E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Treatment in patients with HER2-overexpressing locally advanced or metastatic breast cancer |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10027475 |
E.1.2 | Term | Metastatic breast cancer |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10065430 |
E.1.2 | Term | HER-2 positive breast cancer |
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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 characterize the safety and tolerability of the combination of T-DM1 and pertuzumab administered every 3 weeks to patients with HER2-positive locally advanced or metastatic breast cancer who have previously received trastuzumab • To evaluate the pharmacokinetics of T-DM1 when the combination of T-DM1 and pertuzumab is administered on this schedule • To make a preliminary assessment of the efficacy of the combination of T-DM1 and pertuzumab administered on this schedule, as measured by objective response rate based on investigator assessment using modified RECIST, Version 1.0 |
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E.2.2 | Secondary objectives of the trial |
• To estimate the PFS of patients who receive the combination of T-DM1 and pertuzumab administered on this schedule • To assess the duration of response of the combination of T-DM1 and pertuzumab administered on this schedule • To assess the development of anti-therapeutic antibodies to T-DM1 |
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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 |
DNA Repository Substudy in assocation with trastuzumab-MCC-DM1 (T-DM1) and pertuzumab study TDM4373g/BO22495-A2 dated 23 February 2010. [Note, this substudy is not considered a "clinical trial" as defined by the EU Clinical Trial Directive].
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E.3 | Principal inclusion criteria |
• Signed Informed Consent Form • Age ≥ 18 years • Eastern Cooperative Oncology Group (ECOG) Performance Status 0−2 • Histologically documented breast cancer • Locally advanced or metastatic breast cancer For the purposes of this study, locally advanced breast cancer is defined as unresectable local or regional disease. • HER2-positive breast cancer documented as fluorescence in situ hybridization (FISH)-positive, immunohistochemistry (IHC) 3 + or chromogenic in situ hybridization (CISH)-positive by local laboratory assessment • Confirmed availability (prior to Day 1) of tumor tissue blocks or 15−20 unstained tissue slides at screening for confirmatory central laboratory HER2 status testing and other exploratory assessments. Tissue specimens must be submitted within 60 days after the first dose of study drug. • Second or later line patients must have relapsed following or progressed on HER2-directed therapy. • No prior T-DM1 or pertuzumab therapy • Measurable disease, defined as at least one lesion ≥ 2 cm on computed tomography (CT) scan or ≥ 1 cm on spiral CT scan • Cardiac ejection fraction ≥ 55% by either ECHO or MUGA scan. • Adequate hematologic and end organ function, defined by the following laboratory results obtained within 14 days prior to study enrollment (defined as the day the patient is assigned a subject number [not a screening number] via IVRS): Absolute neutrophil count ≥ 1500 cells/mm3 Platelet count ≥ 100,000 cells/mm3 Hemoglobin ≥ 9.0 g/dL Total bilirubin ≤ 1.5 × ULN SGOT (AST) and SGPT (ALT) ≤ 2.5 × ULN, with the following exception: Patients with documented liver metastases: AST and/or ALT ≤ 5 × ULN Serum creatinine ≤ 1.5 mg/dL, or creatinine clearance ≥ 50 mL/min based on Cockroft-Gault glomerular filtration rate (GFR) estimation: (140 − age) × (weight in kg) × (0.85 if female)/72 × serum creatinine • For women of childbearing potential and men with partners of childbearing potential, agreement to use a highly effective form of non-hormonal contraception or two effective forms of non-hormonal contraception by the patient and/or partner, and to continue the use of contraception for the duration of study treatment and for at least 6 months after the last dose of study treatment. Male patients whose partners are pregnant should use condoms for the duration of the pregnancy. • Life expectancy ≥ 90 days as assessed by the investigator |
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E.4 | Principal exclusion criteria |
• Less than 21 days since the last anti-tumor therapy, including chemotherapy, biologic, experimental, immune, hormonal or radiotherapy for the treatment of breast cancer, with the following exceptions: - Hormone-replacement therapy or oral contraceptives are allowed - Palliative radiation therapy involving ≤ 25% of marrow-bearing bone is allowed if administered ≥ 14 days prior to first study treatment • History of intolerance or hypersensitivity to trastuzumab and/or adverse events related to trastuzumab, murine proteins, or any of the excipients that resulted in trastuzumab being permanently discontinued • Peripheral neuropathy of Grade ≥ 2 per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), Version 3.0, at the time of, or within 3 weeks prior to, the first study therapy • History of exposure to the cumulative doses of anthracyclines listed below. If another anthracycline or more than one anthracycline has been used, then the cumulative dose must not exceed the equivalent of 500 mg/m2 of doxorubicin, using the conversion factors provide in appendix F. The medical monitor should be consulted if there are questions. - Doxorubicin > 500 mg/m2 (or the equivalent dose of another anthracycline) - Liposomal doxorubicin > 900 mg/m2 - Epirubicin > 720 mg/m2 • History of clinically significant cardiac dysfunction, including: - Current uncontrolled hypertension (systolic > 150 mmHg and/or diastolic > 100 mmHg), or unstable angina - History of symptomatic CHF (Grade > 3 by NCI CTCAE or Class > II by New York Heart Association [NYHA] criteria, or serious cardiac arrhythmia requiring treatment, with the exceptions of atrial fibrillation and paroxysmal supraventricular tachycardia - History of myocardial infarction within 6 months prior to first study treatment • Current known active infection with HIV, hepatitis B virus, or hepatitis C virus • Pregnancy or lactation • Current severe, uncontrolled systemic disease (e.g., clinically significant cardiovascular, pulmonary, or metabolic disease) • Patients with severe dyspnea at rest, due to complications of advanced malignancy, or requiring supplementary oxygen therapy are also excluded. • Major surgical procedure or significant traumatic injury within 28 days prior to first study treatment, or anticipation of the need for major surgery during the course of study treatment. • Symptomatic hypercalcemia requiring use of bisphosphonate therapy at the time of, or within 21 days of, the first study treatment Patients who are receiving bisphosphonate therapy specifically for painful bony metastases or to prevent skeletal events and who do not have a history of clinically significant hypercalcemia are eligible. • Brain metastases that: Are untreated, or Are progressive, or Have required any type of therapy (including radiation, surgery, or steroids) to control symptoms from brain metastases within 60 days of the first study treatment. • History of other malignancy within the last 5 years, except for appropriately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, or other malignancy with a similar expected curative outcome. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Phase Ib - Safety of co-administration of TDM-1 + pertuzumab
Phase II - Investigator assessed objective response, defined as a complete or partial response determined on two consecutive occasions ≥4 weeks apart. The primary analysis for efficacy and safety will be conducted around 1 year after the completion of patient enrollment or at study termination, whichever happens first.
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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 | Yes |
E.6.7 | Pharmacodynamic | Yes |
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) | Yes |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | Yes |
E.7.1.3.1 | Other trial type description |
Phase Ib dose finding investigation for T-DM1, followed by a phase II exploratory study. |
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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 | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | No |
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.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
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 | Information not present in EudraCT |
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 |
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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 trial is defined as the timepoint when the last patient enrolled has received upto 1 year of treatment. It is envisaged that data supporting the endpoints of the study (including long-term safety and preliminary efficacy) will be available after a minimum of 6 months of clinical trial treatment. Therefore, in order to achieve this, the end of the trial has been defined as one year after the last patient has received 1 year of trial treatment.
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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 | 2 |
E.8.9.1 | In the Member State concerned months | 4 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 4 |