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

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

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.

Study Overview

• Status: Completed
• Conditions: Cancer; Thrombosis; Pulmonary Embolism
• Intervention / Treatment: Drug: Placebo; Drug: Apixaban

• Study Type: Interventional
• Enrollment (Actual): 130
• Phase: Phase 2

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Hamilton, Ontario, Canada, L8V 2C5
      • Local Institution
    • London, Ontario, Canada, N6A 4L6
      • Local Institution
    • Toronto, Ontario, Canada, M5G 2M9
      • Local Institution
    • Toronto, Ontario, Canada, M4N 3M5
      • Local Institution
  • Quebec
    • Montreal, Quebec, Canada, H1T 2M4
      • Local Institution
    • Montreal, Quebec, Canada, H3G 1A4
      • Local Institution
• United States
  • Arizona
    • Tucson, Arizona, United States, 85724
      • Arizona Cancer Center
  • California
    • Los Angeles, California, United States, 90033
      • Univ. Of Southern Calif. /Norris Comprehensive Cancer Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Dana-Farber Cancer Inst
  • Nevada
    • Las Vegas, Nevada, United States, 89135
      • Nevada Cancer Institute
  • New York
    • New York, New York, United States, 10021
      • Memorial Sloan-Kettering Cancer Center
    • New York, New York, United States, 10029
      • Mount Sinai School of Medicine
    • Rochester, New York, United States, 14642
      • University of Rochester
  • Texas
    • Houston, Texas, United States, 77030
      • University Of Texas Md Anderson Cancer Ctr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 90 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Cohort 1: Placebo; Participants received placebo tablets once daily	Drug: Placebo; Oral tablets administered once daily
Placebo Comparator: Cohort 1: Apixaban, 5 mg; Participants received apixaban as tablet, 5 mg, once daily	Drug: Apixaban; Oral tablets administered once daily in 5-, 10-, or 20-mg dose; Other Names: BMS-562247
Active Comparator: Cohort 1: Apixaban, 10 mg; Participants received apixaban as tablet, 10 mg, once daily	Drug: Apixaban; Oral tablets administered once daily in 5-, 10-, or 20-mg dose; Other Names: BMS-562247
Active Comparator: Cohort 1: Apixaban, 20 mg; Participants received apixaban as tablet, 20 mg, once daily	Drug: Apixaban; Oral tablets administered once daily in 5-, 10-, or 20-mg dose; Other Names: BMS-562247
Placebo Comparator: Cohort 2: Placebo; 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; Oral tablets administered once daily
Active Comparator: Cohort 2: Apixaban, 5 mg; 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; Oral tablets administered once daily in 5-, 10-, or 20-mg dose; Other Names: BMS-562247

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Bristol-Myers Squibb
• Collaborators: Ontario Clinical Oncology Group (OCOG)

Publications and helpful links

General Publications

• Kahale LA, Matar CF, Tsolakian I, Hakoum MB, Barba M, Yosuico VE, Terrenato I, Sperati F, Schunemann H, Akl EA. Oral anticoagulation in people with cancer who have no therapeutic or prophylactic indication for anticoagulation. Cochrane Database Syst Rev. 2021 Oct 8;10(10):CD006466. doi: 10.1002/14651858.CD006466.pub7.
• Rutjes AW, Porreca E, Candeloro M, Valeriani E, Di Nisio M. Primary prophylaxis for venous thromboembolism in ambulatory cancer patients receiving chemotherapy. Cochrane Database Syst Rev. 2020 Dec 18;12(12):CD008500. doi: 10.1002/14651858.CD008500.pub5.

Study record dates

Study Major Dates

• Study Start: June 1, 2006
• Primary Completion (Actual): January 1, 2009
• Study Completion (Actual): January 1, 2009

Study Registration Dates

• First Submitted: April 28, 2006
• First Submitted That Met QC Criteria: May 2, 2006
• First Posted (Estimate): May 3, 2006

Study Record Updates

• Last Update Posted (Estimate): August 16, 2016
• Last Update Submitted That Met QC Criteria: August 11, 2016
• Last Verified: August 1, 2016

More Information

Terms related to this study

• Keywords: anticoagulant
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Respiratory Tract Diseases; Lung Diseases; Embolism and Thrombosis; Embolism; Thrombosis; Thromboembolism; Pulmonary Embolism; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protease Inhibitors; Factor Xa Inhibitors; Antithrombins; Serine Proteinase Inhibitors; Anticoagulants; Apixaban
• Other Study ID Numbers: CV185-027