| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| HER2 positive Metastatic Breast Cancer |
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| E.1.1.1 | Medical condition in easily understood language |
| Breast cancer that has spread beyond the breast into other parts of the body, which is positive for a protein called HER2. |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10027475 |
| E.1.2 | Term | Metastatic breast cancer |
| E.1.2 | System Organ Class | 100000004864 |
|
| 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 |
| In women with breast cancer that has spread to other parts of the body that is positive for a protein called HER2, does adding lapatinib to paclitaxel and trastuzumab, the standrad treatment for advanced HER2 positive breast cancer, slow the rate of disease progression compared to standard treatment alone. |
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| E.2.2 | Secondary objectives of the trial |
The secondary research questions include:
1)Is there a difference in the overall effect on tumour growth (termed objective tumour response rate) between the two treatment groups
2)Is there a difference in the length of time patients survive between the two treatment groups?
2)Is there a difference in side effect profile in the two treatment groups and is there any difference in their quality of life?
3)In tissue and blood samples donated from participating patients, is there any correlation between the markers found in the tissue and the patients' response to treatment?
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|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Written informed consent obtained prior to any study-related procedures
2. Female age 18 years or greater.
3. ECOG Performance Status of 0 or 1.
4. Histologically or cytologically-confirmed invasive metastatic breast cancer.
5. Patients must have measurable disease according to RECIST criteria Version 1.1, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions)) as >20 mm with conventional techniques or as >10 mm with spiral CT scan, MRI, or calipers by clinical exam.
6. Tumor shows HER2 over-expression (3+ by IHC and/or FISH +). By testing of the primary tumour and if available the biopsied metastatic lesion.
7. Patients who received prior radiotherapy must have completed it at least 4 weeks before registration and recovered from all treatment-related toxicities.
8. Cardiac ejection fraction within the institutional range of normal as measured by MUGA or ECHO within 14 days prior to registration. Note that baseline and on treatment scans should be performed using the same modality and preferably at the same institution.
9. Adequate haematological, hepatic, and renal function.
Haemoglobin ≥ 9g/dL
Neutrophils (ANC/AGC) ≥1500/mm³ (1.5 x 10^9/L)
Platelets ≥ (100 x 10^9/L)
Total bilirubin ≤ 1.5mg/dL (25.65 μmol/L)
Both ALT (SGPT) and AST (SGOT) ≤ 3 x ULN with or without liver Metastasis
Alkaline phosphatase ≤ 2.5 x ULN
Serum creatinine ≤ 1.5 ULN or calculated creatinine clearance (CrCl) ≥ 30mL/min according to the Cockcroft and Gault formula (appendix K)
10. Able to swallow and retain oral medication.
11. Women of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control or abstinence) prior to study entry and for the duration of study participation. Female patients of childbearing potential must have pregnancy excluded by urine or serum beta-HCG testing within 7 days prior to registration.
12. Estimated life expectancy greater than 12 weeks. |
|
| E.4 | Principal exclusion criteria |
1. Prior systemic therapy for metastatic disease (except one line of hormonal therapy for metastatic disease without trastuzumab).
2. Recurrence within 12 months from completion of adjuvant chemotherapy to the development of metastatic disease.
3. Recurrence within 6 months from completion of adjuvant trastuzumab to the development of metastatic disease.
4. Prior lapatinib treatment.
5. Peripheral neuropathy ≥ grade 2.
6. Patients with known CNS metastasis should be excluded from this clinical trial.
7. Prior radiotherapy to more than half of the bony pelvis.
8. Uncontrolled or symptomatic angina, uncontrolled arrhythmias, congestive heart failure or a documented myocardial infarction (MI) within 6 months prior to registration or any other cardiac disorders, which in the opinion of the treating physician, would make this protocol unreasonably hazardous for the patient .
9. Immediate or delayed hypersensitivity or untoward reaction to paclitaxel, trastuzumab, or other related compounds, or to drugs chemically related to lapatinib (including other anilinoquinazolines, e.g. gefitinib (Iressa®) and erlotinib (Tarceva®), or other chemically-related compounds).
10. Pregnant or breast feeding women are excluded from this study
11. Patients should not be receiving any other investigational agents (within 30 days prior to registration) or receiving concurrent anticancer therapy.
12. Concomitant requirement for medication classified as CYP3A4 inducers or inhibitors (Table 9).
13. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, or psychiatric illness/social situations that would limit compliance with study requirements.
14. Patients with GI tract disease resulting in an inability to take oral medication, malabsorption syndrome, a requirement for IV alimentation, prior surgical procedures affecting absorption, uncontrolled inflammatory GI disease (e.g., Crohn’s, ulcerative colitis).
15. Have current active hepatic or biliary disease (with exception of patients with Gilbert's syndrome, asymptomatic gallstones, liver metastases or stable chronic liver disease per investigator assessment).
16. Concurrent treatment with ovarian hormonal replacement therapy. Prior treatment must be stopped prior to registration. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary outcome measure is progression free survival. This will be calculated from the date of randomisation to the date of disease progression or death, whichever is reported first. Patients not meeting the primary outcome measure will be censored at the day of their last assessment. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Patients will undergo tumour assessment (by CT/MRI scan) every 12 weeks, progression of disease will be assessed according to RECIST criteria version 1.1.
Overall survival will be measured from the date of randomisation to the date of the patient’s death. If the patient is alive or the vital status is unknown, the date of death will be censored at the date that the patient is last known to be alive. Progression-free survival will be analysed at nine months after enrolment ends and overall survival will be analysed at 30 months after the end of enrolment.
|
|
| E.5.2 | Secondary end point(s) |
1. Objective tumour response rate defined as the proportion of patients in whom a complete or partial response is observed.
2. Overall survival defined as the time from randomisation until death from any cause in the intent-to-treat population.
3. To assess the safety and tolerability of lapatinib when administered with both paclitaxel and trastuzumab compared to the combination of paclitaxel and trastuzumab. Toxicities will be recorded and graded according to the NCI - CTCAE criteria, version 4
4. Health-related quality of life as measured by the FACT-B questionnaire
5. Correlation between EGFR, HER2, HER3, Akt, and other potential biomarkers downstream of the EGFR and HER2 receptors in tumour tissue, where available.
6. Correlation between serum concentrations of HER2 ECD and tumour response.
7. Correlation between circulating mRNAs and miRNAs in patient sera and tumour response.
8. To determine if prophylactic Loperamide significantly reduces the number of diarrhoea-related adverse events. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Objective tumour response will be assessed by CT/MRI scan performed every 12 weeks. For overall survival patients, will be followed up at clinic visits during and after completion of treatment by clinic visits and telephone calls.
Safety and tolerability of treatment, completion of health related questionnaires will be assessed at clinic visits conduicted at every cycle of treatment.
Translational endpoints will be analysed using tissue samples collected from participants throughout and after the end of the study. |
|
| 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 | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| 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 | 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | 8 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 60 |
| 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 | No |
| 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 |
| Finland |
| France |
| Germany |
| Ireland |
| Israel |
| Italy |
| Norway |
| Portugal |
| Spain |
| United Kingdom |
|
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 8 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 1 |
| E.8.9.2 | In all countries concerned by the trial years | 9 |
| E.8.9.2 | In all countries concerned by the trial months | 10 |
| E.8.9.2 | In all countries concerned by the trial days | 10 |
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