E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Women with primary ErbB2 overexpressing and/or gene amplified breast cancer > 2 cm diameter who have not undergone previous treatment for invasive breast cancer |
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E.1.1.1 | Medical condition in easily understood language |
Breast cancer forms in the breast cells. Risk factors for breast cancer include: being female, getting older, having a family history of breast cancer, inherited genes that increase cancer risk. |
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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 | 19.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10057654 |
E.1.2 | Term | Breast cancer female |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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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 evaluate and compare the rate of pathological complete response (pCR) at the time of surgery in patients with ErbB2 overexpressing or amplified operable breast cancer randomised between the study treatment arms. |
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E.2.2 | Secondary objectives of the trial |
-To compare the safety and tolerability of the treatment arms;
-To compare the objective response rate among the treatment arms at week 6 and at definitive surgery;
-To compare the percent of patients with node-negative disease at surgery among the treatment arms;
-To compare the rate of conversion to breast conserving surgery;
-To compare the rate of conversion to breast surgery of patients with non-operable breast cancer;
-To compare event free survival (EFS) and overall survival (OS) from randomization among the treatment arms;
-To assess associations between locoregional pCR and EFS and between locoregional pCR and OS;
-To identify the molecular characteristics of responding tumours;
-To study biomarkers expression and correlate with outcome;
-To establish associations between PET/CT, response, molecular changes;
-To prospectively study the effect on CTCs;
-To prospectively study the prognostic/predictive value of CTCs;
-To study the clinical value of CTCs.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1) Female
2) Age ≥18 years
3) Performance Status- Eastern Cooperative Oncology Group (ECOG) 0-1
4) Histologically confirmed invasive breast cancer:
- Primary tumour greater than 2 cm diameter,
- Any Node,
- No evidence of metastasis (M0) (isolated supraclavicular node involvement allowed)
5) Over expression and/or gene amplification of ErbB2 in the invasive component of the primary tumour according to one of the following definitions and confirmed by a certified laboratory prior to randomisation:
– 3+ over expression by IHC;
– 2+ or 3+ (in 30% or less neoplastic cells) over expression by IHC AND in situ hybridization (FISH/CISH) test demonstrating HER2 gene amplification;
– HER2 gene amplification by FISH/CISH
Patients with a negative or equivocal overall result and staining scores of 0, 1+, 2+ or 3+ (in 30% or less neoplastic cells) by IHC are not eligible
Equivocal local results from non certified laboratories may be submitted for a final determination by the certified laboratory.
ErbB2 status must be tested in local or regional certified laboratories prior to randomisation. Local testing performed in non-certified laboratories, will also need confirmation of the results by a certified laboratory.
6) Hormone receptor (HR) status:
- Oestrogen Receptor (ER) status must be known.
7) Haematopoietic status:
- Absolute neutrophil count ≥1.5 x 10^9/L,
- Platelet count ≥100 x 10^9/L,
- Hemoglobin at least 9 g/dl,
8) Hepatic status:
- Bilirubin ≤ 2 x upper limit of normal (ULN),
- AST and ALT ≤ 2.5 times ULN,
- Alkaline phosphatase ≤ 2.5 times ULN,
9) Renal status:
- Creatinine ≤ 2.0 mg/dL,
0) Cardiovascular:
- Baseline LVEF ≥ 50% measured by echocardiography (ECHO) or Multiple Gate Acquisition (MUGA) scan,
11) Negative serum pregnancy test, within 2-weeks (preferably 7 days) prior to randomization (For women of childbearing potential)
12) Fertile patients must use effective contraception as specified in the protocol
13) Signed informed consent form (ICF)
14) Patient accepts to make available tumour samples for submission to central laboratory to conduct translational studies as part of this protocol |
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E.4 | Principal exclusion criteria |
1) Received any prior treatment for primary invasive breast cancer;
2) History of other malignancy. However, subjects with a past or current history of completely resected basal and squamous cell carcinoma of the skin or successfully treated in situ carcinoma of the cervix are eligible;
3) Diagnosis of inflammatory breast cancer;
4) Bilateral cancer;
5) Multi-focal cancer;
6) Known history of uncontrolled or symptomatic angina, clinically significant arrhythmias, congestive heart failure, uncontrolled hypertension (≥ 180/110), unstable diabetes mellitus, dyspnoea at rest, or chronic therapy with oxygen;
7) Concurrent disease or condition that would make the subject inappropriate for study participation or any serious medical disorder that would interfere with the subject’s safety;
8) Unresolved or unstable, serious adverse events from prior administration of another investigational drug;
9) Active or uncontrolled infection;
10) Dementia, altered mental status, or any psychiatric condition that would prevent the understanding or rendering of ICF;
11) Malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel. Subjects with ulcerative colitis are also excluded;
12) Concurrent neoadjuvant cancer therapy (chemotherapy, radiation therapy, immunotherapy, biologic therapy other than the trial therapies);
13) Concurrent treatment with an investigational agent or participation in another therapeutic clinical trial;
14) Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to trastuzumab or lapatinib or their excipients;
15) Pregnant or lactating women;
16) Concomitant use of CYP3A4 inhibitors or inducers. |
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E.5 End points |
E.5.1 | Primary end point(s) |
To evaluate and compare the rate of pCR (according to NSABP guidelines) [Fisher, 1997; Fisher, 2002] at the time of surgery in patients with ErbB2 overexpressing or amplified operable breast cancer randomised to lapatinib followed by lapatinib plus paclitaxel versus trastuzumab followed by trastuzumab plus paclitaxel versus lapatinib in combination with trastuzumab followed by lapatinib in combination with trastuzumab plus paclitaxel. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
At the time of surgery, approximately 18 weeks after starting anti-HER2 therapy and 12 weeks after starting chemotherapy combined with anti-HER2 therapy. |
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E.5.2 | Secondary end point(s) |
- To compare the safety and tolerability of the three treatment arms;
- To compare the objective response rate (complete plus partial) among the three treatment arms at the end of biological window (week 6) and at definitive surgery;
- To compare the percent of patients with node-negative disease at surgery among the three treatment arms;
- To compare the rate of conversion to breast conserving surgery among the three treatment arms;
- To compare the rate of conversion to breast surgery of patients with non-operable breast cancer among the three treatment arms;
- To compare event free survival (EFS) and overall survival (OS) from randomization among the three treatment arms;
- To assess associations between locoregional pCR and EFS and between locoregional pCR and OS using a more stringent definition of locoregional pCR defined as absence of invasive disease in both the breast and ipsilateral sampled lymph nodes (ypT0/is ypN0);
- To identify the molecular characteristics of responding tumours by immunohistochemical, FISH, genomic and proteomic analysis;
- To study biomarkers expression before and during therapy and establish correlations with clinical outcome;
-Wherever possible to establish associations between PET/CT, tumour response and molecular changes, and to hypothesize about association with number of CTCs and about the predictive value of early PET/CT imaging for evaluation of response to targeted anti-ErbB2 therapies;
- To prospectively study the effect of biologic agents (lapatinib, trastuzumab, or their combination) on CTCs;
- To prospectively study the prognostic/predictive value of monitoring CTCs in patients with breast cancer;
- To study the clinical value of CTCs within the context of tumour molecular and metabolic changes in patients receiving anti-HER2 therapies.
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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 | No |
E.6.7 | Pharmacodynamic | Yes |
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 | 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) | 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 | Yes |
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 | 3 |
E.8.3 |
The trial involves single site in the Member State concerned
| Information not present in EudraCT |
E.8.4 | The trial involves multiple sites in the Member State concerned | Information not present in EudraCT |
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 | 101 |
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 |
Argentina |
Belgium |
Brazil |
Canada |
Czech Republic |
France |
Germany |
Hong Kong |
Hungary |
India |
Italy |
Korea, Republic of |
Lithuania |
Norway |
Peru |
Romania |
Russian Federation |
South Africa |
Spain |
Taiwan |
Ukraine |
United Kingdom |
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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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End of study is reached ten (10) years from the date of randomization of the last enrolled patient. |
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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 | 10 |
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 | 10 |
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 |