| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| HER2 - positive metastatic breats cancer |
|
| E.1.1.1 | Medical condition in easily understood language |
| HER2 - positive metastatic breats cancer |
|
| 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 | PT |
| E.1.2 | Classification code | 10055113 |
| E.1.2 | Term | Breast cancer metastatic |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 compare the efficacy of THL versus TH in first line treatment of metastatic HER2 positive breast cancer |
|
| E.2.2 | Secondary objectives of the trial |
1. To examine the objective tumour response rate and overall survival of lapatinib with trastuzumab and paclitaxel compared to the paclitaxel and trastuzumab alone.
2. To assess the safety and tolerability of lapatinib when administered with both paclitaxel and trastuzumab compared to the combination of paclitaxel and trastuzumab.
3. To examine the effects of the TH regimen versus the THL regimen on health-related quality of life using the FACT-B questionnaire
4. To examine the correlation between EGFR, HER2, HER3, Akt, and other potential biomarkers downstream of the EGFR and HER2 receptors in tumour tissue, where available
5. To examine the correlation between serum concentrations of HER2 Extracellular Domain (ECD) and tumour response.
6. To examine the correlation between circulating mRNAs and miRNAs in patient sera and tumour response.
7. To determine if prophylactic Loperamide significantly reduces the number of diarrhoea-related adverse events.
|
|
| 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. Tumour 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 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 and up to 6 months after completion of therapy. 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 (i.e. adjuvant taxane and/or anthracycline based regimens) 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, a documented 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 .
Patients with a long QT syndrome or who are taking additional medication that prolongs QT interval are excluded from the study.
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 breastfeeding 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 hormone replacement therapy. Prior treatment must be stopped prior to registration.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| 1. The primary efficacy endpoint is progression free survival (PFS) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Progression free survival |
|
| E.5.2 | Secondary end point(s) |
1. Objective tumour response rate
2. Overall survival
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 AEs.
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
-Objective tumour response rate
-Overall survival
-To assess the safety and tolerability of lapatinib when administrated with both paclitaxel and trastuzumab compared to the combination of paclitaxel and trastuzumab. Toxicities will be recorded and graded according to the NCI - CTC criteria, version 4
-FACT-B questionnaire
|
|
| 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 | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| 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
| 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 | 40 |
| 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 |
| Denmark |
| Finland |
| France |
| Germany |
| Iceland |
| Ireland |
| Israel |
| Italy |
| Netherlands |
| Norway |
| Poland |
| Portugal |
| Spain |
|
| 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
|
| a maximum of 5 years after the last patient is enrolled into study |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 7 |
| 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 | 7 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
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