell carcinoma of the skin that has been previously treated with curative intent.
7. Current clinical or radiographic evidence of central nervous system (CNS) metastases. CT or MRI scan of the brain is mandatory (within 28 days of randomization) in cases of clinical suspicion of brain metastases.
8. History of exposure to the following cumulative doses of anthracyclines:
•doxorubicin or liposomal doxorubicin > 360 mg/m2
•epirubicin > 720 mg/m2
•mitoxantrone > 120 mg/m2 and idarubicin > 90 mg/m2
•Other (e.g., liposomal doxorubicin or other anthracycline > the equivalent of 360 mg/m2 of doxorubicin)
•If more than 1 anthracycline has been used, then the cumulative dose must not exceed the equivalent of 360 mg/m2 of doxorubicin.
Hematological, Biochemical, and Organ Function
9. Current uncontrolled hypertension (systolic > 150 mmHg and/or diastolic > 100 mmHg) or unstable angina
10. History of CHF of any New York Heart Association (NYHA) criteria, or serious cardiac arrhythmia requiring treatment (exception, atrial fibrillation, paroxysmal supraventricular tachycardia)
11. History of myocardial infarction within 6 months of randomization
12. History of LVEF decline to below 50% during or after prior trastuzumab neo-adjuvant or adjuvant therapy
13. Current dyspnea at rest due to complications of advanced malignancy, or other diseases that require continuous oxygen therapy
General Exclusion Criteria
14. Inadequate organ function, evidenced by the following laboratory results within 28 days prior to randomization:
•Absolute neutrophil count < 1,500 cells/mm3
•Platelet count < 100,000 cells/mm3
•Hemoglobin < 9 g/dL
•Total bilirubin > upper limit of normal (ULN) (unless the patient has documented Gilbert’s syndrome)
•SGOT (AST) and SGPT (ALT) > 2.5 x ULN
•SGOT (AST) or SGPT (ALT) > 1.5 x ULN with concurrent serum alkaline phosphatase > 2.5 x ULN Serum alkaline phosphatase may be > 2.5 × ULN only if bone metastases are present and AST (SGOT) and ALT (SGPT) < 1.5 × ULN.
•Serum creatinine > 2.0 mg/dL or 177 μmol/L
•International normalized ratio (INR) and activated partial thromboplastin time or partial thromboplastin time (aPTT or PTT) > 1.5 x ULN (unless on therapeutic coagulation)
15. Current severe, uncontrolled systemic disease (e.g., clinically significant cardiovascular, pulmonary, or metabolic disease; wound healing disorders; ulcers; or bone fractures)
16. Major surgical procedure or significant traumatic injury within 28 days prior to study treatment start or anticipation of the need for major surgery during the course of study treatment
17. Pregnant or lactating women
18. History of receiving any investigational treatment within 28 days of randomization
19. Current known infection with HIV, HBV, or HCV
20. Receipt of IV antibiotics for infection within 14 days of 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
23. Assessed by the investigator to be unable or unwilling to comply with the requirements of the protocol
24. Concurrent Interventional or Non–Interventional Studies (NIS) are not permitted. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Progression-free survival (PFS) based on Independent Review Facility (IRF) evaluations. PFS is defined as the time from randomization to the first documented progressive disease, as determined by the IRF using RECIST (Therasse et al. 2000), or death from any cause, whichever occurs first. Assessments will be based on review of radiographic (e.g., MRI, CT, bone scans, chest x-ray, etc.), as well as cytologic (e.g., relevant cytology reports documenting malignant pleural effusions, bone marrow aspirations, cerebral spinal fluid, etc.), and photographic data, if available, generated from all patients. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The primary analysis of the primary endpoint will take place when approximately 381 IRF-assessed PFS events have occurred. |
|
| E.5.2 | Secondary end point(s) |
-Overall survival: OS is defined as the time from the date of randomization to the date of death from any cause.
-PFS based on investigator assessment: PFS based on investigator assessment is defined as the time from randomization to the first documented radiographic progressive disease, as determined by the investigator using current RECIST (Therasse et al. 2000), or death from any cause, whichever comes first. Carcinomatous meningitis diagnosed by cytologic evaluation of cerebral spinal fluid will also define progressive disease. Medical photography will also be allowed to monitor chest wall recurrences of subcutaneous lesions.
-Objective response: Objective response is defined as a CR or PR determined by the IRF using current RECIST (Therasse et al. 2000) on two consecutive occasions >= 4 weeks apart. Patients with disease localized only to the bone will not be included in the analysis of objective response.
-Duration of response: Duration of response is defined as the period from the date of initial confirmed PR or CR until the date of progressive disease or death from any cause. Tumor responses will be based on the IRF evaluations using current RECIST (Therasse et al. 2000).
-Time to symptom progression: This is defined as the time from randomization to the first symptom progression in the FACT TOI-PFB. The TOI-PFB is a 24-item subscale generated using 3 subsections from the FACT-B questionnaire: Physical Well-being, Functional Well-being and Additional Concerns. A decrease of five points is considered clinically significant, and thus symptom progression.
-Biomarker analysis: The relationship between molecular markers and efficacy outcomes will be evaluated
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Once there have been 385 deaths |
|
| 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 | 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 | Yes |
| E.6.12 | Pharmacoeconomic | Yes |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Evaluation of biomarkers, Quality of Life |
|
| 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.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 64 |
| 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 |
| Argentina |
| Brazil |
| Canada |
| China |
| Costa Rica |
| Croatia |
| Ecuador |
| European Union |
| Guatemala |
| Hong Kong |
| Japan |
| Korea, Republic of |
| Macedonia, the former Yugoslav Republic of |
| Mexico |
| Philippines |
| Russian Federation |
| Singapore |
| Thailand |
| 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
|
| In May 2012, the second interim analysis of OS met statistical significance, and as of February 2014, 385 deaths had been reported. To allow for longer-term follow-up of safety and survival for all patients, the end of study will now occur 3 years after the last patient’s Treatment Discontinuation Visit (or study termination by Genentech and Roche, whichever occurs sooner). After this time, patients will no longer be followed, and no further data will be collected. |
|
| 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 | 1 |
| 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 | 1 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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