Esophageal Cancer, Gastric Cancer
Conditions
Keywords
adenocarcinoma of the esophagus, adenocarcinoma of the stomach, recurrent esophageal cancer, stage III esophageal cancer, stage IV esophageal cancer, recurrent gastric cancer, stage III gastric cancer, stage IV gastric cancer
Brief summary
RATIONALE: Everolimus may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor. PURPOSE: This phase II trial is studying how well everolimus works in treating patients with previously treated unresectable or metastatic esophageal cancer or stomach cancer.
Detailed description
OBJECTIVES: Primary * To determine the overall disease-control rate (complete response, partial response, or stable disease) in patients with previously treated unresectable or metastatic adenocarcinoma of the upper gastrointestinal tract treated with everolimus. Secondary * To determine the safety and toxicity of everolimus in these patients. * To determine the efficacy of everolimus, in terms of time to response, duration of response, time to tumor progression, progression-free survival, and overall survival, in these patients. * To explore potential correlations between clinical outcome and biomarkers of interest, including S6 protein overexpression and/or other mTOR-related proteins in blood and tumor biopsy samples from these patients. OUTLINE: This is a multicenter study. Patients receive oral everolimus once daily on days 1-14. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity. Blood, serum, and tumor tissue samples are collected for biomarker analysis. After completion of study treatment, patients are followed up every 3 months for 1 year and then every 6 months thereafter.
Interventions
DRUGeverolimus
OTHERlaboratory biomarker analysis
Sponsors
National Cancer Institute (NCI)
University of California, Los Angeles
Translational Oncology Research International
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Diagnosis of adenocarcinoma of the upper gastrointestinal tract * Metastatic or unresectable disease * Received 1-2 prior chemotherapy or biological therapy regimens for unresectable or metastatic disease * Measurable disease in ≥ 1 dimension by CT scan or MRI * Patients whose only measurable lesion is a metastatic lymph node are eligible provided they have permission from the principal investigator * ECOG performance status 0-1 * Life expectancy \> 3 months * ANC ≥ 1,500/mm\^3 * Platelet count ≥ 100,000/mm\^3 * Hemoglobin ≥ 9 g/dL * Total bilirubin ≤ 1.5 times upper limit of normal (ULN) * AST and ALT ≤ 2.5 times ULN (≤ 5.0 times ULN if there is liver metastasis) * Creatinine clearance \> 60 mL/min * Fasting serum cholesterol \< 300 mg/dL or \< 7.75 mmol/L\* * Fasting triglycerides \< 2.5 times ULN\* * INR ≤ 3.5 (for patients on warfarin) * Negative pregnancy test * Fertile patients must use effective contraception during and for ≥ 4 months after completion of study treatment (oral, implantable, or injectable contraceptives are not considered effective contraception for this study) * More than 30 days since prior chemotherapy, surgery, radiotherapy, or investigational agents
Exclusion criteria
* uncontrolled diabetes mellitus, defined as fasting serum glucose \> 1.5 times ULN * severely impaired lung function * known HV infection * active, bleeding diathesis * unstable angina pectoris, symptomatic congestive heart failure, or myocardial infarction within the past 6 months * serious uncontrolled cardiac arrhythmia * active or uncontrolled infection requiring parenteral antimicrobials * known liver disease (e.g., cirrhosis, chronic active hepatitis, or chronic persistent hepatitis) * inability to swallow, impaired gastrointestinal (GI) function, or GI disease (e.g., ulcerative colitis, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection) that would significantly alter the absorption of study drugs or preclude the use of oral medications * other malignancy within the past 5 years except for nonmelanoma skin cancer or cervical carcinoma in situ * known hypersensitivity to everolimus, sirolimus, or temsirolimus or to their excipients * other medical conditions that, in the opinion of the investigator, would preclude study participation * prior mTOR inhibitors (e.g., rapamycin, CCI-779) * concurrent chronic treatment with steroids or another immunosuppressive agent * concurrent prophylactic use of hematopoietic growth factors * concurrent anticancer agents or therapy (including radiotherapy) * other concurrent experimental agents * concurrent strong inhibitors or inducers of the isoenzyme CYP3A4
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Disease-control Rate in Patients With Previously Treated Unresectable or Metastatic Adenocarcinoma of the Upper Gastrointestinal Tract Treated With Everolimus. | Radiologic disease assessment was performed every 8 weeks (14 days = 1 cycle) treatment discontinuation. | Disease control rate (DCR), defined as complete response (CR) + partial response (PR) + stable disease (SD) according to Response Evaluation Criteria In Solid Tumors (RECIST) criteria. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | 2.5 year | Overall Survival (OS), defined as the time from date of initial treatment to date of death. Survival function was estimated using the Kaplan-Meier method. |
| Efficacy in Terms of Progression Free Response | evry 3 months in year 1, every 6 months after that | Progression-free survival (PFS), was defined as the time from the date of initial treatment to first objective documentation of disease progression, or death. Estimated using the Kaplan-Meier method. Complete response (CR) + partial response (PR) + stable disease (SD) were determined according to Response Evaluation Criteria In Solid Tumors (RECIST) criteria. Radiologic disease assessments were utilized. |
| Observed Biomarkers | 30 months | Potential correlations between clinical outcome and biomarkers of interest, including S6 protein overexpression and/or other mTOR-related proteins in tumor tissue samples from these patients. |
| Biomarker Correlations: Progression Free Survival | 30 months | Potential correlations between progression free survival and S6 protein and mTOR-related proteins in tumor tissue samples from these patients. |
| Biomarker Correlations: Time to Progression | 30 months | Potential correlations between time to progression and S6 protein and mTOR-related proteins in tumor tissue samples from these patients. |
Countries
United States
Participant flow
Pre-assignment details
A total of 49 patients were enrolled between December of 2007 and November of 2009 from 18 participating sites including the University of California Los Angeles hospitals and clinics participating in the TRIO-US Network.
Participants by arm
| Arm | Count |
|---|---|
| Everolimus Patients receive oral everolimus once daily on days 1-14. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity
everolimus
laboratory biomarker analysis | 45 |
| Total | 45 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Determined to be Ineligible During Trial | 2 |
| Overall Study | Disease Progression | 1 |
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Everolimus |
|---|---|
| Age, Continuous | 64 years |
| Disease Site Esophagus | 11 participants |
| Disease Site Gastric | 21 participants |
| Disease Site Gastroesophageal Junction | 13 participants |
| Eastern Cooperative Oncology Group (ECOG) score 0 | 15 participants |
| Eastern Cooperative Oncology Group (ECOG) score 1 | 30 participants |
| Race/Ethnicity, Customized Asian | 4 participants |
| Race/Ethnicity, Customized Black | 3 participants |
| Race/Ethnicity, Customized Hispanic | 10 participants |
| Race/Ethnicity, Customized White | 28 participants |
| Region of Enrollment United States | 45 participants |
| Sex: Female, Male Female | 8 Participants |
| Sex: Female, Male Male | 37 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 47 / 47 |
| serious Total, serious adverse events | 24 / 47 |
Outcome results
Primary
Overall Disease-control Rate in Patients With Previously Treated Unresectable or Metastatic Adenocarcinoma of the Upper Gastrointestinal Tract Treated With Everolimus.
Disease control rate (DCR), defined as complete response (CR) + partial response (PR) + stable disease (SD) according to Response Evaluation Criteria In Solid Tumors (RECIST) criteria.
Time frame: Radiologic disease assessment was performed every 8 weeks (14 days = 1 cycle) treatment discontinuation.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Everolimus | Overall Disease-control Rate in Patients With Previously Treated Unresectable or Metastatic Adenocarcinoma of the Upper Gastrointestinal Tract Treated With Everolimus. | 40 percent subjects with disease control |
Secondary
Biomarker Correlations: Progression Free Survival
Potential correlations between progression free survival and S6 protein and mTOR-related proteins in tumor tissue samples from these patients.
Time frame: 30 months
Population: Exploratory analysis of translational endpoints in patient samples, Representative paraffin blocks were required for all participating patients. Tissue blocks were obtained on 39 patients.~p-s6 and p-mTOR IHC expression in tumors
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Everolimus | Biomarker Correlations: Progression Free Survival | p-S6 level 0-2 | 1.8 months |
| Everolimus | Biomarker Correlations: Progression Free Survival | p-S6 level >2 | 3.5 months |
| Everolimus | Biomarker Correlations: Progression Free Survival | p-mTOR level 0-2 | 1.8 months |
| Everolimus | Biomarker Correlations: Progression Free Survival | p-mTOR level >2 | 2.6 months |
Secondary
Biomarker Correlations: Time to Progression
Potential correlations between time to progression and S6 protein and mTOR-related proteins in tumor tissue samples from these patients.
Time frame: 30 months
Population: Exploratory analysis of translational endpoints in patient samples, Representative paraffin blocks were required for all participating patients. Tissue blocks were obtained on 39 patients.~p-s6 and p-mTOR IHC expression in tumors
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Everolimus | Biomarker Correlations: Time to Progression | p-S6 level 0-2 | 1.75 months |
| Everolimus | Biomarker Correlations: Time to Progression | p-S6 level >2 | 3.4 months |
| Everolimus | Biomarker Correlations: Time to Progression | p-mTOR level 0-2 | 1.8 months |
| Everolimus | Biomarker Correlations: Time to Progression | p-mTOR level >2 | 2.6 months |
Secondary
Efficacy in Terms of Progression Free Response
Progression-free survival (PFS), was defined as the time from the date of initial treatment to first objective documentation of disease progression, or death. Estimated using the Kaplan-Meier method. Complete response (CR) + partial response (PR) + stable disease (SD) were determined according to Response Evaluation Criteria In Solid Tumors (RECIST) criteria. Radiologic disease assessments were utilized.
Time frame: evry 3 months in year 1, every 6 months after that
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Everolimus | Efficacy in Terms of Progression Free Response | 1.8 months |
Secondary
Observed Biomarkers
Potential correlations between clinical outcome and biomarkers of interest, including S6 protein overexpression and/or other mTOR-related proteins in tumor tissue samples from these patients.
Time frame: 30 months
Population: Exploratory analysis of translational endpoints in patient samples, Representative paraffin blocks were required for all participating patients. Tissue blocks were obtained on 39 patients.~p-s6 and p-mTOR IHC expression in tumors
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Everolimus | Observed Biomarkers | Tumor Grade 0, p-S6 | 4 number of tissue blocks |
| Everolimus | Observed Biomarkers | Tumor Grade 1+, p-S6 | 15 number of tissue blocks |
| Everolimus | Observed Biomarkers | Tumor Grade 2+, p-S6 | 8 number of tissue blocks |
| Everolimus | Observed Biomarkers | Tumor Grade 3+, p-S6 | 9 number of tissue blocks |
| Everolimus | Observed Biomarkers | Tumor Grade 4+, p-S6 | 3 number of tissue blocks |
| Everolimus | Observed Biomarkers | Tumor Grade 0, p-mTOR | 0 number of tissue blocks |
| Everolimus | Observed Biomarkers | Tumor Grade 1+, p-mTOR | 8 number of tissue blocks |
| Everolimus | Observed Biomarkers | Tumor Grade 2+, p-mTOR | 22 number of tissue blocks |
| Everolimus | Observed Biomarkers | Tumor Grade 3+, p-mTOR | 9 number of tissue blocks |
| Everolimus | Observed Biomarkers | Tumor Grade 4+, p-mTOR | 0 number of tissue blocks |
Secondary
Overall Survival
Overall Survival (OS), defined as the time from date of initial treatment to date of death. Survival function was estimated using the Kaplan-Meier method.
Time frame: 2.5 year
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Everolimus | Overall Survival | 3.4 months |