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A Phase II Randomized Trial of Neoadjuvant Trastuzumab or Lapatinib or the Combination of Trastuzumab and Lapatinib, Followed by Docetaxel and Carboplatin with Trastuzumab and/or Lapatinib in Patients with HER2+ Breast Cancer

ABSTRACT: A Phase II Randomized Trial of Neoadjuvant Trastuzumab or Lapatinib or the Combination of Trastuzumab and Lapatinib, Followed by Docetaxel and Carboplatin with Trastuzumab and/or Lapatinib in Patients with HER2+ Breast Cancer

PROVIDER: PRJNA541356 | ENA |

REPOSITORIES: ENA

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Project description:CALGB 40601 was activated as a 3-arm study (paclitaxel + trastuzumab + lapatinib [THL], paclitaxel + trastuzumab [TH] and paclitaxel + lapatinib [TL]). In December 2010, twoneoadjuvant studies were presented at the Cancer Therapy and Research Center-American Association for Cancer Research (CTRC-AACR) San Antonio Breast Cancer Symposium that affected the scientific and practical enthusiasm for the TL arm. For this reason the CALGB 40601 has been amended to omit the TL treatment arm (arm 3). In the Geparquinto trial, patients with HER2-positive breast cancer received epirubicin/cyclophosphamide followed by docetaxel combined either with trastuzumab (EC-DOC-H) or lapatinib (EC-DOC-L) neoadjuvantly, then trastuzumab for a total of 12 months adjuvantly [34]. Pathologic complete response (pCR) in breast and axilla was the primary endpoint. Among 620 patients randomized, there was a higher pCR rate (31% vs 22%) and lower toxicity with fewer discontinuations (10% vs 16%) among patients on the trastuzumab arm than the lapatinib arm. The first results of the NeoALTTO trial were similar [35]. Approximately 450 women with HER2-positive breast cancer received a lead-in phase of 6 weeks of biologic therapy withlapatinib (L), trastuzumab (H), or both, then paclitaxel was added for an additional 12 weeks prior to surgery. All drugs were given at doses similar to CALGB 40601. Postoperative adjuvant therapy included additional chemotherapy and biologic therapy, however, the presentation focused solely on the primary endpoint of pCR in the breast at surgery; no longterm outcomes were presented. There were more grade > 3 adverse events in the lapatinib arm compared with the trastuzumab arm, including diarrhea (23% vs 2%), hepatic abnormalities (13% vs 1%), and neutropenia (16% vs 3%). The only death occurred in the combined biologic (LH) arm. Failure to complete treatment as planned was higher in the L (34%) and LH arms (39%) that in the H arm (u%). PCR was highest with LH-paclitaxel (51%), followed by H-paclitaxel (30%), and L-paclitaxel (25%). Based on the inferior results and higher toxicity of the investigational lapatinib arms of these studies and in discussion with CTEP, in January 2011 it was decided to amend CALGB 40601 to omit Arm 3 (TL). Those patients on this arm will complete protocol therapy as perthe original study design. In CALGB 40601, it is recommended that all patients receive trastuzumab adjuvantly for 1 year, hence all of the patients including those previously randomized to the TL neoadjuvant arm, will be able to receive the known benefit of trastuzumab. After local IRB approval of Update #5, the remainder of the patients will be enrolled and randomized to Arm 1 (THL) and Arm 2 (TH) in a 2:1 fashion. Given that TH isthe standard regimen, and is also clearly the best tolerated, we will continue that arm of thestudy as the comparator, with THL as the only investigational arm.

Project description:Background: Current protocols for the treatment of ovarian cancer include combination chemotherapy with a platinating agent and a taxane. However, many patients experience relapse of their cancer and the development of drug resistance is not uncommon, making successful second line therapy difficult to achieve. The objective of this study was to develop a cell line resistant to both carboplatin and docetaxel (dual drug resistant ovarian cell line A2780CBNDXL), along with single agent resistant lines (docetaxel resistant A2780DXL and carboplatin resistant A2780CBN), to investigate the mechanisms which underlie the development of dual drug resistance. Methods: The A2780 epithelial ovarian cancer cell line was used to select for isogenic carboplatin, docetaxel and dual drug resistant cell lines. A selection method of gradually increasing drug doses was implemented to avoid clonal selection. Resistance was confirmed using a clonogenic assay. Changes in gene expression associated with the development of drug resistance were determined by microarray analysis compared to parental co-culture control A2780CC. Changes in selected genes were validated by QPCR and immunoblotting. Results: Three isogenic cell lines were developed and resistance to each drug or the combination of drugs was confirmed. Development of resistance was accompanied by a reduced growth rate. The microarray and QPCR analyses showed that unique changes in gene expression occurred in the dual drug resistant cell line and that genes known to be involved in resistance could be identified in all cell lines. Conclusions: Novel changes in gene expression can occur in the development of dual drug resistance, indicating that dual drug resistance is not a simple combination of the changes occurring in single agent resistance Carboplatin, docetaxel (GSE26129) and carboplatin/docetaxel dual resistant cell lines of ovarian A2780 were generated for gene expression profilling. Two colour microarray of Agilent whole human genome nucleotide arrays was conducted with two replicate of both forward and reverse labellings for each cell line. Four arrays were used for this experiments. And it was four replicate of both forward and reverse labellings for A2780 cells. Eight arrays were used for this experiments

Dataset Information

A Phase II Randomized Trial of Neoadjuvant Trastuzumab or Lapatinib or the Combination of Trastuzumab and Lapatinib, Followed by Docetaxel and Carboplatin with Trastuzumab and/or Lapatinib in Patients with HER2+ Breast Cancer

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