Neoplasms

All Conditions

Skin and Connective Tissue Diseases

Carcinoma

Breast Neoplasms

Carcinoma, Ductal

Carcinoma, Ductal, Breast

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Adenocarcinoma

Breast Diseases

Skin Diseases

Antineoplastic Agents

All Drugs and Chemicals

Amino Acids

Trastuzumab

Paclitaxel

Albumin-Bound Paclitaxel

Immunomodulating Agents

Lapatinib

Tubulin Modulators

Antimitotic Agents

Antineoplastic Agents, Immunological

Tyrosine Kinase Inhibitors

Protein Kinase Inhibitors

Enzyme Inhibitors

Tyrosine

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, biopsy before and after three weeks of study treatment

Core biopsies for histological analyses, to be analysed by the central pathology

Biopsy before and after three weeks of study treatment

paclitaxel

lapatinib

trastuzumab

Mathias Warm, MD

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.

Phase II Trial to Validate Markers for a Response Evaluation of a Combined Therapy in Patients With HER2+ Breast Cancer

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

Proliferation Ki-67, Aurora A Kinase (STK15), survivin, Myb-related protein B (MYBL2),Cyclin B1 and apoptosis genes Bcl2, Epidermal Growth Factor-like 2 (SCUBE2), cleaved caspase C3 will be assessed in the samples from diagnostic and sequential biopsy.

pCR was defined at the time of surgery and measured by size of residual tumor, proportion of vital cells within invasive carcinoma, number of positive lymph nodes (ypN) and size of the largest lymph node metastasis and ductal carcinoma in situ (ypT). pCR is defined as ypT0/is, ypN0. Further exploratory pCR definitions were ypT0, ypN0 (total pCR) and ypT0/is (near pCR).

GlaxoSmithKline

West German Study Group

Safety population for analysis of toxicities, comprised of 61 patients who were allocated to intervention and received at least one dose of study treatment.

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, biopsy before and after three weeks of study treatment

Biopsy before and after three weeks of study treatment: Core biopsies for histological analyses, to be analysed by the central pathology

paclitaxel

lapatinib

trastuzumab

Paclitaxel + Lapatinib + Trastuzumab

Age, Categorical

Age, Continuous

Sex: Female, Male

Race and Ethnicity were not collected from any participant.

Race and Ethnicity Not Collected

Germany

Region of Enrollment

ITT: Intent-to-treat population of all randomized patients without screening failures, comprising 61 patients (3 screening failures).

Only a limited number of core biopsies was available evaluation of dynamic biological changes.

Very slow patient recruitment. Negative study results from ALTTO study did no longer justify further conduct.

Anja Braschoss, Consultant Clinical Research and Medical Writing

ypT0, ypN0

ypT0/is

ypT0/is, ypN0

Measurement of pCR: at time of surgery, measured by size of residual tumor, proportion of vital cells per invasive carcinoma, number of positive lymph nodes (ypN), size of largest lymph node metastasis, ductal carcinoma in situ (ypT). Definition of pCR: ypT0/is, ypN0. Exploratory pCR definition: ypT0, ypN0 (total pCR), ypT0/is (near pCR).

Spots Global Cancer Trial Database for biopsy before and after three weeks of study treatment