Phase II Study of Neoadjuvant XELOX + Lapatinib in HER2(+) Gastric Cancer Patients With Liver Metastasis
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|ClinicalTrials.gov Identifier: NCT02015169|
Recruitment Status : Completed
First Posted : December 19, 2013
Last Update Posted : January 17, 2018
|Condition or disease||Intervention/treatment||Phase|
|HER2-positive Gastric Cancer Patients With Liver Metastasis||Drug: Lapatinib||Phase 2|
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  and is the most common malignancy in Korea. 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 . 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 . 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%). 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. 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 Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||32 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||Phase II Study of Neoadjuvant XELOX + Lapatinib in HER2(+) Gastric Cancer Patients With Liver Metastasis|
|Actual Study Start Date :||July 9, 2012|
|Actual Primary Completion Date :||July 17, 2017|
|Actual Study Completion Date :||November 17, 2017|
D1 Oxaliplatin130mg/m2 + D5W 500ml MIV over 2hrs
D1-D14 Capecitabine 850mg/m2 p.o bid
D1 ~ Lapatinib 1250 mg qd dailiy
lapatinib 1250mg qd daily up to 8 cycles (3 weeks * 8 cycles = 24 weeks)
Other Name: Tykerb, GSK
- complete resection rate (R0 resection rate) (defined as no macroscopic or microscopic residual tumor). [ Time Frame: after surgery, up to 3weeks ]
- response rate based on RECIST 1.1 [ Time Frame: every 3 cycles, up to 24weeks ]
- disease-free survival [ Time Frame: after surgery, every 3 months ]
- progression-free survival [ Time Frame: every 3 cycles for 6 months and ten every 3 months up to 3 years ]from date of study enrollment until the date of first documented progression or date of death from any cause, whichever came first
- safety and toxicity based on NCI CTCAE ver. 4.0 [ Time Frame: every cycles, up to 24 weeks ]Number of participants with adverse events
- Exploratory biomarker analysis [ Time Frame: every 3 cycles, up to 24weeks ]change in circulating tumor cells, HER2 positivity in primary and metastatic tumors, Receptor tyrosine kinase activation profiling including total HER1, HER2, HER3, phosphorylated HER1, HER2, HER3 - Prometheus, USA, Correlation between response rate and p95HER2 (truncated HER2)) Correlation between RR and RNA sequencing (all available tissue specimens)
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02015169
|Korea, Republic of|
|Samsung Medical Center|
|Seoul, Korea, Korea, Republic of, 135-720|
|Principal Investigator:||Jeeyun Lee, MD, PhD||Division of Oncology, Department of Medicine, Samsung Medical Center|