A Phase II Neo-adjuvant Study Assessing TCH (Docetaxel, Carboplatin and Trastuzumab) and TCHL (Docetaxel, Carboplatin, Trastuzumab and Lapatinib) in HER-2 Positive Breast Cancer Patients.
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
(histologically or cytologically confirmed) or
- Any T with lymph node positive disease (histologically or cytologically
- 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)
6. Oestrogen and progesterone receptor status known prior to study entry
7. ECOG performance status score < or equal to 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
-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
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
1. Absolute neutrophil count ≥ 1.0 x 10^9/L
2. Haemoglobin ≥ 9.0 g/dL
3. Platelet count ≥ 100 x 10^9/L
13. Adequate renal function within 14 days prior to randomisation as defined by:
1. Serum creatinine < or equal to 1.25 x upper limit of normal (ULN), defined by
2. Serum creatinine clearance of > 60 mg/ml/min
14. Adequate hepatic function within 14 days prior to randomisation as defined by:
1. Total bilirubin < or equal to 1.0 x upper limit of normal (ULN). Patients with
Gilbert's syndrome prior to study entry must have total bilirubin <3X ULN.
2. Alkaline phosphatase and AST/ALT within parameters specified by protocol.
15. Able to swallow and retain oral medication
16. Patients must be deemed potentially operable following neo-adjuvant treatment.
1. Prior therapy with systemic cytotoxic chemotherapy Lapatinib or Trastuzumab.
2. Prior taxanes
3. Radiotherapy (Except for radiotherapy localised to radiotherapy to a primary squamous
or basal cell skin cancer).
4. Patients with metastatic disease (M1).
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, 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 oestrogen receptor modulators (SERMs), either for osteoporosis or
prevention of breast cancer. Patients 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
10. Poorly controlled hypertension (e.g. systolic >180mm Hg or diastolic >100mm Hg.)
11. Any history of myocardial infarction, angina pectoris or congestive heart failure.
Patients on current therapy for arrythmias are excluded. For other patients with a
history of self-limiting cardiac dieases (e.g. pericarditis, temporary secondary
arrythmias) 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 patient at undue risk for treatment complications
15. Male patients.
16. Patients 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
anti-retroviral 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
20. Concomitant requirement for medication classified as CYP3A4 inducers or inhibitors as
defined in Table 2.
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)