Ignite Creation Date:
2024-05-05 @ 11:59 AM
Last Modification Date:
2024-10-26 @ 9:18 AM
Study NCT ID:
NCT00206492
Status:
TERMINATED
Last Update Posted:
2017-08-01
First Post:
2005-09-14
Brief Title:
Trial of ZD1839 Iressa and Tamoxifen in Breast Cancer Patients
Sponsor:
Baylor Breast Care Center
Organization:
Baylor Breast Care Center
Study Overview
Official Title:
A Neoadjuvant Phase II Trial of ZD1839 Iressa and Tamoxifen in Inoperable Locally Advanced HER2-Overexpressing ER-Positive Breast Cancer Patients Biologic Correlative Study AZ 1839US0303
Status:
TERMINATED
Status Verified Date:
2017-07
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
halted by the PI only 3 of 45 subjects were accrued
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
The researchers want to learn whether ZD1839 can improve the activity of tamoxifen a drug that participants will receive for the treatment of the type of breast cancer being studied Tamoxifen medicine is part of the standard treatment for the type of breast cancer being studied It is approved for the treatment of this problem In order to help the researchers understand how the cancer responds to these medicines the researchers will take a small tissue sample biopsy of the breast cancer before beginning treatment and after two weeks of treatment at 6 weeks and when surgery is done as part of treatment for the cancer If participants do not respond to treatment another biopsy will be done to see why the participants did not respond These samples will also be collected to look at different characteristics of the cancer The researchers cannot and do not guarantee that participants will benefit if they take part in this study
Detailed Description:
Epidermal growth factor receptor EGFR is expressed or over-expressed in many human solid tumors and plays an important role in progression to invasion and metastases The EGFR tyrosine kinase is activated by binding of a variety of ligands to the external domain Autophosphorylation by the EGFR tyrosine kinase initiates a signaling cascade that feeds downstream cell cycle control machinery regulating cell proliferation and these reactions are a major component in growth factor-induced proliferation of cancer cells
The Erb-B HER receptor family consists of four transmembrane tyrosine kinases Erb-B1-epithermal growth factor receptor EGFR HER1 Erb-B2neu HER2 Erb-B3 HER3 and Erb-B4 HER4 The ectodomain of Erb-B1 Erb-B3 and Erb-B4 interacts with a specific set of ligand whereas no ligand has been identified thus far for the Erb-B2 receptor Nonetheless Erb-B2 can be activated by any of the other ligand-activated Erb-B coreceptors Upon ligand binding to the active domain of Erb-B1 Erb-B3 or Erb-B4 these receptors preferentially recruit Erb-B2 into a heterodimeric complex in which the Erb-B2 kinase can modulate receptor internalization and prolong signal transduction
Data are now emerging that Erb-B2 modulates cellular p27 and cyclin D1 protein levels through both RasMAP kinase and PI3KAkt signaling Reversible interruption of Erb-B2 function by trastuzumab Herceptin has been shown to inhibit MAPk and reduce MAPk-mediated transcription through cyclin D1 In addition the signaling molecule Akt is important in the cell survival pathway Akt inhibits apoptosis and is present in the PI3 kinase pathway which is activated by the EGF family and the IGF family Several biologic arguments support the use of EGR inhibitors to block HER2 signaling In HER2-overexpressing cell lines the HER2 receptor is constitutively phosphorylated This suggests that HER2 may be transactivated through ligand-stimulated EGFR also present in tumor cells In addition overexpression of HER2 enhances the binding of EGFR ligands to the receptor and potentiates EGFR signaling HER2 inactivation has been shown to impair EGFR- mediated transformation and conversely EGFR blocking antibodies can augment the growth inhibitory effect of antiHER2 antibodies in cells with high levels of HER2 Taken together these data suggest that EGFRHER2 crosstalk is present in a subset of human tumors and that interruption of EGFR may reduce HER2 signaling Cell cycle progression is regulated predominantly by cyclin-dependent kinases CDKs which in turn are controlled by a family of CDK inhibitory proteins that include P27KIP1 and P21CIP1-WAF1 Pathways involving CDK inhibitors are commonly destructive in cancer cells ZD1839 is an orally active selective EGFR tyrosine kinase inhibitor that blocks signal transduction pathways implicated in cancer cell proliferation survival and other host-dependent processes promoting cancer growth
In preclinical studies ZD1839 causes tumor growth delay in a range of cancer cell lines and xenografts and tumor regression has been observed at higher doses ZD1839 was also shown to inhibit proliferation in DCIS together with significantly increased apoptosis in these tissues Data from these different cell lines and xenografts suggest that ZD1839 may act via dose-dependent growth inhibition and by increasing apoptosis and may even potentiate the activity of cytotoxic chemotherapy
In one phase II multicenter study 63 women with metastatic breast cancer who could have had any number of previous chemotherapy or hormonal regimens were treated with an oral daily dose of 500 mg of ZD1839 until disease progression intolerable toxicity or withdrawal of consent Dosage reduction to 250 mg daily was allowed for toxicity The primary end point was clinical benefit rate complete response partial response modified ICCWHO criteria stable disease at 6 months There was 1 partial response and 2 patients with stable disease for more than 4 months 4 months in 1 patient and 7 months in the other for a total of 48 clinical benefit An additional 4 patients had stable disease lasting 1 to 2 months and another 2 patients had stable disease lasting 1 month resulting in an overall 143 partial response or stable disease in this heavily pre-treated population 15 were on treatment for 4 to 8 months and 2 patients stayed on treatment despite progression because of significant bone pain palliation
Preliminary efficacy and toxicity data from another phase II trial of 22 ER-positive or ER-negative patients were reported at the same conference In that study patients could have had 1 previous chemotherapy regimen or were experiencing disease progression while on tamoxifen and were given 500 mg of ZD1839 daily Two patients had a partial response and 10 had stable disease at 4 weeks In both trials the toxicity profile was identical to that seen in patient with NSCLC
The Erb-B HER receptor family consists of four transmembrane tyrosine kinases Erb-B1-epithermal growth factor receptor EGFR HER1 Erb-B2neu HER2 Erb-B3 HER3 and Erb-B4 HER4 The ectodomain of Erb-B1 Erb-B3 and Erb-B4 interacts with a specific set of ligand whereas no ligand has been identified thus far for the Erb-B2 receptor Nonetheless Erb-B2 can be activated by any of the other ligand-activated Erb-B coreceptors Upon ligand binding to the active domain of Erb-B1 Erb-B3 or Erb-B4 these receptors preferentially recruit Erb-B2 into a heterodimeric complex in which the Erb-B2 kinase can modulate receptor internalization and prolong signal transduction
Data are now emerging that Erb-B2 modulates cellular p27 and cyclin D1 protein levels through both RasMAP kinase and PI3KAkt signaling Reversible interruption of Erb-B2 function by trastuzumab Herceptin has been shown to inhibit MAPk and reduce MAPk-mediated transcription through cyclin D1 In addition the signaling molecule Akt is important in the cell survival pathway Akt inhibits apoptosis and is present in the PI3 kinase pathway which is activated by the EGF family and the IGF family Several biologic arguments support the use of EGR inhibitors to block HER2 signaling In HER2-overexpressing cell lines the HER2 receptor is constitutively phosphorylated This suggests that HER2 may be transactivated through ligand-stimulated EGFR also present in tumor cells In addition overexpression of HER2 enhances the binding of EGFR ligands to the receptor and potentiates EGFR signaling HER2 inactivation has been shown to impair EGFR- mediated transformation and conversely EGFR blocking antibodies can augment the growth inhibitory effect of antiHER2 antibodies in cells with high levels of HER2 Taken together these data suggest that EGFRHER2 crosstalk is present in a subset of human tumors and that interruption of EGFR may reduce HER2 signaling Cell cycle progression is regulated predominantly by cyclin-dependent kinases CDKs which in turn are controlled by a family of CDK inhibitory proteins that include P27KIP1 and P21CIP1-WAF1 Pathways involving CDK inhibitors are commonly destructive in cancer cells ZD1839 is an orally active selective EGFR tyrosine kinase inhibitor that blocks signal transduction pathways implicated in cancer cell proliferation survival and other host-dependent processes promoting cancer growth
In preclinical studies ZD1839 causes tumor growth delay in a range of cancer cell lines and xenografts and tumor regression has been observed at higher doses ZD1839 was also shown to inhibit proliferation in DCIS together with significantly increased apoptosis in these tissues Data from these different cell lines and xenografts suggest that ZD1839 may act via dose-dependent growth inhibition and by increasing apoptosis and may even potentiate the activity of cytotoxic chemotherapy
In one phase II multicenter study 63 women with metastatic breast cancer who could have had any number of previous chemotherapy or hormonal regimens were treated with an oral daily dose of 500 mg of ZD1839 until disease progression intolerable toxicity or withdrawal of consent Dosage reduction to 250 mg daily was allowed for toxicity The primary end point was clinical benefit rate complete response partial response modified ICCWHO criteria stable disease at 6 months There was 1 partial response and 2 patients with stable disease for more than 4 months 4 months in 1 patient and 7 months in the other for a total of 48 clinical benefit An additional 4 patients had stable disease lasting 1 to 2 months and another 2 patients had stable disease lasting 1 month resulting in an overall 143 partial response or stable disease in this heavily pre-treated population 15 were on treatment for 4 to 8 months and 2 patients stayed on treatment despite progression because of significant bone pain palliation
Preliminary efficacy and toxicity data from another phase II trial of 22 ER-positive or ER-negative patients were reported at the same conference In that study patients could have had 1 previous chemotherapy regimen or were experiencing disease progression while on tamoxifen and were given 500 mg of ZD1839 daily Two patients had a partial response and 10 had stable disease at 4 weeks In both trials the toxicity profile was identical to that seen in patient with NSCLC
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None