A Phase 2 Pilot Study of Apixaban for the Prevention of Thromboembolic Events in Patients With Advanced (Metastatic) Cancer

Study Overview
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Brief Summary
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The purpose of this study is to learn whether apixaban is well-tolerated and acceptable as anticoagulant therapy, when administered to patients with advanced or metastatic cancer and at increased risk for venous thromboembolic events. Demonstration of a favorable benefit:risk profile could lead to significant reduction in this serious and sometimes fatal complication of ongoing cancer and its treatment.

Official Title
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A Randomized, Double-blind, Placebo-controlled Study of Apixaban for the Prevention of Thromboembolic Events in Patients Undergoing Treatment for Advanced Cancer: A Phase 2 Pilot Study

Conditions
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Cancer, Thrombosis, Pulmonary Embolism

Intervention / Treatment
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* Drug: Apixaban
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Recipients of either first- or second-line chemotherapy for advanced or metastatic lung, breast, gastrointestinal, bladder, ovarian, or prostate cancer or myeloma, selected lymphomas, or cancer of unknown origin Able to begin study medication ≤6 weeks of starting either first- or second-line chemotherapy. Expected course of chemotherapy must have been ≥ 90 days after the start of chemotherapy Per Protocol Amendment 5, patients receiving bevacizumab were eligible to participate, provided that bevacizumab was used for indications approved by local country law Key Exclusion Criteria: Women who are pregnant, breastfeeding History of deep vein thrombosis or pulmonary embolism Active bleeding or at high risk of bleeding Metastatic brain cancer Familial bleeding diathesis Serious hemorrhage requiring hospitalization, transfusion, or surgical intervention within 4 weeks of study entry Expected survival <6 months or an Eastern Cooperative Oncology Group performance status ≥3. Candidates for bone marrow transplantation within the 12-week treatment period or 30-day follow-up period Uncontrolled hypertension (systolic blood pressure >200 mm Hg and/or diastolic blood pressure >110 mm Hg Coagulopathy (international normalized ratio >1.5 or platelet count <100*10^9/L) if not yet receiving chemotherapy or <50*10^9/L if receiving chemotherapy). Platelet count must have been >100*10^9/L before starting study medication One or more of the following: alanine aminotransferase >3 times the upper limit of normal (ULN), total bilirubin >2*ULN, or calculated creatinine clearance <30 mL/min.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 90 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Cohort 1: Placebo<br>Participants received placebo tablets once daily | Drug: Placebo<br>* Oral tablets administered once daily<br>|
| Placebo Comparator: Cohort 1: Apixaban, 5 mg<br>Participants received apixaban as tablet, 5 mg, once daily | Drug: Apixaban<br>* Oral tablets administered once daily in 5-, 10-, or 20-mg dose<br>* Other names: BMS-562247;|
| Active Comparator: Cohort 1: Apixaban, 10 mg<br>Participants received apixaban as tablet, 10 mg, once daily | Drug: Apixaban<br>* Oral tablets administered once daily in 5-, 10-, or 20-mg dose<br>* Other names: BMS-562247;|
| Active Comparator: Cohort 1: Apixaban, 20 mg<br>Participants received apixaban as tablet, 20 mg, once daily | Drug: Apixaban<br>* Oral tablets administered once daily in 5-, 10-, or 20-mg dose<br>* Other names: BMS-562247;|
| Placebo Comparator: Cohort 2: Placebo<br>Participants in this cohort were admitted to the trial following the addition of a protocol amendment (Amendment 5), which removed the prohibition of inclusion of patients receiving chemotherapy with concomitant antiangiogenic therapy with bevacizumab. Patients received placebo once daily. | Drug: Placebo<br>* Oral tablets administered once daily<br>|
| Active Comparator: Cohort 2: Apixaban, 5 mg<br>Participants in this cohort were admitted to the trial following the addition of a protocol amendment (Amendment 5), which removed the prohibition of inclusion of patients receiving chemotherapy with concomitant antiangiogenic therapy with bevacizumab. Patients received apixaban as tablet, 5 mg, once daily. | Drug: Apixaban<br>* Oral tablets administered once daily in 5-, 10-, or 20-mg dose<br>* Other names: BMS-562247;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Composite of Confirmed Major Bleeding and Clinically Relevant Nonmajor (CRNM) Bleeding | Major bleeding was defined as clinically overt bleeding accompanied by 1 or more of the following: A decrease in hemoglobin of 20 g/L or more or Required transfusion of 2 or more units of packed red blood cells or whole blood, or Occurred in a critical site Contributed to death. CRNM bleeding was defined as bleeding that did not meet the criteria for major bleeding but that, in routine clinical practice, would be considered relevant and not trivial by a patient and physician. Such bleeding satisfied a priori criteria defined by the ICAC, including: Skin hematoma Epistaxis that lasted for longer than 5 minutes, was repetitive, or led to an intervention Hematuria that was macroscopic and either spontaneous or lasted for longer than 24 hours after instrumentation of the urogenital tract Any other bleeding type that was considered to have clinical consequences. | From first dose to 2 days following last dose of study drug | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Composite of Venous Thromboembolism (VTE) and All-cause Death | VTE includes symptomatic deep vein thrombosis (DVT) and pulmonary embolism (PE). Any 1 of the following was considered diagnostic for DVT: New or previously undocumented noncompressibility of 1 or more proximal venous segments of the legs on CUS Constant intraluminal filling defects on 2 or more views on contrast venography in 1 or more venous segments in the legs or pelvis or involving the inferior vena cava. Any 1 of the following was considered diagnostic for PE: Constant intraluminal filling defects in 2 or more views on pulmonary angiography Sudden contrast cutoff of 1 or more vessels more than 2.5 mm in diameter on a pulmonary angiogram A high probability VQ lung scan showing 1 or more segmental perfusion defects with corresponding normal ventilation (mismatch defect) An abnormal VQ lung scan with satisfaction of either criterion 1 or 2 Abnormal spiral computed tomography scan showing thrombus in pulmonary vessels. | First dose to 2 days following last dose of study drug | 
| Number of Participants With Proximal Deep Vein Thrombosis (DVT), Nonfatal Pulmonary Embolism (PE), and All-cause Death | Any 1 of the following was considered diagnostic for DVT: New or previously undocumented noncompressibility of 1 or more proximal venous segments (popliteal vein or higher) of the legs on CUS Constant intraluminal filling defects on 2 or more views on contrast venography in 1 or more venous segments in the legs or pelvis or involving the inferior vena cava. Any 1 of the following was considered diagnostic for PE: Constant intraluminal filling defects in 2 or more views on pulmonary angiography Sudden contrast cutoff of 1 or more vessels more than 2.5 mm in diameter on a pulmonary angiogram A high probability VQ lung scan showing 1 or more segmental perfusion defects with corresponding normal ventilation (mismatch defect) An abnormal VQ lung scan (nonhigh probability) with satisfaction of either criterion 1 or 2 Abnormal spiral computed tomography scan showing thrombus in pulmonary vessels. | First dose to 30 days following last dose of study drug | 
| Number of Participants With Composite of Venous Thromboembolism (VTE) and VTE-related Death | VTE includes symptomatic deep vein thrombosis (DVT) and pulmonary embolism (PE). Any 1 of the following was considered diagnostic for DVT: New or previously undocumented noncompressibility of 1 or more proximal venous segments of the legs on CUS Constant intraluminal filling defects on 2 or more views on contrast venography in 1 or more venous segments in the legs or pelvis or involving the inferior vena cava. Any 1 of the following was considered diagnostic for PE: Constant intraluminal filling defects in 2 or more views on pulmonary angiography Sudden contrast cutoff of 1 or more vessels more than 2.5 mm in diameter on a pulmonary angiogram A high probability VQ lung scan showing 1 or more segmental perfusion defects with corresponding normal ventilation (mismatch defect) An abnormal VQ lung scan with satisfaction of either criterion 1 or 2 Abnormal spiral computed tomography scan showing thrombus in pulmonary vessels. | First dose to 2 days following last dose of study drug | 
| Number of Participants With Composite of Proximal Deep Vein Thrombosis (DVT), Nonfatal Pulmonary Embolism (PE), and Venous Thromboembolism (VTE)-Related Death | VTE includes symptomatic DVT and PE. Any 1 of the following was considered diagnostic for DVT: New or previously undocumented noncompressibility of 1 or more proximal venous segments of the legs on CUS Constant intraluminal filling defects on 2 or more views on contrast venography in 1 or more venous segments in the legs or pelvis or involving the inferior vena cava. Any 1 of the following was considered diagnostic for PE: Constant intraluminal filling defects in 2 or more views on pulmonary angiography Sudden contrast cutoff of 1 or more vessels more than 2.5 mm in diameter on a pulmonary angiogram A high probability VQ lung scan showing 1 or more segmental perfusion defects with corresponding normal ventilation (mismatch defect) An abnormal VQ lung scan with satisfaction of either criterion 1 or 2 Abnormal spiral computed tomography scan showing thrombus in pulmonary vessels. | First dose to 2 days following last dose of study drug | 
| Number of Participants With All-Cause Death |  | First dose to 2 days following last dose of study drug | 
| Number of Participants With Pulmonary Embolism (Fatal or Nonfatal) | Any 1 of the following was considered diagnostic for PE: Constant intraluminal filling defects in 2 or more views on pulmonary angiography Sudden contrast cutoff of 1 or more vessels of greater than 2.5 mm in diameter on a pulmonary angiogram A high probability VQ lung scan showing 1 or more segmental perfusion defects with corresponding normal ventilation (mismatch defect) An abnormal VQ lung scan with satisfaction of either criterion 1 or 2 Abnormal spiral computed tomography scan showing thrombus in pulmonary vessels. | First dose to 2 days following last dose of study drug | 
| Number of Participants With Nonfatal Pulmonary Embolism | Any 1 of the following was considered diagnostic for PE: Constant intraluminal filling defects in 2 or more views on pulmonary angiography Sudden contrast cutoff of 1 or more vessels more than 2.5 mm in diameter on a pulmonary angiogram A high probability VQ lung scan showing 1 or more segmental perfusion defects with corresponding normal ventilation (mismatch defect) An abnormal VQ lung scan with satisfaction of either criterion 1 or 2 Abnormal spiral computed tomography scan showing thrombus in pulmonary vessels. | First dose to 2 days following last dose of study drug | 
| Number of Participants With Deep Vein Thrombosis | Any 1 of the following was considered diagnostic for DVT: New or previously undocumented noncompressibility of 1 or more proximal venous segments of the legs on CUS Constant intraluminal filling defects on 2 or more views on contrast venography in 1 or more venous segments in the legs or pelvis or involving the inferior vena cava. | First dose to 2 days following last dose of study drug | 
| Number of Participants With Distal Deep Vein Thrombosis | Any 1 of the following was considered diagnostic for DVT: New or previously undocumented noncompressibility of 1 or more proximal venous segments of the legs on CUS Constant intraluminal filling defects on 2 or more views on contrast venography in 1 or more venous segments in the legs or pelvis or involving the inferior vena cava. | First dose to 2 days following last dose of study drug | 
| Number of Participants With Proximal Deep Vein Thrombosis | Any 1 of the following was considered diagnostic for DVT: New or previously undocumented noncompressibility of 1 or more proximal venous segments of the legs on CUS Constant intraluminal filling defects on 2 or more views on contrast venography in 1 or more venous segments in the legs or pelvis or involving the inferior vena cava. | First dose to 2 days following last dose of study drug | 
| Number of Participants Who Died and With Adverse Events (AEs), Serious Adverse Events (SAEs), Bleeding AEs, and Discontinuations Due to AEs | AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. SAE=a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization. | First dose to 2 days following last dose of study drug | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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anticoagulant