E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Advanced HER2 breast cancer. HER2 is a member of the epidermal growth factor (EGFR) family of receptors involved in cell proliferation, tumorigenesis, and metastasis and abnormally expressed in multiple tumor types. EGFR may also be over-expressed in breast cancer, play a role in tumorigenesis, and also confers a worse prognosis. Coexpression of EGFR family (HER1, 2 and 3) has been associated with a negative synergistic effect on 15-year disease specific survival of breast cancer patients. |
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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 | 10055113 |
E.1.2 | Term | Breast cancer metastatic |
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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 |
Primary objectives:
Part 1: To assess the safety and tolerability, and to define the MTD of orally administered HKI-272 in combination with trastuzumab in subjects with advanced breast cancer. Part 2: To determine the 16 week progression free survival (PFS) rate for subjects with advanced breast cancer treated at the MTD with HKI-272 and trastuzumab.
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E.2.2 | Secondary objectives of the trial |
Secondary objectives:
Part 1: To obtain additional safety information and to assess the preliminary antitumour activity. Part 2: To obtain safety and PK information and assess additional efficacy parameters including objective response rate (ORR), clinical benefit rate (CR+PR+SD >/= 24 weeks), progression free survival (PFS) and duration of response of HKI-272 in combination with trastuzumab. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Women aged >= 18 years. 2. Pathologic diagnosis of advanced or metastatic breast cancer (stage IIIB, IIIC or IV) not curable by available therapy. 3. Progression following at least 1 trastuzumab-containing cytotoxic chemotherapy regimen for localy advanced or metastatic disease (Progression on or following adjuvant trastuzumab without an additional trastuzumab-chemotherapy regimen does not meet this criteria). 4. HER2 positive tumor (documented by either FISH+, or IHC 3+). Prior documentation is acceptable, otherwise tumor tissue must be available and adequate for this analysis prior to study day 1. 5. At least one measurable lesion as defined by modified RECIST criteria. 6. ECOG 0 to 2/Karnofsky performance status >= 70. 7. LVEF within institutional limits of normal (by MUGA or ECHO). 8. Screening laboratory values within the following parameters: - ANC: >= 1.5 x 10^9/L (1,500/mm^3) - Platelet count: >= 75 x 10^9/L (75,000/mm^3) - Hemoglobin: >= 9.0 g/dL (90g/L) - Serum creatinine: <= 1.5 x upper limit of normal (ULN) - Total bilirubin: <= 1.5 x ULN - AST and ALT: <= 2.5 x ULN (<= 5 x ULN if liver metastases are present) 9. For women of child bearing potential, a negative serum or urine pregnancy test result before study entry. A woman of child bearing potential is one who is biologically capable of becoming pregnant. This includes women who are using contraceptves or other means of birth control or whose sexual partners are either sterile or using contraceptives. 10. All subjects who are not surgically sterile or postmenopausal must agree and commit to the use of a reliable method of birth contol for the duration of the study and for 28 days after the last dose of the test article. |
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E.4 | Principal exclusion criteria |
1. More than 3 cytotoxic chemotherapy treatment regimens for locally advanced or metastatic disease. 2. Major surgery, chemotherapy, radiotherapy, investigational agents, trastuzumab or other cancer therapy within 2 weeks of treatment day 1. 3. Subjects with bone and/or skin as the only site of disease. 4. Extensive visceral disease including bilateral diffuse lymphangitic involvement of the lung with more than 50% lung involvement or extensive hepatic involvement defined as involvement of more than 1/3 of the liver confirmed by CT scan and/or MRI. 5. History of inflammatory breast cancer (IBC). 6. Active central nervous system (CNS) metastases, as indicated by clinical symptoms, cerebral edema, and/or progresive growth (subjects with a history of CNS metastases or cord impression are allowable if they have been definitively treated and are clinically stable, and off steroids and/or anticonvulsants, for at least 4 weeks before first dose of test article). 7. Prior treatment with anthracyclines with a cumulative dose of doxorubicin of >400mg/m^2 or the equivalent dose for other anthracyclines or derivatives. 8. Presence of clinically significant or uncontrolled cardiac disease, including congestive heart failure (New York Heart Association [NYHA] functional classification of >= 2), angina requiring treatment, myocardial infarction within the past 12 months, or any clinically significant supraventricular arrhythmia or ventricular arrhythmia requiring treatment or intervention. 9. QTc interval > 0.47 second. 10. Known hypersensitivity or intolerance to trastuzumab. 11. Pregnant or breast-feeding women. 12. Significant chronic or recent acute gastrointestinal disorder with diarrhea as a major symptom (e.g, Crohn's disease, malabsorption, or Grade 2 or greater diarrhea of any etiology at baseline). 13. Inability or unwillingness to swallow the HKI-272 capsules. 14. Prior exposure to HKI-272 and any other HER2 targeted agents, except trastuzumab. 15. Any other cancer within 5 years prior to screening with the exception of contralateral breast carcinoma, adequately treated cervical carcinoma in situ, or adequately treated basal or squamous cell carcinoma of the skin. 16. Evidence of significant medical illness or abnormal laboratory findings that would, in the investigator's judgment, make the subject inappropriate for this study. Examples include, but are not limited to, serious active infection (i.e, requiring intravenous antibiotic or antiviral agent) or uncontrolled major seizure disorder |
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E.5 End points |
E.5.1 | Primary end point(s) |
Part 1: To assess the safety and tolerability, and to define the MTD of orally administered HKI-272 in combination with trastuzumab in subjects with advanced breast cancer. Part 2: To determine the 16-week progression free survival (PFS) rate for subjects with advanced breast cancer treated at the MTD (or at a recommended dose) with HKI-272 and trastuzumab. |
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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 | 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 | Yes |
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 | 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 | No |
E.8.1.1 | Randomised | Information not present in EudraCT |
E.8.1.2 | Open | Information not present in EudraCT |
E.8.1.3 | Single blind | Information not present in EudraCT |
E.8.1.4 | Double blind | Information not present in EudraCT |
E.8.1.5 | Parallel group | Information not present in EudraCT |
E.8.1.6 | Cross over | Information not present in EudraCT |
E.8.1.7 | Other | Information not present in EudraCT |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
E.8.2.2 | Placebo | Information not present in EudraCT |
E.8.2.3 | Other | Information not present in EudraCT |
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 | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 8 |
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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last visit of the last subject. |
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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 | 1 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 6 |