| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Classification code | 10027475 |
|
| 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 evaluate the overall response rate (percentage of patients with a CR or PR
according to the RECIST criteria) for Herceptin alone or in combination with a
taxane, in patients with metastatic HER2 positive breast cancer, who have relapsed
after receiving Herceptin in the adjuvant setting.
|
|
| E.2.2 | Secondary objectives of the trial |
To determine in each cohort (Herceptin monotherapy and Herceptin plus a taxane):
• Clinical benefit rate (defined as SD for at least 6 months or CR or PR).
• Duration of response, progression free survival (PFS), time to treatment failure and
survival (until approximately 2 years after cessation of enrolment).
• Safety and tolerability (including changes in LVEF and incidence of symptomatic
heart failure) of Herceptin with or without a taxane in this patient population.
|
|
| E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
| E.3 | Principal inclusion criteria |
1. Female patients, > 18 years old.
2. Histologically or cytologically proven diagnosis of breast cancer, which is metastatic. For this protocol, relapse in supra- or infraclavicular lymph nodes is regarded as metastatic disease.
3. Patients must have relapsed 12 months after discontinuation of Herceptinâ in the adjuvant setting for HER2 positive early breast cancer. Patients should have completed at least 10 months of adjuvant Herceptinâ treatment.
4. HER2 positive primary disease (3+ HER2 overexpression measured by immunohistochemistry, or HER2 amplification measured by FISH), confirmed by the central laboratory. Confirmation of HER2 positivity of the primary tumour by the central laboratory is not required for patients previously in a Roche or Genentech sponsored trial of adjuvant Herceptinâ (e.g. the HERA, BCIRG006, NSABP B31, or Intergroup/NCCTG/H2061s trials).
5. Measurable disease according to RECIST criteria (i.e. a minimum dimension of 20mm by conventional or 10mm by spiral CT scan). Previously irradiated lesions should not be selected as target lesions unless there has been clear progression since the radiotherapy. Lesions newly appearing in a previously irradiated area are allowed as target lesions.
6. ECOG Performance Status 0-2 and life expectancy at least 3 months.
7. Baseline LVEF 50% (measured by MUGA or echocardiography).
8. Patients should have recovered from the acute, reversible effects of prior surgery or radiotherapy. This generally means that at least 3 weeks should have elapsed since prior radiotherapy.
9. Signed written informed consent (approved by the Institutional Review Board [IRB]/Independent Ethics Committee [IEC]) obtained prior to any study specific procedures.
10. Able to comply with the protocol.
11. Patients who received prior therapy with Herceptinâ and taxanes concomitantly in the adjuvant setting are only eligible for cohort A (Herceptinâ monotherapy). Otherwise the choice of cohort A or cohort B is according to the investigator’s clinical judgement. |
|
| E.4 | Principal exclusion criteria |
1. Pregnant or lactating women. Documentation of a negative pregnancy test must be available for pre-menopausal women with intact reproductive organs and for women less than one year after menopause.
2. Women of childbearing potential unless (1) surgically sterile or (2) using adequate measures of contraception (intra-uterine device or barrier method of contraception in conjunction with spermicidal jelly).
3. Prior chemotherapy for metastatic breast cancer. Prior surgery, endocrine therapy and/or radiotherapy are allowed. Patients receiving hormone therapy should stop it prior to the first dose of study medication.
4. Patients with pleural effusions, ascites, or bone lesions as the only manifestation of disease.
5. Patients with known allergy or severe reactions to Herceptinâ or its constituents. Patients who stopped therapy with Herceptinâ in the adjuvant setting due to asymptomatic LVEF changes or for reasons of convenience/compliance may be entered into the study, at the investigator’s discretion, if it is thought likely that the patient will be able to tolerate re-treatment. Patients who develop symptomatic CHF may be entered at the investigator’s discretion providing symptomatic CHF occurred >6 months prior to enrolment. Enrolment of patients with a history of symptomatic CHF must be discussed with the Roche medical advisor before enrolment.
6. Patients with CNS metastases.
7. Invasive malignancy (including second primary breast cancer) other than metastatic breast cancer which could affect compliance with the protocol or interpretation of results. Patients who have been curatively treated and free of malignant disease for greater than 5 years are generally eligible.
8. Other serious illness or medical condition including:
• Congestive heart failure (NYHA class III-IV) or history of congestive heart failure (but see exclusion criterion number 5), unstable angina pectoris, myocardial infarction in the last 6 months, poorly controlled hypertension (systolic >180 mmHg or diastolic >100 mmHg), clinically significant valvular heart disease, or high-risk uncontrolled arrhythmias.
• Patients with dyspnoea at rest due to malignant or other disease (e.g. pulmonary metastases with lymphangitis) or who require supportive oxygen therapy.
• Active serious uncontrolled infections.
• Poorly controlled diabetes mellitus.
• Active peptic ulcer or other contraindication to high dose of corticosteroid therapy such as herpes zoster, cirrhosis.
9. Patients with a history of uncontrolled seizures, central nervous system disorders or psychiatric disability, which could affect ability to give informed consent, or compliance with study therapy.
10. Current peripheral neuropathy NCI-CTCAE version 3 grade 2.
11. Treatment with any investigational drug within 30 days before the beginning of treatment with study drug.
12. Prior treatment with anti-HER therapies, other than adjuvant Herceptinâ.
13. Inadequate bone marrow, hepatic and renal functions as evidenced by the following:
• Neutrophil count of <1500/L, platelet count of <100,000/L
• Haemoglobin <10 g/dL
• Serum total bilirubin >1.5 times upper limit of normal (ULN)
• For patients without liver or bone metastases: alkaline phosphatase, AST, and ALT >2.5 times ULN
• For patients with liver or bone metastases: alkaline phosphatase >5 times ULN
• For patients with liver metastases; ALT and AST >5 ULN
• Patients with AST and/or ALT > 1.5 times ULN concomitantly with alkaline phosphatase > 2.5 times ULN
• Serum creatinine >1.5 times ULN
• Serum calcium >1.5 times ULN |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Overall response rate (percentage of patients with a CR or PR according to the RECIST criteria) for Herceptin alone or in combination with a taxane, in patients with metastatic HER2 positive breast cancer, who have relapsed after receiving Herceptin in the adjuvant setting. |
|
| 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 | Information not present in EudraCT |
| 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) | No |
| E.7.1.1 | First administration to humans | Information not present in EudraCT |
| E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
| E.7.1.3 | Other | Information not present in EudraCT |
| 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 | Yes |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| 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) | 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.8.5 | The trial involves multiple Member States | Yes |
| 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 |
|
| E.8.7 | Trial has a data monitoring committee | Information not present in EudraCT |
| 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
|
| Recruitment of each cohort is estimated to take at least 2 years. Efficacy (response rate) will be assessed for at least 6 months after the last patient in each cohort is recruited so the study will take at least 2.5 – 3 years. However, patients will be followed for survival after disease progression or completion of treatment. In each cohort, survival information will be collected yearly until 2 years from randomisation of the last patient. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
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