Ignite Creation Date:
2024-05-06 @ 1:55 PM
Last Modification Date:
2024-10-26 @ 1:22 PM
Study NCT ID:
NCT04168931
Status:
TERMINATED
Last Update Posted:
2023-01-17
First Post:
2019-11-05
Brief Title:
Trastuzumab to Patients With Advanced Gastric Cancer With HER2 Positive Expression in CTC
Sponsor:
AC Camargo Cancer Center
Organization:
AC Camargo Cancer Center
Study Overview
Official Title:
Efficacy of Adding Trastuzumab to Standard Chemotherapy in Patients With Advanced HER2-negative Gastric Cancer and HER2 Positive Expression in Circulating Tumor Cells
Status:
TERMINATED
Status Verified Date:
2023-01
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
recruitment failure
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
GASTHER2
Brief Summary:
BACKGROUND Gastric cancer is one of the most common cancers and is one of the most deadly cancers Most patients have advanced disease and should receive first-line trastuzumab-associated chemotherapy when the biopsy is positive for immunocytochemical expression and or HER2 gene amplification A study conducted by our group noted that there may be disagreement in HER2 expression between circulating tumor cells CTCs and tumor tissue However the effectiveness of using anti-HER2 treatment when only CTC express HER2 is unknown The present study aims to evaluate the expression of HER2 in patients with relapsed or metastatic gastric cancer and what would be the efficacy of adding trastuzumab to chemotherapy when tumor tissue is negative for HER2 but there is expression of this gene in CTCs
OBJECTIVES The primary objectives are to evaluate HER2 expression in circulating tumor cells of relapsed or metastatic gastric cancer patients with negative HER2 expression on tissue biopsy and response to standard treatment with combined anti-HER2 chemotherapy in this population Secondary objectives are to assess the prognostic impact of HER2 positivity on circulating tumor cells in advanced gastric tumors and to evaluate HER2 expression in CTCs at the time of treatment progression
METHODS The investigators will prospectively evaluate HER2 expression in CTC and its response to treatment with standard chemotherapy and addition of trastuzumab in patients with relapsed or metastatic gastric cancer with positive expression of HER2 only in CTC HER2 expression in tissue and in CTC will be evaluated by immunocytochemistry Descriptive statistics will be used to report the results of categorical and continuous variables and respective dispersion measures Time-to-event variables will be reported in Kaplan Meyer medians and curves
EXPECTED RESULTS Upon completion of the study the investigators expect to show the frequency of HER2 expression in this specific population higher radiological response rate with trastuzumab combination compared to chemotherapy alone determine the prognostic impact associated with HER2 expression in CTCs and show the frequency of HER2 expression in CTCs at the time of study treatment progression This study may open a new opportunity for anti-HER2 treatment for gastric cancer patients
OBJECTIVES The primary objectives are to evaluate HER2 expression in circulating tumor cells of relapsed or metastatic gastric cancer patients with negative HER2 expression on tissue biopsy and response to standard treatment with combined anti-HER2 chemotherapy in this population Secondary objectives are to assess the prognostic impact of HER2 positivity on circulating tumor cells in advanced gastric tumors and to evaluate HER2 expression in CTCs at the time of treatment progression
METHODS The investigators will prospectively evaluate HER2 expression in CTC and its response to treatment with standard chemotherapy and addition of trastuzumab in patients with relapsed or metastatic gastric cancer with positive expression of HER2 only in CTC HER2 expression in tissue and in CTC will be evaluated by immunocytochemistry Descriptive statistics will be used to report the results of categorical and continuous variables and respective dispersion measures Time-to-event variables will be reported in Kaplan Meyer medians and curves
EXPECTED RESULTS Upon completion of the study the investigators expect to show the frequency of HER2 expression in this specific population higher radiological response rate with trastuzumab combination compared to chemotherapy alone determine the prognostic impact associated with HER2 expression in CTCs and show the frequency of HER2 expression in CTCs at the time of study treatment progression This study may open a new opportunity for anti-HER2 treatment for gastric cancer patients
Detailed Description:
INTRODUCTION Gastric cancer is one of the most common cancers worldwide Its incidence varies according to its geographic region being more common in East Asia Eastern Europe and South America About 70 of gastric neoplasms occur in developing countries Globally it is estimated that in 2018 over 1 million cases were diagnosed with about 780000 deaths making gastric cancer the 5th in frequency and 3rd in mortality In Brazil 13540 new cases were diagnosed in 2018 being the third leading cause of cancer death in Brazil in males Most patients already have inoperable advanced or metastatic disease at diagnosis thus requiring palliative treatment Over 90 of stomach tumors are adenocarcinomas and in terms of histology Laurens classification subdivided gastric cancer into diffuse undifferentiated or intestinal cancer and both types have distinct clinical and pathological features The diffuse type occurs in all age groups with equal gender distribution involves the body or the entire stomach and has a greater tendency to invade the gastric wall resulting in plastic linitis and to metastasize as well as a faster disease progression and worse prognosis On the other hand the intestinal type predominates in men and the elderly occurring predominantly in the gastric antrum and notch Although both subtypes are related to H pylori infection in the intestinal type the evolution of sequential preneoplastic alterations is observed namely atrophic gastritis intestinal metaplasia dysplasia and adenocarcinoma Such a sequence may not occur in diffuse type There is also a rare genetically related type called hereditary diffuse gastric cancer HDGC that is not related to H pylori infection Diffuse-type adenocarcinoma is the major histological subtype of HDGC In addition to diffuse hereditary gastric cancer syndrome gastric cancer is present in the description of several other hereditary syndromes such as Lynch syndrome juvenile polyposis syndrome Peutz-Jeghers syndrome Familial Adenomatous Polyposis ataxia-telangiectasia syndrome Li-Fraumeni and Xeroderma Pigmentosa Regardless of association with genetic syndrome or even histological type it is necessary to investigate the amplification of the human epidermal growth factor 2 HER2 gene in the case of recurrent or metastatic gastric cancer Today of well-defined importance in gastric cancer HER2 was initially recognized 30 years ago as an amplified oncogene in over 20 of breast cancers and after the genomic revolution has recently been seen to amplify in many other cancers HER2 is a tyrosine kinase-like receptor that crosses the cell membrane of cells with the extracellular half not coupling to ligands but designed to recognize ligand-activated forms of family members as the factor of human epidermal growth EGFR HER3 or HER4 leading to dimerization with these receptors The cytoplasmic part of HER2 and its partners contains a kinase domain that triggers HER2 kinase activity The end result is phosphorylation at various tyrosine residues and recruitment of second messenger proteins for these phosphotyrosines When the gene is amplified in cancer cells the result is massive overexpression of HER2 which causes continuous activation of the various biological pathways that promote cell proliferation For gastric cancer positivity for HER2 expression as assessed by immunohistochemistry IHC or in situ hybridization immunofluorescence FISH may vary between 8 and 36 between studies in the literature However those studies that considered only intestinal histology found positive expression of HER2 between 20 and 30 in patients biopsies A study conducted at AC Camargo identified 12 HER2 expression and 8 amplification in gastric tumors with greater association with intestinal subtype and poor survival Because it has a worse prognosis and has a target drug treatment of tumors with HER2 amplification requires HER2-targeted agents often in combination with chemotherapy or hormone therapies Trastuzumab-associated chemotherapy fluoro-uracil and platinum is the first-line standard treatment for HER2-positive metastatic gastric cancer based on the phase III ToGA study Trastuzumab for Gastric Cancer This study recruited 594 patients and showed a median overall survival gain of 138 months for the combination versus 111 months in the chemotherapy arm alone hazard ratio HR 074 95 CI 060 to 091 P 00046 Survival gain was even more significant in the HER2 overexpressed subgroup IHC 3 or IHC 2 with positive FISH which achieved a median overall survival of 16 months Regarding the second line however phase III studies failed to demonstrate the benefit of using anti-HER2 therapy In the TyTan study the addition of lapatinib in the second line was not superior to chemotherapy alone In the GATSBY study the use of trastuzumab emtansine was also not superior to taxane chemotherapy In this study 77 of patients received first-line anti-HER2 agents Several clinical reasons may explain these disappointing results One of these is resistance acquired after use of anti-HER2-based therapy Another reason is the loss of HER2 expression as reported in a study by Pietroantonio et al that demonstrated loss of HER2 positivity and overexpression in 32 of the tissue samples analyzed after anti-HER2 therapy It is already known that in selective breast cancer treatment pressure can eradicate HER2-expressing clones and lead to proliferation of those HER2-negative clones a phenomenon that can occur in gastric cancer because of the marked heterogeneity that exists in stomach tumors In addition it is known that HER2 expression discrepancy may exist between primary and metastatic or recurrent breast tumors probably due to sample variability In discordant cases HER2-positive metastases from negative primary tumors are more frequent than the opposite Therefore it is recommended that metastatic disease on first relapse be biopsied as part of the investigation and HER2 status should be reevaluated In cases of gastric cancer this issue has not been widely explored
In this sense the GASTHER 1 study investigated the role of HER2 expression reassessment in stomach cancer at primary metastatic or recurrent sites in patients whose primary tumor was initially negative for HER2 expression The results showed a positive rescue of 87 confirming the relevant heterogeneity of HER2 status This heterogeneity however may also be associated with the HER2 status assessment method A prospective study in patients with localized gastric adenocarcinoma and treated with perioperative chemotherapy at our institution found 694 agreement for HER2 expression in primary tumor tissue biopsy and in paired circulating tumor cells CTCs HER2 in CTCs showed higher positivity compared to tumor tissue 43 x 11 The positivity in HER2 CTCs was 60 for HER2-negative localized gastric cancer patients treated with perioperative chemotherapy whose disease recurred Also HER2 expression in CTCs correlated with progression-free survival but in the tumor tissue the same relationship was not found
BACKGROUND Analysis of CTCs from the blood of patients with gastric adenocarcinoma may be useful to better understand the behavior of the disease as well as patients more likely to respond to treatment and may offer a less invasive way of investigating tumor dynamics In addition prospective evaluation of HER2 expression in CTCs has not been evaluated in metastatic gastric cancer and the frequency with which this expression changes after first-line treatment with standard regimen with trastuzumab at the time of disease progression Thus this study is necessary to evaluate the frequency with which these phenomena occur and thus expand the knowledge of the dynamics of gastric cancer tumor biology
Hypothesis
Primary
1 There is disagreement in HER2 expression positivity between diagnostic tissue biopsy preferably metastasis and circulating tumor cells in metastatic intestinal cancer
2 Positivity for HER2 expression in circulating tumor cells in relapsed or metastatic gastric cancer may predict response to standard treatment with trastuzumab combination chemotherapy
Secondary
1 HER2 expression may have prognostic effect when positive in CTCs
2 HER2 expression in CTCs may be modified following treatment with anti-HER2 therapy
Objectives
Primary
1 Evaluate HER2 expression in circulating tumor cells of patients with relapsed or metastatic gastric cancer with negative HER2 expression on tissue biopsy
2 To evaluate the response to standard treatment with combination chemotherapy with trastuzumab in relapsed or metastatic gastric cancer with positive expression of HER2 on CTC and negative on tissue biopsy
Secondary
1 To verify the prognostic impact of HER2 positivity in circulating tumor cells in advanced gastric tumors
2 Evaluate HER2 expression in CTCs at the time of progression to standard first-line treatment with anti-HER2 therapy in patients who previously had HER2 positivity
In this sense the GASTHER 1 study investigated the role of HER2 expression reassessment in stomach cancer at primary metastatic or recurrent sites in patients whose primary tumor was initially negative for HER2 expression The results showed a positive rescue of 87 confirming the relevant heterogeneity of HER2 status This heterogeneity however may also be associated with the HER2 status assessment method A prospective study in patients with localized gastric adenocarcinoma and treated with perioperative chemotherapy at our institution found 694 agreement for HER2 expression in primary tumor tissue biopsy and in paired circulating tumor cells CTCs HER2 in CTCs showed higher positivity compared to tumor tissue 43 x 11 The positivity in HER2 CTCs was 60 for HER2-negative localized gastric cancer patients treated with perioperative chemotherapy whose disease recurred Also HER2 expression in CTCs correlated with progression-free survival but in the tumor tissue the same relationship was not found
BACKGROUND Analysis of CTCs from the blood of patients with gastric adenocarcinoma may be useful to better understand the behavior of the disease as well as patients more likely to respond to treatment and may offer a less invasive way of investigating tumor dynamics In addition prospective evaluation of HER2 expression in CTCs has not been evaluated in metastatic gastric cancer and the frequency with which this expression changes after first-line treatment with standard regimen with trastuzumab at the time of disease progression Thus this study is necessary to evaluate the frequency with which these phenomena occur and thus expand the knowledge of the dynamics of gastric cancer tumor biology
Hypothesis
Primary
1 There is disagreement in HER2 expression positivity between diagnostic tissue biopsy preferably metastasis and circulating tumor cells in metastatic intestinal cancer
2 Positivity for HER2 expression in circulating tumor cells in relapsed or metastatic gastric cancer may predict response to standard treatment with trastuzumab combination chemotherapy
Secondary
1 HER2 expression may have prognostic effect when positive in CTCs
2 HER2 expression in CTCs may be modified following treatment with anti-HER2 therapy
Objectives
Primary
1 Evaluate HER2 expression in circulating tumor cells of patients with relapsed or metastatic gastric cancer with negative HER2 expression on tissue biopsy
2 To evaluate the response to standard treatment with combination chemotherapy with trastuzumab in relapsed or metastatic gastric cancer with positive expression of HER2 on CTC and negative on tissue biopsy
Secondary
1 To verify the prognostic impact of HER2 positivity in circulating tumor cells in advanced gastric tumors
2 Evaluate HER2 expression in CTCs at the time of progression to standard first-line treatment with anti-HER2 therapy in patients who previously had HER2 positivity
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None