Ignite Creation Date:
2025-12-24 @ 10:58 PM
Ignite Modification Date:
2026-01-03 @ 8:39 PM
Study NCT ID:
NCT02015169
Status:
COMPLETED
Last Update Posted:
2018-01-17
First Post:
2013-09-17
Is NOT Gene Therapy:
True
Has Adverse Events:
False
Brief Title:
Phase II Study of Neoadjuvant XELOX + Lapatinib in HER2(+) Gastric Cancer Patients With Liver Metastasis
Sponsor:
Samsung Medical Center
Organization:
Study Overview
Official Title:
Phase II Study of Neoadjuvant XELOX + Lapatinib in HER2(+) Gastric Cancer Patients With Liver Metastasis
Status:
COMPLETED
Status Verified Date:
2018-01
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
We planned this study to investigate the efficacy and safety of XELOX (capecitabine and oxaliplatin) plus lapatinib treatment in HER2-positive gastric cancer patients with liver metastasis.
Detailed Description:
Gastric cancer is the leading cause of cancer death worldwide with the incidence of 18.9/100,000 per year and the mortality rate of 14.7/100,000 per year \[1\] and is the most common malignancy in Korea\[2\]. Metastatic gastric cancer remains a therapeutic challenge for medical oncologists due to poor prognosis. Several randomized phase III trials comparing combination chemotherapy such as 5-fluorouracil (5-FU), doxorubicin, and mitomycin (FAM), or 5-FU, doxorubicin, and high-dose methotrexate (FAMTX) with best supportive care have demonstrated significantly prolonged overall survival (8 - 10 months) for chemotherapy group as compared to best supportive care alone (3 - 5 months)\[3, 4\].
In quest of a novel therapeutic target for gastric cancer, HER2 overexpression has been tested and was reported in 6-35% of stomach and gastroesophageal tumors \[5\]. Trastuzumab, a humanized monoclonal antibody which selectively targets HER2, has shown survival benefit in patients with HER2(+) metastatic breast cancer \[6-8\]. The ToGA trial is the first randomized, prospective, multicenter, phase III trial to study the efficacy and safety of trastuzumab in HER2(+) GC \[9\]. Of 3,807 tumor samples screened for Her2 status, 22.1% were Her2 positive and 594 patients were randomized to receive chemotherapy alone or chemotherapy + trastuzumab.
The ToGA trial demonstrated a significant survival benefit in the transtuzumab +chemotherapy when compared with chemotherapy alone arm: 13.5 vs. 11.1 months, respectively (p=0.0048; HR 0.74; 95% CI 0.60, 0.91). ORR was 47.3% in the trastuzumab + 5-FU/CDDP (or capecitabine/CDDP) arm and 34.5% in the chemotherapy alone arm (p=0.0017). The ToGA trial is the first phase III trial to demonstrate survival benefit from molecularly targeted agent in gastric cancer.
Of note, 70 - 80% of patients HER2 overexpressing breast cancer do not respond to trastuzumab due to either primary or acquired resistance. One of the important mechanisms for trastuzumab resistance is the accumulation of truncated forms of the HER2 receptor which lack the extracellular trastuzumab-binding domain (Figure 2). P95HER2, an amino terminally truncated carboxyl terminal fragments of HER2, is frequently found in HER2(+) breast cancer cell lines and tumor specimens (\~20%)\[11\]. Intriguingly, recent study showed that p95HER2 (+) breast cancer cells were resistant to trastuzumab but remained sensitive to the antiproliferative effects of the tyrosine kinase inhibitor lapatinib, both in vitro and in vivo\[11\]. In addition, patients with p95HER2(+)breast cancer were resistant to trastuzumab with significantly lower response rate when compared with full-length HER2(+) breast cancer (11.1% vs 51.4%, respectively; P = 0.029).
We have surveyed the incidence of p95HER2 expression in fresh frozen tissues from gastric cancer and found that \> 60% of HER2 (3+) GC demonstrated p95HER2. Hence, the role of lapatinib may be more promising than trastuzumab in GC HER2(+) patients with truncation.
In quest of a novel therapeutic target for gastric cancer, HER2 overexpression has been tested and was reported in 6-35% of stomach and gastroesophageal tumors \[5\]. Trastuzumab, a humanized monoclonal antibody which selectively targets HER2, has shown survival benefit in patients with HER2(+) metastatic breast cancer \[6-8\]. The ToGA trial is the first randomized, prospective, multicenter, phase III trial to study the efficacy and safety of trastuzumab in HER2(+) GC \[9\]. Of 3,807 tumor samples screened for Her2 status, 22.1% were Her2 positive and 594 patients were randomized to receive chemotherapy alone or chemotherapy + trastuzumab.
The ToGA trial demonstrated a significant survival benefit in the transtuzumab +chemotherapy when compared with chemotherapy alone arm: 13.5 vs. 11.1 months, respectively (p=0.0048; HR 0.74; 95% CI 0.60, 0.91). ORR was 47.3% in the trastuzumab + 5-FU/CDDP (or capecitabine/CDDP) arm and 34.5% in the chemotherapy alone arm (p=0.0017). The ToGA trial is the first phase III trial to demonstrate survival benefit from molecularly targeted agent in gastric cancer.
Of note, 70 - 80% of patients HER2 overexpressing breast cancer do not respond to trastuzumab due to either primary or acquired resistance. One of the important mechanisms for trastuzumab resistance is the accumulation of truncated forms of the HER2 receptor which lack the extracellular trastuzumab-binding domain (Figure 2). P95HER2, an amino terminally truncated carboxyl terminal fragments of HER2, is frequently found in HER2(+) breast cancer cell lines and tumor specimens (\~20%)\[11\]. Intriguingly, recent study showed that p95HER2 (+) breast cancer cells were resistant to trastuzumab but remained sensitive to the antiproliferative effects of the tyrosine kinase inhibitor lapatinib, both in vitro and in vivo\[11\]. In addition, patients with p95HER2(+)breast cancer were resistant to trastuzumab with significantly lower response rate when compared with full-length HER2(+) breast cancer (11.1% vs 51.4%, respectively; P = 0.029).
We have surveyed the incidence of p95HER2 expression in fresh frozen tissues from gastric cancer and found that \> 60% of HER2 (3+) GC demonstrated p95HER2. Hence, the role of lapatinib may be more promising than trastuzumab in GC HER2(+) patients with truncation.
Study Oversight
Has Oversight DMC:
True
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?: