Bevacizumab, Everolimus (RAD001), and Lapatinib as Neoadjuvant Chemotherapy Regimes for Primary Breast Cancer — GeparQuinto  

Breast Cancer Clinical Trial

Official title: A Phase III Trials Program Exploring the Integration of Bevacizumab, Everolimus (RAD001), and Lapatinib Into Current Neoadjuvant Chemotherapy Regimes for Primary Breast Cancer

Status Completed

Clinical Trial Summary

Anthracycline-taxane based chemotherapy regimens are recommended mainly by current guidelines for neoadjuvant application of systemic treatment. The addition of other cytotoxic agents, e.g. antimetabolites, vincaalkaloids, or platinum salts resulted in marginal increase in efficacy, but was associated also with an increase in toxicity. Recently, only the addition of the Her-2 antibody trastuzumab has significantly improved pathologic response rate.

Therefore, two major strategies are followed in current research projects:

• To improve the selection of patients according to their tumors' sensitivity to chemotherapy.

• To implement small molecules with specific mechanism of action.

Within the GeparQuinto trial, the first strategy is followed by:

• The PREDICT substudy. A gene signature specific for the response to anthracyclines and taxanes will be prospectively evaluated for its ability to identify patients with chance higher than 50% for a pCR. The results may leed to a better risk-benefit ratio for the use of conventional chemotherapy.

• Adapting further chemotherapy to the response of the tumor to the first couple of chemotherapy cycles. Based on the previous experience made by the GeparTrio study, patients not responding early have a low chance to respond with a pCR irrespective of the type of chemotherapy. So, if further chemotherapy is planned, therapy should be selected according to a favorable toxicity profile.

The second strategy is followed by investigating in three parallel group comparisons the efficiency of three distinct small molecules which appear to be generally active in breast cancer:

• Bevacizumab, an inhibitor of the VEGF pathway targeting tumor neo-angiogenesis.

• Lapatinib, an inhibitor of the Her-1 and Her-2 receptor tyrosine kinase.

• RAD001 (Everolimus), an inhibitor of the mTOR molecule, a central controller of tumor cell growth and angiogenesis and chemosensitizer.

Treatment for patients participating in the GeparQuinto study will be allocated according to the Her-2 status of the tumor as well as according to the sonographic response after the first 4 cycles of treatment. Experimental therapy with bevacizumab, lapatinib, and everolimus (RAD001) will be randomly added in distinct settings.

Clinical Trial Description

Primary objectives:

To compare the pCR rates of neoadjuvant treatment of epirubicin / cyclophosphamide followed by docetaxel (EC-T) with or without bevacizumab (EC-T vs. ECB-TB) in patients with Her-2 negative primary breast cancer (Setting I).

To compare the pCR rates of neoadjuvant treatment with weekly paclitaxel with or without Everolimus (RAD001) (Pw vs. PwR) in patients with Her-2 negative primary breast cancer showing no sonographic response to 4 cycles of EC +/-B (Setting II).

To compare the pCR rates of neoadjuvant treatment with epirubicin / cyclophosphamide followed by docetaxel with either trastuzumab or lapatinib (ECH-TH vs. ECL-TL) in patients with Her-2 positive primary breast cancer (Setting III).

Secondary objectives:

1. To assess the toxicity of and compliance to all six treatments.

2. To determine the response rates of the breast tumor and axillary nodes by physical examination and imaging tests (sonography, mammography, or MRI) after treatment in all arms.

3. To determine the breast conservation rate after each treatment.

4. To determine the (loco-regional and distant) disease-free and overall survival after each treatment. In Her-2 positive disease, the cerebral disease-free survival will be determined separately.

5. To assess treatment efficacies in subgroups defined according to tumor stage (T2-3 vs. T4), receptor status (ER and / or PgR positive vs. ER and PgR negative) and response by best appropriate imaging method to the first four cycles of treatment (complete vs. partial vs. no change).

6. To examine and compare pre-specified molecular markers such as Ki-67, phospho-mTOR, YB-1, COX-2, HuR, phospho-p70 S6K, p65 NF kappa B, PTEN, PI3-K, Akt, and a marker for stem cell like breast cancers (SOX-10) on core biopsy before and after end of chemotherapy.

Objectives of Substudies:

1. To assess and correlate circulating tumor cells and proteins with the effect of treatment(CTC Substudy).

2. To compare the pathologic complete response (pCR), breast conservation, clinical and imaging response rate (after four cycles and before surgery) in patients where the tumor shows a favorable profile of a predetermined combined biomarker set to those where the tumor does not show it (PREDICT Substudy).

3. To determine the percentage of patients in which conventional axillary clearance can be substituted by sentinel node biopsy when a predetermined clinical algorithm is used (SENTINA Substudy).

4. To assess the surgical outcome according to patient's and surgeon's perspectives in correlation with clinical and pathological response to systemic treatment (SOS - Surgical Outcome Substudy).

5. To correlate Single Nucleotide Polymorphisms (SNPs) of genes which are either involved in the metabolism or in the effectiveness of the distinct therapies with the associated toxicity and histologically assessed treatment effect (Pharmacogenomic Substudy). ;

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Breast Cancer
• Breast Neoplasms

• NCT number: NCT00567554
• Study type: Interventional
• Source: German Breast Group
• Status: Completed
• Phase: Phase 3
• Start date: October 2007
• Completion date: October 2015