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 in any line of therapy, have received chemotherapy combined with HER2-targeted therapy for advanced disease, and have progressed while receiving their most recent therapy • 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 dated 09 December 2008. [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 that has progressed on the patient’s most recent prior regimen - For the purposes of this study, locally advanced breast cancer is defined as unresectable local or regional disease that has previously been treated with radiation therapy, chemotherapy, and HER2-directed therapy. • 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 • Tumor tissue blocks or 15−20 unstained tissue slides for confirmatory central laboratory HER2 status testing and other exploratory assessments • Prior trastuzumab in any line of therapy • Prior chemotherapy combined with HER2-targeted therapy for locally advanced or metastatic disease • 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 first study treatment: - Absolute neutrophil count ≥ 1500 cells/mm3 - Platelet count ≥ 100,000 cells/mm3 - Hemoglobin ≥ 9.0 g/dL - Albumin ≥ 2.5 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, agreement to use an effective form of contraception (patient and/or partner [e.g., surgical sterilization, a reliable barrier method, birth control pills, or contraceptive hormone implants]), and to continue its use for the duration of the study • Life expectancy ≥ 90 days |
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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 - Palliative radiation therapy involving ≥ 25% of marrow-bearing bone within 14 days prior to first study treatment • History of intolerance or hypersensitivity to trastuzumab and/or adverse events related to trastuzumab 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 following cumulative doses of anthracyclines: - Doxorubicin > 500 mg/m2 (or the relevant 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 dyspnea at rest due to complications of advanced malignancy, or other diseases that require continuous oxygen therapy • 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) • 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 to prevent skeletal events and who do not have a history of clinically significant hypercalcemia are eligible. • Brain metastases that are either: - Untreated or - Require 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, basal cell carcinoma, or synchronous or subsequent HER2-positive breast cancer 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.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 5 |
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.
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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 |