| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Her 2 positive locally advanced or primary breast cancer |
|
| E.1.1.1 | Medical condition in easily understood language |
| Patients with locally advanced or primary breast 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 | 18.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10006187 |
| E.1.2 | Term | Breast cancer |
| 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 assess the efficacy of TCH and TCHL in neo-adjuvant treatment of HER-2 positive breast cancer (Phase II). |
|
| E.2.2 | Secondary objectives of the trial |
To identify biomarkers of response/resistance to T and T+L.
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.Age > 18 years
3.Histologically proven breast cancer, for which neo-adjuvant chemotherapy and trastuzumab is considered a valid therapeutic strategy.
4.Patients with the following TNM stages (refer to AJCC 7th Edition – Appendix M) of breast cancer are eligible:
•T2, T3, T4a, T4b, T4c, T4d which is node negative or node positive or
•T1 with lymph node positive disease (histologically or cytologically confirmed)
•Patients with multifocal tumours are not excluded; T stage assignment must be based on the largest tumour.
•Patients presenting with bilateral breast cancer are not eligible
5.Tumour HER2/neu positive (3+ by IHC or fluorescence in situ hybridization (FISH) positive)
6.Oestrogen and progesterone receptor status known prior to study entry
7.ECOG performance status score <1
8.Cardiac ejection fraction ≥ 50% as measured by echocardiogram or MUGA scan within 3 months prior to randomisation. Note that baseline and on treatment scans should be performed using the same modality and preferably at the same institution
9.The effects of lapatinib on the developing human foetus at the recommended therapeutic dose are unknown. For this reason, women of child-bearing potential and men must agree to use adequate contraception (non-hormonal or barrier method of birth control, abstinence or a vasectomy partner) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately.
If applicable, post-menopausal status will be defined as patients who are amenorrheic for > 1 year or for a shorter duration if FSH, LH and/or oestradiol levels are within the post-menopausal range
10.Patient is accessible and willing to comply with treatment, tissue acquisition and follow up.
11.Formalin-fixed paraffin-embedded tissue available from diagnostic biopsy and/or definitive surgical intervention
Where possible fresh frozen tissue will be sought as outlined per protocol.
12.Adequate bone marrow function within 14 days prior to randomisation as defined by the following laboratory values
a. Absolute neutrophil count > 1.0 x 109/L
b. Haemoglobin > 9.0 g/dL
c. Platelet count > 100 x 109/L
13.Adequate renal function within 14 days prior to randomisation as defined by:
a. Serum creatinine < 1.25 x upper limit of normal (ULN), defined by institution
b. Serum creatinine clearance of > 60 ml/min
14.Adequate hepatic function within 14 days prior to randomisation as defined by:
a. Total bilirubin < 1.0 x upper limit of normal (ULN). Patients with Gilbert’s syndrome prior to study entry must have total bilirubin <3X ULN.
b. Alkaline phosphatase and AST/ALT within the following parameters.
AST or ALT
Alk Phos ≤ ULN >1x ULN but ≤1.5x ULN >1.5x ULN but ≤2.5x ULN >2.5x ULN
<ULN Eligible Eligible Eligible Ineligible
>1x ULN but <2.5x ULN Eligible Eligible Ineligible Ineligible
>2.5x ULN but <5x ULN Eligible Ineligible Ineligible Ineligible
>5x ULN Ineligible Ineligible Ineligible Ineligible
15.Able to swallow and retain oral medication
16.Patients must be deemed potentially operable following neo-adjuvant treatment.
|
|
| E.4 | Principal exclusion criteria |
1. Prior therapy with with systemic cytotoxic chemotherapy, Trastuzumab or Lapatinib
2. Prior taxanes
3. Radiotherapy (Except for radiotherapy localised to radiotherapy to a primary squamous or basal cell skin cancer).
4. Patients with metastaic disease (M1) other than patients with ipsilateral axillary lymph nodes.
5. Concurrent therapy with any other non-protocol anti-cancer therapy
6. History of any other malignancy within the past 5 years, with the exception of non-melanoma skin cancer, contralateral in situ carcinoma of the breast (ductal or lobular) or carcinoma-in-situ of the cervix.
7. Current therapy with any hormonal agent such as raloxifene, tamoxifen, or other selective estrogen receptor modulators (SERMs), either for osteoporosis or prevention of breast cancer. Subjects must have discontinued these agents 14 days prior to enrolment.
8. Concurrent treatment with ovarian hormonal replacement therapy. Prior treatment must be stopped prior to enrolment.
9. Pre-existing motor or sensory neurotoxicity of a severity >=Grade 2 by NCI-CTCAE version 4.0.
10. Poorly controlled hypertension (e.g. systolic > 180 mm Hg or diastolic > 100 mm Hg)
11. Any history of myocardial infarction, angina pectoris or congestive heart failure. Patients on current therapy for arrhythmias are excluded. For other patients with a history of self-limiting cardiac diseases (e.g. pericarditis, temporary secondary arrhythmias) more than 1 year must have past prior to enrolment on the study.
12. Inflammatory bowel disease or other bowel condition causing chronic diarrhoea, requiring active therapy.
13. Active, uncontrolled infection requiring parenteral antimicrobials or any condition requiring maintenance therapeutic (i.e. non-replacement) doses of corticosteroids.
14. The presence of any other medical or psychiatric disorder that, in the opinion of the treating physician, would contraindicate the use of the drugs in this protocol or place the subject at undue risk for treatment complications
15. Male subjects.
16. Subjects with known hypersensitivity to Chinese hamster ovary products or other recombinant human or humanized antibodies and/or known hypersensitivity to any of the study drugs or their ingredients (eg, polysorbate 80 in docetaxel)
17. Pregnant women are excluded from this study because lapatinib is member of the 4-anilinoquinazoline class of kinase inhibitors
with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events
in nursing infants secondary to treatment of the mother with lapatinib, breastfeeding should be discontinued if the mother is treated with lapatinib
18. HIV-positive patients receiving combination anti-retroviral therapy are excluded from the study because of possible pharmacokinetic interactions with lapatinib. Appropriate studies
will be undertaken in patients receiving combination antiretroviral therapy when indicated.
19. 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).
20. Concomitant requirement for medication classified as CYP3A4 inducers or inhibitors.
21. 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) |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
To determine the pathological complete response (pCR) to (i) trastuzumab, docetaxel and carboplatin TCH
(ii) and trastuzumab, docetaxel, carboplatin and lapatinib TCHL |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Following 6 cycles of neo-adjuvant treatment |
|
| E.5.2 | Secondary end point(s) |
1. Assess the efficacy of the TCH and TCHL regimens in producing objective responses
2. Assess the safety, tolerability of the TCHL and TCH combination regimens
3. Examine potential molecular markers of response to trastuzumab and lapatinib treatment
4. Assess DFS and OS
5.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 |
1. Following 6 cycles of neo-adjuvant treatment
2. Following 6 cycles of neo-adjuvant treatment
3. Pre, during and post treatment with neo-adjuvant therapy
4. Patients will be followed up for 5 years from randomisation |
|
| 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 |
| to assess molecular biomarkers of response to Trastuzumab and lapatinib treatment |
|
| 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 | 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 | 12 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| 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
|
• Unacceptable toxicity occurs as defined by the protocol.
• Disease recurs (if disease recurs locally or distantly, protocol treatment should be discontinued).
• A second primary develops.
• Extraordinary Medical Circumstances: If, at any time, the constraints of this protocol are detrimental to the
patient’s health, protocol treatment should be discontinued.
• Patient withdraws consent.
• Pregnancy occurs |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| 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 | 0 |
| 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 |
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