Adenocarcinoma, Pancreatic Neoplasms
Conditions
Keywords
Advanced Stage, Chemotherapy Naive
Brief summary
The aims of this protocol are: 1. To study the safety and tolerability of the combination of etanercept and gemcitabine in patients with advanced pancreatic cancer: 2. To estimate the anti-tumor effect as measured by the proportion of patients free of disease-progression at six months after treatment initiation.
Detailed description
Rationale: The standard treatment for pancreatic cancer is gemcitabine. This study combines gemcitabine with etanercept, a drug that binds with tumor necrosis factor (TNF) molecules and blocks their activity through inhibiting their interaction with cell surface TNF receptors. TNF is the name for a protein in the body that often helps fight foreign substances. However, research suggests that pancreatic tumors develop resistance to TNF and then use it to support cancer growth. Combining etanercept, a TNF inhibitor, with gemcitabine is a novel approach to advanced pancreatic cancer. Because etanercept has not been tested in combination with gemcitabine, a Phase I study will be conducted first to identify the safest dosage of etanercept, and then a Phase II study will evaluate the efficacy of this combination. Purpose: This study is evaluating the safety of etanercept and gemcitabine for advanced pancreatic cancer in Phase I, and the efficacy of etanercept and gemcitabine for this condition in Phase II. TNF and other inflammatory markers will also be measured in the study. Treatment: Patients in this study will receive gemcitabine and etanercept. Gemcitabine will be administered through an intravenous infusion weekly for seven weeks followed by one week of rest. Additional treatments with gemcitabine will be given for three weeks followed by one week of rest. Patients will administer etanercept to themselves through a small injection underneath the skin twice each week. Six patients will initially be enrolled in Phase I. If severe side effects appear in at least two patients in Phase I, then additional patients will be enrolled and treated with lower dosages of gemcitabine. When the treatments do not produce unacceptable side effects, the Phase I portion of the study will end and Phase II will begin enrolling patients. Patients in the Phase II portion of the study will also receive gemcitabine and etanercept at the safest dosages identified in Phase I. Several tests and exams will be given throughout both portions of the study to closely monitor patients. Treatments will be discontinued due to disease growth or unacceptable side effects.
Interventions
DRUGGemcitabine
The starting dose will be 1000mg/m2 IV, weekly x 7 with a one week rest followed by weekly x 3 with one week rest for the remainder of treatment.
DRUGEtanercept
Etanercept will be self administered subcutaneously by patients with injections 11 prepared by the investigational pharmacy, beginning 7 days prior to the first dose of gemcitabine and continued twice weekly for the duration of the study.
Sponsors
Immunex Corporation
Ohio State University Comprehensive Cancer Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Must have pathological diagnosis recurring or metastatic Pancreatic Adenocarcinoma * No prior chemotherapy, immunology treatments or hormonal treatments * Measurable disease * Must be \>18 years old * ONLY CONTROL ARM IS OPEN TO ACCRUAL Inclusion Criteria: * Pregnant and nursing mothers. * Psychiatric disorders that would interfere with consent ability. * Patients with known brain or leptomeningeal disease. * Patients with history of myocardial infarction with in six previous months. * Any concurrent illness that would constitute a hazard to participation in study. * Known sensitivity to gemcitabine or etanercept. * Prior treatment with etanercept.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Anti-tumor Effect as Measured by the Proportion of Patients Free of Disease-progression at Six Months After Treatment Initiation | up to 6 months | Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. Percentages were calculated by a Kaplan Meier analysis. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients With Response | up to 12 months | Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. |
| Percentage of Patients With Clinical Benefit Response | Up to 12 months | A clinical benefit was defined by the improvement of at least one parameter over at least 4 weeks, without worsening of any other parameter (change in weight, ECOG performance status, Quality of life). |
| Median Overall Survival Rates for Patients | up to 1 year | Median survival is defined as the time of initiation of the first dose of intervention to the date of death |
| Serial Levels of TNF (Tumor Necrosis Factor) and Other Inflammatory Cytokines | up to 6 months | — |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Interventional Arm Patients received Etanercept with gemcitabine | 30 |
| Control Arm Patients received Gemcitabine alone | 8 |
| Total | 38 |
Baseline characteristics
| Characteristic | Interventional Arm | Control Arm | Total |
|---|---|---|---|
| Age, Continuous | 59 years | 59 years | 59 years |
| ECOG Performance Status (PS) PS 0 (Fully active) | 7 patients | 3 patients | 10 patients |
| ECOG Performance Status (PS) PS 1 (Restricted in physical activity) | 21 patients | 5 patients | 26 patients |
| ECOG Performance Status (PS) PS 2 (Ambulatory and capable of selfcare) | 2 patients | 0 patients | 2 patients |
| Metastatic Site Liver only | 16 patients | 0 patients | 16 patients |
| Metastatic Site Liver + other | 10 patients | 6 patients | 16 patients |
| Metastatic Site other site | 4 patients | 2 patients | 6 patients |
| Region of Enrollment United States | 30 participants | 8 participants | 38 participants |
| Sex: Female, Male Female | 14 Participants | 5 Participants | 19 Participants |
| Sex: Female, Male Male | 16 Participants | 3 Participants | 19 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 29 / 29 | 8 / 8 |
| serious Total, serious adverse events | 0 / 29 | 0 / 8 |
Outcome results
Primary
Anti-tumor Effect as Measured by the Proportion of Patients Free of Disease-progression at Six Months After Treatment Initiation
Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. Percentages were calculated by a Kaplan Meier analysis.
Time frame: up to 6 months
Population: 5 patients of the experimental group were non evaluable and 2 patients in the control group were non evaluable for disease progression.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Experimental Group | Anti-tumor Effect as Measured by the Proportion of Patients Free of Disease-progression at Six Months After Treatment Initiation | 28 percent of patients with PFS |
| Control Group | Anti-tumor Effect as Measured by the Proportion of Patients Free of Disease-progression at Six Months After Treatment Initiation | 14 percent of patients with PFS |
Secondary
Median Overall Survival Rates for Patients
Median survival is defined as the time of initiation of the first dose of intervention to the date of death
Time frame: up to 1 year
Population: all evaluable patients
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Experimental Group | Median Overall Survival Rates for Patients | 5.43 months |
| Control Group | Median Overall Survival Rates for Patients | 8.1 months |
Secondary
Number of Patients With Response
Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.
Time frame: up to 12 months
Population: 2 patients in the control group were non evaluable for disease response due to patient withdrawal and another no baseline imaging for comparison.~5 patients in experimental group were non evaluable for response.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Experimental Group | Number of Patients With Response | Partial Response | 12 percentage of patients |
| Experimental Group | Number of Patients With Response | Stable Disease | 32 percentage of patients |
| Control Group | Number of Patients With Response | Partial Response | 17 percentage of patients |
| Control Group | Number of Patients With Response | Stable Disease | 50 percentage of patients |
Secondary
Percentage of Patients With Clinical Benefit Response
A clinical benefit was defined by the improvement of at least one parameter over at least 4 weeks, without worsening of any other parameter (change in weight, ECOG performance status, Quality of life).
Time frame: Up to 12 months
Population: All evaluable patients
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Experimental Group | Percentage of Patients With Clinical Benefit Response | 33 percentage of patients |
| Control Group | Percentage of Patients With Clinical Benefit Response | 0 percentage of patients |
Secondary
Serial Levels of TNF (Tumor Necrosis Factor) and Other Inflammatory Cytokines
Time frame: up to 6 months
Population: Compare CBR with responders and non responders with available blood samples.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Experimental Group | Serial Levels of TNF (Tumor Necrosis Factor) and Other Inflammatory Cytokines | IL-10 | 28.04 delta Ct values | Standard Deviation 1.93 |
| Experimental Group | Serial Levels of TNF (Tumor Necrosis Factor) and Other Inflammatory Cytokines | IL-1b | 16.2 delta Ct values | Standard Deviation 7.29 |
| Experimental Group | Serial Levels of TNF (Tumor Necrosis Factor) and Other Inflammatory Cytokines | NFkB | 6.03 delta Ct values | Standard Deviation 4.62 |
| Experimental Group | Serial Levels of TNF (Tumor Necrosis Factor) and Other Inflammatory Cytokines | IL-12 | 35.66 delta Ct values | Standard Deviation 1.86 |
| Experimental Group | Serial Levels of TNF (Tumor Necrosis Factor) and Other Inflammatory Cytokines | TNF | 26.66 delta Ct values | Standard Deviation 3.84 |
| Experimental Group | Serial Levels of TNF (Tumor Necrosis Factor) and Other Inflammatory Cytokines | IFN | 28.7 delta Ct values | Standard Deviation 2.13 |
| Experimental Group | Serial Levels of TNF (Tumor Necrosis Factor) and Other Inflammatory Cytokines | IL-6 | 29.25 delta Ct values | Standard Deviation 1.31 |
| Control Group | Serial Levels of TNF (Tumor Necrosis Factor) and Other Inflammatory Cytokines | NFkB | 4.38 delta Ct values | Standard Deviation 3.13 |
| Control Group | Serial Levels of TNF (Tumor Necrosis Factor) and Other Inflammatory Cytokines | IL-10 | 26.85 delta Ct values | Standard Deviation 1.38 |
| Control Group | Serial Levels of TNF (Tumor Necrosis Factor) and Other Inflammatory Cytokines | TNF | 27.26 delta Ct values | Standard Deviation 4.82 |
| Control Group | Serial Levels of TNF (Tumor Necrosis Factor) and Other Inflammatory Cytokines | IL-1b | 13.07 delta Ct values | Standard Deviation 7.44 |
| Control Group | Serial Levels of TNF (Tumor Necrosis Factor) and Other Inflammatory Cytokines | IL-6 | 29.29 delta Ct values | Standard Deviation 1.39 |
| Control Group | Serial Levels of TNF (Tumor Necrosis Factor) and Other Inflammatory Cytokines | IFN | 28.63 delta Ct values | Standard Deviation 1.55 |
| Control Group | Serial Levels of TNF (Tumor Necrosis Factor) and Other Inflammatory Cytokines | IL-12 | 36.11 delta Ct values | Standard Deviation 1.24 |