Advanced Pancreatic, Colon, Lung, Gastric and Ovarian Cancer
Conditions
Keywords
enoxaparin
Brief summary
Research studies have shown a strong association between cancer and blood clots in the veins (also known as deep vein thrombosis). These blood clots can flow to the lungs (pulmonary embolism) which in severe cases may be life threatening. The purpose of this research study is to see if enoxaparin is effective in preventing blood clots in the veins in participants who have cancer of the pancreas, colorectal, non-small cell lung, ovary, or gastric and also have high levels of tissue factor bearing microparticles in their blood (TFMP). TFMP are small particles that are generated from different types of blood cells in the body. In people who have cancer, TFMP are thought to be generated from cancer cells and may represent a risk factor for deep vein thrombosis. Enoxaparin has been used to prevent formation of blood clots in patients after abdominal or orthopedic surgery and in patients who suffer from a severe medical illness. Based on these studies, we are investigating to see if it prevents thrombosis in people with certain types of cancer.
Detailed description
The study was a randomized phase II trial to evaluate the cumulative incidence of VTE in cancer outpatients. At baseline, measurement of tissue factor-bearing microparticles (TFMP) was performed by impedance-based flow cytometry based on established methods. (Zwicker et al, 2009) Patients were classified as having high or low TFMP levels based on a reference repository of plasmas from sixty cancer patients. The top tercile of tissue factor-bearing microparticle concentrations from the reference specimens (3.5 x 104 microparticles/µl) was considered a cutoff for high and corresponds with previously described detectable levels. Patients with high levels were randomized (2:1) to enoxaparin 40 mg subcutaneously once daily or observation. Randomization was stratified based on cancer diagnosis. Low TFMP patients were observed without anticoagulation. Both the treating physicians and patients were blinded to microparticle status in the observation arms.
Interventions
DRUGEnoxaparin
Sponsors
Massachusetts General Hospital
North Shore Medical Center
University of Southern California
VA Boston Healthcare System
Sanofi
Beth Israel Deaconess Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologically confirmed malignancy that is metastatic or unresectable and for which standard curative therapies do not exist. Eligible malignancies include: * Adenocarcinoma of the pancreas (locally advanced or metastatic) * Colorectal (stage IV) * Non-small cell lung (unresectable stage III or IV) * Relapsed ovarian or stage IV * Surgically unresectable or metastatic gastric adenocarcinoma * First or second line therapy (within 4 weeks of initiating therapy). * Minimum age 18 years * Life expectancy of greater than 6 months * ECOG Performance Status 0, 1, or 2 (Karnofsky 60% or greater). * Participants must have normal organ and marrow function as outlined in the protocol.
Exclusion criteria
* Participants may not be receiving any other study agents. * Known brain metastases should be excluded from this clinical trial because of their poor prognosis and higher potential for intracranial hemorrhage. * Prior history of documented venous thromboembolic event or pulmonary embolism within the last 5 years years (excluding central line associated events whereby patients completed anticoagulation \> 3 months previously) * Active bleeding or high risk for bleeding (e.g. known acute gastrointestinal ulcer) * Any history of significant hemorrhage (requiring hospitalization or transfusion) outside of a surgical setting within the last 5 years * History of allergic reactions attributed to compounds of similar chemical or biologic composition to enoxaparin or heparin. * History of heparin-induced thrombocytopenia * Presence of coagulopathy (PT or PTT\> 1.5 x upper limit of normal) * Familial bleeding diathesis * Known diagnosis of disseminated intravascular coagulation * Currently receiving anticoagulant therapy * Current use of aspirin (\>81mg daily), Clopidogrel (Plavix), cilostazol (Pletal), aspirin-dipyridamole (Aggrenox), or regular use of non-steroidal anti-inflammatory agents more than twice weekly. Maximum dose of ibuprofen is 400mg no more than twice per week. * Uncontrolled intercurrent illness including, but not limited to, ongoing active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 2-Month Cumulative Incidence of VTE | Assessment with lower extremity ultrasound occured at day 60/ month 2 | 2-month cumulative incidence of venous thromboembolism (VTE) is the probability of experiencing within 2 months of study entry the following events: any symptomatic proximal or distal lower extremity deep vein thrombosis, symptomatic pulmonary embolism or fatal pulmonary embolism diagnosed by autopsy, or asymptomatic proximal deep vein thrombosis diagnosed by screening compression ultrasound. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Major Hemorrhage Events | Assessed during the 60 day therapy | Incidence is the number of patients experiencing at least one major hemorrhage events as defined according to International Society on Thrombosis and Haemostasis (ISTH) guidelines. (Schulman and Kearon 2005) |
| Overall Survival | Assessed up to approximately 30 months | Overall survival is defined as the time from study entry to death or date last known alive and estimated using Kaplan-Meier (KM) methods. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| High TFMP: Enoxaparin Patients received enoxaparin 40 mg subcutaneously once daily for 2 months (60 days).
Only patients with high TFMP status at baseline were randomized to treatment or observation. | 23 |
| High TFMP: Observation Patients undergo observation until evaluation with lower extremity ultrasound at 2 months (day 60). Only patients with high TFMP status at baseline were randomized to treatment or observation. | 11 |
| Low TFMP: Observation Patients undergo observation until evaluation with lower extremity ultrasound at 2 months (day 60). Patients with low TFMP status at baseline were directly assigned to observation. | 32 |
| Total | 66 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Presence VTE dx or Absent VTE eval | 1 | 1 | 2 |
Baseline characteristics
| Characteristic | High TFMP: Observation | Low TFMP: Observation | High TFMP: Enoxaparin | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 7 Participants | 13 Participants | 13 Participants | 33 Participants |
| Age, Categorical Between 18 and 65 years | 4 Participants | 19 Participants | 10 Participants | 33 Participants |
| Age, Continuous | 63.4 years STANDARD_DEVIATION 15 | 63.3 years STANDARD_DEVIATION 11.7 | 65.3 years STANDARD_DEVIATION 10.5 | 64.0 years STANDARD_DEVIATION 11.8 |
| Region of Enrollment United States | 11 Participants | 32 Participants | 23 Participants | 66 Participants |
| Sex: Female, Male Female | 6 Participants | 13 Participants | 9 Participants | 28 Participants |
| Sex: Female, Male Male | 5 Participants | 19 Participants | 14 Participants | 38 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 6 / 23 | 2 / 11 | 7 / 32 |
| serious Total, serious adverse events | 0 / 23 | 0 / 11 | 0 / 32 |
Outcome results
Primary
2-Month Cumulative Incidence of VTE
2-month cumulative incidence of venous thromboembolism (VTE) is the probability of experiencing within 2 months of study entry the following events: any symptomatic proximal or distal lower extremity deep vein thrombosis, symptomatic pulmonary embolism or fatal pulmonary embolism diagnosed by autopsy, or asymptomatic proximal deep vein thrombosis diagnosed by screening compression ultrasound.
Time frame: Assessment with lower extremity ultrasound occured at day 60/ month 2
Population: The analysis dataset is comprised of all evaluable patients.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| High TFMP: Enoxaparin | 2-Month Cumulative Incidence of VTE | 5.6 percent probability |
| High TFMP: Observation | 2-Month Cumulative Incidence of VTE | 27.2 percent probability |
| Low TFMP: Observation | 2-Month Cumulative Incidence of VTE | 7.2 percent probability |
p-value: 0.0695% CI: [1.03, 43.17]Fine and Gray regression
Secondary
Incidence of Major Hemorrhage Events
Incidence is the number of patients experiencing at least one major hemorrhage events as defined according to International Society on Thrombosis and Haemostasis (ISTH) guidelines. (Schulman and Kearon 2005)
Time frame: Assessed during the 60 day therapy
Population: The analysis dataset is comprised of evaluable patients.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| High TFMP: Enoxaparin | Incidence of Major Hemorrhage Events | 0 Participants |
| High TFMP: Observation | Incidence of Major Hemorrhage Events | 0 Participants |
| Low TFMP: Observation | Incidence of Major Hemorrhage Events | 0 Participants |
Secondary
Overall Survival
Overall survival is defined as the time from study entry to death or date last known alive and estimated using Kaplan-Meier (KM) methods.
Time frame: Assessed up to approximately 30 months
Population: The analysis dataset is comprised of all evaluable patients.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| High TFMP: Enoxaparin | Overall Survival | 17.8 months |
| High TFMP: Observation | Overall Survival | 11.8 months |
| Low TFMP: Observation | Overall Survival | 17.3 months |