E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Treatment of patients with HER2-positive 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 | 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 explore and potentially define molecular biomarker signatures which could alter during HER2 targeted therapy and predict decreased or increased sensitivity to treatment with trastuzumab. Biomarker signatures will be correlated with the following efficacy end points: Time to Progression (TTP), Progression Free Survival (PFS) and Overall Response Rate (ORR) during Part 1 and Part 2, based on the per-protocol population. |
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E.2.2 | Secondary objectives of the trial |
Efficacy: 1. TTP, PFS and ORR (in patients with measurable disease), in Part 1 and Part 2. 2. Overall Survival (OS).
Safety: 3. Safety of serial biopsies in women with metastatic breast cancer. 4. Safety of the study treatments in Part 1 and Part 2.
Exploratory objectives: Correlations between various evaluated biomarkers may be explored as appropriate.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Written and signed informed consent prior to beginning protocol-specific procedures. 2. Female patients age ≥18 years. 3. Evaluable with or without measurable metastatic breast cancer and at least one metastatic lesion which is amenable to multiple core biopsies. 4. HER2-positive metastatic lesion, defined as IHC3+ and/or ISH positive (FISH, CISH or SISH), as confirmed by the central laboratory testing. 5. All tumor biopsy material can be made available for central laboratory testing. 6. ECOG performance status ≤ 2. |
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E.4 | Principal exclusion criteria |
Prior or Current Treatments 1. Prior chemotherapy for metastatic disease. 2. Prior trastuzumab-based therapy for metastatic breast cancer. 3. Prior therapy with capecitabine. 4. Prior adjuvant/neoadjuvant trastuzumab, or adjuvant bevacizumab or tyrosine kinase inhibitor (TKI) completed <6 months prior to first study treatment. 5. Prior doxorubicin >360 mg/m2 or epirubicin 720 mg/m2 or equivalent. 6. Prior adjuvant taxane completed <12 months prior to first study treatment. 7. Biopsy of metastatic or breast lesion with fine needle aspiration only. 8. CNS disease as the only site of metastatic disease. 9. Use of immunotherapy or biological anticancer therapy within 21 days prior to study entry. 10. Oral or parenteral anticoagulation within 7 days prior to the baseline biopsy and/or coagulation profile outside the normal laboratory range within 48 hrs prior to the baseline biopsy. 11. Concurrent treatment with other experimental drugs. Participation in another clinical trial with any investigational drug within 30 days prior to study screening. 12. Concurrent immunotherapy or anticancer hormonal therapy.
Laboratory 13. Inadequate bone marrow function: ANC < 1.5 x 109/L, platelet count < 100 x 109/L or Hb < 9 g/dL. 14. Inadequate renal function: serum creatinine > 2.0 mg/dL or 177 μmol/L. 15. Inadequate liver function: • serum (total) bilirubin > 1.5 ULN, • AST and ALT > 3 x ULN (>6 x ULN for patients with liver metastases), • AST or ALT > 3 x ULN concurrent with serum alkaline phosphatase levels > 6 x ULN at baseline.
Prior or Concomitant Conditions 16. Serious concurrent disease which could affect compliance with the protocol or interpretation of results, including, but not limited to: • Known bleeding diastheses • Co-morbid condition which does not permit cessation of anti-platelet therapy (such as clopidigrel, aspirin) for 7 days before and after serial core biopsies • Existing peripheral neuropathy NCI grade > 2 from any cause • Active infection requiring antibiotics • Uncontrolled hypertension (systolic > 150 mm Hg and/or diastolic > 100 mm Hg) • Clinically significant cardiovascular disease: Cerebrovascular accident / stroke (≤ 6 months prior to registration), myocardial infarction (≤ 6 months prior to registration), unstable angina, New York Heart Association (NYHA) Class 2 or greater congestive heart failure, serious cardiac arrhythmia requiring medication • Dyspnoea at rest requiring supportive oxygen therapy or with significant pleural effusions • Patients requiring chronic daily treatment with corticosteroids (dose of >10 mg/day methylprednisolone equivalent) (excluding inhaled steroids)
17. Cardiac toxicity during previous trastuzumab treatment that necessitated discontinuation of trastuzumab. 18. Left ventricular ejection fraction (LVEF) of < 50% by echocardiogram or MUGA. 19. Evidence of any other serious intercurrent disease, metabolic or psychological dysfunction, physical examination finding, or clinical laboratory finding, sociological or geographical condition which would contraindicate the use of an investigational drug, or preclude adequate follow-up and compliance with the study protocol. 20. History of another malignancy which could affect compliance with the protocol or interpretation of results. Cancer patients treated with curative intent (including for contralateral invasive or in situ breast cancer) are generally eligible if disease-free for at least 5 years, as are patients treated curatively for carcinoma in situ of the cervix or non-melanomatous skin cancer. 21. Malabsorption syndrome, disease significantly affecting gastrointestinal function, resection of the stomach or small bowel, or ulcerative colitis. 22. Known hypersensitivity to any of the study drugs or excipients. 23. Known deficiency of dihydropyrimidine dehydrogenase (DPD).
Other 24. Pregnant or lactating females. 25. Females of childbearing age (defined as less than 2 years after last menstruation) not having a negative pregnancy test < 7 days prior to commencing chemotherapy or not willing/able to use an effective non-hormonal means of contraception (intrauterine contraceptive device, barrier method of contraception in conjunction with spermicidal jelly) throughout the study (unless surgically sterile). 26. Eligible for participation in either the AVEREL or Cleopatra clinical trials (at applicable sites). Note: If the patient is ineligible, the reason for ineligibility should be stated.
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E.5 End points |
E.5.1 | Primary end point(s) |
To explore and potentially define molecular biomarker signatures which could alter during HER2 targeted therapy and predict decreased or increased sensitivity to treatment with trastuzumab. Biomarker signatures will be correlated with the following efficacy end points: Time to Progression (TTP), Progression Free Survival (PFS) and Overall Response Rate (ORR) during Part 1 and Part 2, based on the per-protocol population. |
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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 | 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 |
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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 | 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 | 6 |
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 | 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
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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 | 4 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |