Carcinoma, Ductal, Breast Clinical Trial
Official title:
A Multicenter Site, Open Label, Phase II Trial to Validate Predictive Markers for the Response Evaluation of a Combined Chemo-immunotherapy in Patients With HER2-positive Early Breast Cancer
The Neo-PREDICT-HER2 Study is phase II trial to validate predictive markers for the response evaluation of a combined chemo-immunotherapy in patients with HER2-positive early breast cancer. The only treatment arm consists of Paclitaxel 80 mg/m2 weekly for 12 weeks with lapatinib 750 mg P.O. daily and trastuzumab 2 mg/kg IV (loading dose 4 mg/kg) weekly for 12 weeks.
Trastuzumab (T)-containing neoadjuvant chemotherapy has been reported to increase the
probability of pathological complete response (pCR) in HER2 positive disease up to 67 %.
Large trials revealed pCR rates (no remaining invasive and in situ components) of about 30-40
%, if anthracyclines/taxane based polychemotherapy was applied or about 40-45 % if no
invasive tumor in the breast and lymph nodes was used as a pCR definition.
Nevertheless, resistance to trastuzumab remains one of the most important challenges in
adjuvant and metastatic breast cancer therapy causing poor prognosis with an increased
incidence of cerebral metastasis and limited therapeutic options after disease progression6.
An improvement shows the combination of trastuzumab and lapatinib, which has been reported to
have increased efficacy in in-vitro and in metastatic setting in patients who were mostly
resistant to both therapies in the previous course of disease. Recent data from the
neoadjuvant setting (neoALTTO) - on a paclitaxel backbone - showed a significantly higher pCR
rate after L + T than with either compound separately (47 % vs. 20 % and 27.6 %
respectively). Several trials are planned to evaluate the combination of both therapies in
the adjuvant and neoadjuvant setting.
Clinical response measured by sequential evaluation of different proliferation markers (such
as Ki-67) following a course of neoadjuvant chemotherapy has been demonstrated to correlate
significantly with an increased risk of relapse in patients not achieving pathological
complete response. It is therefore clinically relevant to evaluate such proliferation tools
for early prediction of combination therapy efficacy (chemotherapy and HER2 targeted
therapy). So far, it remains unclear which method of proliferation measurement is the optimal
marker for response evaluation regarding a combined chemo-immunotherapy. However, measurement
of proliferation and apoptosis genes as well as assessment of changes in Phosphatidylinositol
3-kinases (PI3K), Protein Kinase B (AKT), Insulin-like Growth Factor (IGF) and stem cell
signalling after a short course of therapy could provide a unique signature for a dynamic
response evaluation.
The planned trial will validate predictive markers and a dynamic model based on the
sequential evaluation of different proliferation and apoptosis markers. Furthermore it will
assess the pCR-rate after 12 weeks of therapy. The aim of the study is to define a predictive
marker for the response evaluation of a combined chemo-immunotherapy.
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