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Keywords:

  • apixaban;
  • cancer;
  • prevention;
  • thrombosis;
  • venous

Summary.

  1. Top of page
  2. Summary.
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Addendum
  8. Disclosure of Conflict of Interests
  9. References

Background: Cancer patients receiving chemotherapy are at increased risk for thrombosis. Apixaban, a factor Xa inhibitor, is oral and does not require laboratory monitoring.

Objectives:  A pilot study was conducted to evaluate whether apixaban would be well tolerated and acceptable in cancer patients receiving chemotherapy.

Patients/Methods:  Subjects receiving either first-line or second-line chemotherapy for advanced or metastatic lung, breast, gastrointestinal, bladder, ovarian or prostate cancers, cancer of unknown origin, myeloma or selected lymphomas were randomized to 5 mg, 10 mg or 20 mg once daily of apixaban or placebo in a double-blind manner for 12 weeks. Use of the study drug began within 4 weeks of the start of chemotherapy. The primary outcome was either major bleeding or clinically relevant non-major (CRNM) bleeding. Secondary outcomes included venous thromboembolism (VTE) and grade III or higher adverse events related to the study drug. Thirty-two patients received 5 mg, 30 patients 10 mg, 33 patients 20 mg, and 30 patients placebo. In these groups, there were 0, 0, 2 and 1 major bleeds, respectively. The corresponding data for CRNM bleeds were 1, 1, 2, and 0. The rate of major bleeding in the 93 apixaban patients was 2.2% (95% confidence interval 0.26–7.5%). There were no fatal bleeds. Three placebo patients had symptomatic VTE.

Conclusions:  Apixaban was well tolerated in our study population. These results support further study of apixaban in phase III trials to prevent VTE in cancer patients receiving chemotherapy.


Introduction

  1. Top of page
  2. Summary.
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Addendum
  8. Disclosure of Conflict of Interests
  9. References

Cancer patients receiving chemotherapy as outpatients are at risk of venous thromboembolism (VTE). The occurrence of VTE complicates their care, because of the need for anticoagulant treatment [1]. Currently available antithrombotic drugs are not ideal for extended VTE prophylaxis in cancer patients who are receiving cancer therapy out of hospital. Unfractionated heparin (UFH) and low molecular weight heparin (LMWH) require daily subcutaneous injection. Warfarin can be difficult to administer because of variability in the anticoagulant effect, owing to nausea and vomiting, poor nutrition, and interaction with other medications.

There is limited experience with extended VTE prophylaxis in ambulatory cancer patients. A regimen of low-dose warfarin was safe and effective for the prevention of thromboembolic complications in women with stage IV breast cancer on chemotherapy [2]. In the TOPIC-1 and TOPIC-2 trials, certoparin LMWH did not reduce VTE in patients with metastatic breast cancer and patients with stage III or IV non-small-cell lung carcinoma, respectively [3]. The PRODIGE trial of dalteparin LMWH in patients with newly diagnosed malignant glioma failed to show a benefit of prophylaxis [4], whereas, in the PROTECHT trial, nadroparin LMWH reduced VTE in patients with advanced-stage lung, breast, gastrointestinal (GI), ovarian or head and neck cancer undergoing chemotherapy [5]. In a randomized trial of VTE prophylaxis in myeloma patients, no difference was detected between LMWH, aspirin, and warfarin [6]. In the recent SAVE ONCO trial, daily subcutaneous semuloparin (an ultra-low molecular weight heparin) reduced VTE as compared with placebo in patients with metastatic or locally advanced cancer of the lung, colon/rectum, stomach, ovary, pancreas or bladder who were starting a new chemotherapy course [7].

Although routine VTE prophylaxis is recommended for cancer patients undergoing surgery and for hospitalized cancer patients, it is not recommended for outpatients receiving anticancer therapy, except for myeloma patients on thalidomide [8]. The reasons why prophylaxis is not used are the conflicting results from clinical trials, the fear of bleeding, and the lack of a suitable agent that can be easily administered out of hospital.

Apixaban, a new factor Xa inhibitor that targets the active site of FXa without requiring antithrombin III, is administered orally and does not require laboratory monitoring and dose adjustment. It has been evaluated for the prevention of VTE in orthopedic surgery and the treatment of acute symptomatic VTE [9–13]. We felt that apixaban could potentially overcome the limitations of existing therapies in ambulatory cancer patients. Thus, we conducted a pilot study to evaluate whether apixaban would be well tolerated and acceptable in patients receiving chemotherapy.

Methods

  1. Top of page
  2. Summary.
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Addendum
  8. Disclosure of Conflict of Interests
  9. References

Population

Subjects were eligible if they were over 18 years of age and receiving either first-line or second-line chemotherapy for advanced or metastatic lung, breast, GI (colon, rectum, pancreas, stomach), bladder, cancer of unknown origin, ovarian or prostate cancer, myeloma or selected lymphomas, if they were able to begin study medication within 6 weeks of starting either first-line or second-line chemotherapy, and if the expected course of chemotherapy was 90 days or more. Exclusion criteria were as follows: women of childbearing potential who were unwilling or unable to use an acceptable method of contraception to avoid pregnancy for the entire study period, who were using a prohibited contraceptive method, or who were pregnant or breastfeeding; prior history of documented deep vein thrombosis (DVT) or pulmonary embolism (PE); active bleeding or high risk for bleeding; having a serious hemorrhage that had required hospitalization, transfusion or surgical intervention within 4 weeks of study entry; familial bleeding diathesis; overt metastasis of cancer to the brain; expected survival of < 6 months or an Eastern Cooperative Oncology Group performance status of ≥ 3; candidate for bone marrow transplantation within the 12-week treatment period or 30-day follow-up period; uncontrolled hypertension (systolic blood pressure of > 200 mmHg and/or diastolic blood pressure of > 110 mmHg); presence of a coagulopathy (e.g. International Normalized Ratio [INR] of > 1.5, or platelet count of < 100 × 109 L−1 if not yet receiving chemotherapy, or platelet count of < 50 × 109 L−1 if receiving chemotherapy); alanine aminotransferase greater than three times the upper limit of normal (ULN); total bilirubin greater than two times the ULN; calculated creatinine clearance of < 30 mL min−1; and requiring long-term oral anticoagulant therapy, > 165 mg daily aspirin, clopidogrel, cilostazol, or aspirin–dipyridamole. Initially, subjects who had received bevacizumab within the previous 6 months were not eligible to participate in the study. During the trial, the protocol was amended to allow patients receiving bevacizumab to participate, provided that it was used for indications approved by local country law. Sunitinib or sorafenib were not permitted within 3 months of subjects being treated with the study drug.

Eligible patients underwent history and physical examination, routine blood work, including complete blood counts, platelet count, INR, and activated partial thromboplastin time, creatinine and liver function tests (LFTs). Written informed consent was obtained from all eligible patients. The study protocol was approved by the Institutional Review Board of each participating center.

Interventions

Randomization was performed centrally by contacting a computerized telephone voice response system provided by Bristol Myers Squibb (BMS) (Lawrenceville, NJ, USA). BMS generated and kept the randomization schedules. Treatment assignments were implemented with a randomization schedule with blocks of size four; blocks were stratified by the presence (or not) of metastatic liver disease and clinical center. Subjects were randomized to one of four treatment arms (apixaban 5 mg, 10 mg or 20 mg daily, or placebo) in a 1 : 1 : 1 : 1 ratio. The doses of apixaban were based on those used in phase II trials in patients undergoing elective knee surgery and with acute DVT. Subjects received blister packs containing a combination of apixaban (2.5-mg or 10-mg tablets) and matching placebo tablets supplied by BMS. All subjects took four tablets orally once daily; these consisted of a combination of apixaban and matching placebo tablets for the apixaban treatment groups, or all placebo tablets for the placebo treatment group, such that the study supplies for subjects in all treatment groups were identical in appearance. Each subject was to be given study tablets daily for 12 weeks, beginning within 4 weeks of the date on which the first-line or second-line chemotherapy was begun. Study medication could be started at any time of the day, but then was to be taken at the same time each day. Temporary interruptions of study drug administration before the end of the 12-week treatment period were allowed if the subject: (i) needed a surgical or invasive procedure (in which case the subject was to receive standard thromboprophylaxis perioperatively, according to local practice); (ii) developed severe thrombocytopenia (platelet count of < 50 × 109 L−1); or (iii) required the use of open-label anticoagulants (UFH, LMWH, or fondaparinux) or antiplatelet agents (other than ≤ 165 mg of aspirin), including clopidogrel and glycoprotein IIb/IIIa antagonists.

Follow-up

The baseline visit was to occur within 48 h of randomization. Study follow-up visits were scheduled to coincide with patient visits for chemotherapy. Accordingly, visits occurred at weeks 3, 6, 9 and 12 (unless prematurely discontinued) for subjects who received chemotherapy weekly, or every 3 weeks and at weeks 4, 8 and 12 (unless prematurely discontinued) for subjects who received chemotherapy every 2 or 4 weeks. Study visits were to occur on the designated visit day ± 3 days during weeks 1–9 and no more than 7 days after the scheduled final visit at week 12 (day 84). At each study visit, history-taking and physical examination were performed, and blood samples were collected for a complete blood cell count, platelets, serum chemistry, pharmacokinetics, and biomarkers. All of the subjects were either seen in the clinic (i.e. those who received chemotherapy weekly) or contacted by telephone at weeks 1 and 2 for assessment of adverse events (AEs), serious AEs (SAEs), suspected bleeding, and suspected DVT or PE. AEs were graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE, Version 3.0) (Cancer Therapy Evaluation Program National Cancer Institute, Bethesda, Maryland, USA).

All of the subjects were contacted by telephone to record SAEs, bleeding events and suspected DVT/PE approximately 30 days after completion of the 12-week double-blind treatment period (114–121 days) or premature discontinuation of study medication or of the study.

Outcomes  The primary outcome for assessment of tolerability was the occurrence of either a major bleeding event or a clinically relevant non-major (CRNM) bleeding event. Major bleeding was defined as clinically overt and satisfying one of the following criteria: bleeding that resulted in a decrease in hemoglobin of 20 g L−1 (2.0 g dL−1) or more; bleeding that led to a transfusion of two or more units of packed red blood cells or whole blood; bleeding that occurred in a critical site – intracranial, intraspinal, intraocular, pericardial, intra-articular, intramuscular with compartment syndrome, or retroperitoneal; or bleeding that contributed to death [14]. Clinically overt bleeding was defined as new-onset, visible bleeding or signs and symptoms suggestive of bleeding. In the absence of visible bleeding, confirmatory imaging techniques that can detect the presence of bleeding (e.g. ultrasound [US], computed tomography [CT], and magnetic resonance imaging) could be used. CRNM bleeding was defined as bleeding not meeting the criteria for major bleeding but that in routine clinical practice would be considered to be relevant and not trivial by a patient and physician. Such bleeding satisfied criteria defined a priori, which included, for example: epistaxis if it lasted for more than 5 min, if it was repetitive (i.e. two or more episodes within 24 h), or if it led to an intervention (e.g. packing or electrocoagulation); or hematuria, if it was macroscopic and either spontaneous or lasted for more than 24 h after instrumentation (e.g. catheter placement or surgery) of the urogenital tract. A bleeding event that occurred more than two calendar days after the study drug had been discontinued was not attributed to apixaban or placebo.

Secondary outcomes included symptomatic DVT, symptomatic PE and grade 3 or higher adverse events considered to be probably or certainly related to the study drug, and death. Objective tests were used to diagnose VTE. DVT was confirmed by compression US (new or previous undocumented non-compressibility of one or more proximal venous segments, popliteal or higher of the legs) or venography (constant intraluminal filling defect[s] in two or more views). PE was confirmed by spiral CT (thrombus in pulmonary vessel) or ventilation/perfusion lung scan (one or more segmental ventilation/perfusion mismatches). Arm vein thrombosis and central vein catheter-related thrombosis were not considered as secondary outcome measures for the analysis, but were documented if they occurred.

All bleeding and VTE events were adjudicated by a committee unaware of treatment allocation.

Biomarkers of thrombosis

Blood samples were collected at baseline (prior to the start of study medication), weeks 3–4, weeks 8–9, and week 12. The specimens were assayed for: prothrombin fragments F1 + 2, thrombin–antithrombin III (TAT) complexes, D-dimer, and interleukin (IL)-6.

F1 + 2 in human citrate plasma was quantified at the Esoterix Coagulation Laboratory (Englewood, CA, USA), with a validated ELISA method (Enzygnost F1 + 2 [monoclonal]; Dade Behring, Deerfield, IL, USA). The reportable range of the assay was approximately 0.08–4.80 pmol mL−1; the normal reference interval was 0.09–0.33 pmol mL−1. TAT complex was quantified at the Esoterix Coagulation Laboratory with a validated colorimetric sandwich ELISA method (Enzygnost TAT micro; Dade Behring). The reportable range of the assay was approximately 2–600 ng mL−1; the normal reference interval was < 5.1 ng mL−1. D-dimer in human citrate plasma was quantified at the Esoterix Coagulation Laboratory with a validated ELISA method (Asserachrom D-dimer; Diagnostica Stago, Parsippany, NJ, USA). The reportable range of the assay was approximately 17–11 200 ng mL−1; the normal reference interval was < 251 ng mL−1. IL-6 in human serum was quantified at MDS Pharma Services (Mississauga, Ontario, Canada) with a DPC Immunite 2000 System. The reportable range of the assay was 2–10 000 pg mL−1; the normal reference interval was 0–3.4 pg mL−1.

Statistical analysis

We initially planned a randomized phase II trial, using a design described by Simon et al. [15]. Randomizing 40 patients in each of the three apixaban groups (5 mg, 10 mg, and 20 mg) would allow a probability of 80% to select, among the three dose groups, the one with the highest proportion of patients remaining free of the composite of major bleeding and CRNM bleeding during the treatment period. This calculation assumed the smallest response rate of 90% and an 8% superiority margin. We also recognized that other factors, including VTE event rates and serious toxicities related to the study drug, could influence the selection of the optimal dose. Hence, we also considered the proportion of patients remaining free of major bleeding, CRNM bleeding, VTE and grade 3 or higher AEs probably or certainly related to the study drug during the treatment period in sample size estimation. With Simon’s design, with 40 subjects randomized to each group, the probability of choosing the treatment group with the highest observed response rate of this endpoint was 90%, assuming a smallest response rate of 70% and a 15% superiority margin.

A placebo control group was also included as a fourth arm, because patients with advanced cancer could experience bleeding events as a result of their underlying malignancy. Hence, having a non-anticoagulant control arm would serve as a benchmark for any potential bleeding in the apixaban groups. In addition, a placebo control would be an important comparator for the analysis of biomarkers. Thus, approximately 160 patients would be randomized to one of four treatment groups.

The proportion of patients remaining free of major bleeding or CRNM bleeding during the treatment period was estimated by treatment group with 95% exact binomial confidence intervals (CIs). Similarly, the incidence of confirmed VTE events, including symptomatic DVT and symptomatic fatal and non-fatal PE, the incidence of grade 3 or higher AEs considered to be probably or certainly related to study drug, and mortality, were summarized by using point estimates with 95% CIs for each treatment group. No formal comparisons of treatment groups were to be performed for the clinical outcomes.

As planned, all biomarker data were transformed onto a logarithmic scale. Values below the lower limit of detection (LLD) were assigned half of the LLD, and values above the upper limit of detection (ULD) were assigned the ULD. The transformed biomarker data were modeled with linear mixed model repeated measures analyses, with the baseline value as a covariate and visit (3/4, 8/9 and 12 weeks) and treatment group as the factors. Interactions between visit and treatment were assessed. An unstructured covariance model was assumed for the repeated assessments over time. Within this model, we assessed relative changes from baseline, and differences between apixaban and placebo. With the placebo group removed, we tested for an apixaban dose–response effect. For all analyses, P < 0.05 was considered to be statistically significant. sas (version 9.1; SAS, Cary, NC, USA) was used for all of the statistical analyses.

Results

  1. Top of page
  2. Summary.
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Addendum
  8. Disclosure of Conflict of Interests
  9. References

The first patient was enrolled in June 2006. Six sites in Canada and eight in the USA participated. In September 2008, a decision was made by the Steering Committee and BMS to close the trial because of the slow rate of accrual. It was felt that the main study objectives could be met despite not reaching the intended sample size.

Population

Before the change in trial design, 125 patients were randomized to one of the four treatment arms. Only five patients were enrolled after the amendment. In the first cohort of patients, 32 patients were allocated to apixaban 5 mg, 30 patients to apixaban 10 mg, 33 patients to apixaban 20 mg, and 30 patients to placebo. Three patients were randomized but did not receive the study drug: one in the 10-mg arm was not eligible; one in the 20-mg arm was uneasy about multiple changes in the expiration date on the study medication box; and one placebo patient had brain metastases. The treatment groups were reasonably balanced for baseline characteristics (Table 1).

Table 1.   Baseline characteristics
CharacteristicApixaban 5 mg (n = 32)Apixaban 10 mg (n = 30)Apixaban 20 mg (n = 33)Placebo (n = 30)
  1. ECOG, Eastern Cooperative Oncology Group; VTE, venous thromboembolism.

Age (years), median (min.–max.)57 (41–67)60 (39–76)64 (25–86)59 (20–82)
Male gender, n (%)15 (46.9)13 (43.3)20 (60.6)15 (50.0)
ECOG, n (%)
 016 (50.0)16 (53.3)19 (57.6)11 (36.7)
 114 (43.8)7 (23.3)11 (33.3)16 (53.3)
 22 (6.3)4 (13.3)3 (9.1)2 (6.7)
 301 (3.3)00
VTE risk factors, n (%)
 Surgery within 3 months2 (6.3)2 (6.7)4 (12.1)3 (10.0)
 Recent hospitalization2 (6.3)4 (13.3)1 (3.0)3 (10.0)
 Central vein catheter9 (28.1)11 (36.7)10 (30.3)7 (23.3)
Cancer type, n (%)
 Solid tumors26 (81.3)25 (83.3)27 (81.8)24 (80.0)
  Breast8 (25.0)12 (40.0)6 (18.2)6 (20.0)
  Lung3 (9.4)4 (13.3)2 (6.1)3 (10.0)
  Pancreas4 (12.5)1 (3.3)6 (18.2)4 (13.3)
  Stomach01 (3.3)01 (3.3)
  Colon/rectum5 (15.6)2 (6.7)5 (15.2)2 (6.7)
  Ovary001 (3.0)1 (3.3)
  Prostate2 (6.3)4 (13.3)3 (9.1)4 (13.3)
 Hematologic
  Hodgkin’s disease1 (3.1)01 (3.0)2 (6.7)
  Non-Hodgkin lymphoma02 (6.7)2 (6.1)2 (6.7)
  Myeloma4 (12.5)3 (10.0)3 (9.1)1 (3.3)
 Liver metastases6 (18.8)7 (23.3)8 (24.2)8 (26.7)
Time from cancer diagnosis to randomization (years), n (%)
 < 120 (62.5)17 (56.7)22 (66.7)17 (56.7)
 1–23 (9.4)1 (3.3)3 (9.1)5 (16.7)
 > 29 (28.1)12 (40.0)8 (24.2)8 (26.7)
Time from starting chemotherapy to randomization (days), mean (SD)16.8 (14.2)16.9 (13.3)14.9 (15.1)16.9 (13.4)

The median duration of exposure from the first to last dose of blinded study drug was 84 days in each of the treatment groups, with mean durations for 5 mg, 10 mg and 20 mg of apixaban and placebo of 79.2 days (29–90 days), 76.0 days (16–90 days), 73.6 days (14–92 days), and 69.6 days (7–91 days), respectively. The percentages of patients in each group completing the full 12 weeks of study drug were 78%, 80%, 76%, and 63% respectively. No patients were lost to follow-up.

Clinical outcomes

The number of patients with major bleeds in the apixaban 5 mg, 10 mg and 20 mg groups and the placebo group were 0, 0, 2 (drop in hemoglobin with overt bleeding, lower GI) and 1 (upper GI), respectively (Table 2). There were no fatal bleeds. The corresponding data for CRNM bleeding were 1 (epistaxis), 1 (urogenital), 2 (gingival and urogenital), and 0 (Table 2). There were no major or CRNM bleeding events in patients with liver metastases. Two patients in the apixaban 5 mg group experienced AEs graded as 3 or higher, possibly or probably related to treatment. One was a rectal bleed; the independent adjudication committee had not called it a major or CRNM bleed. The second patient had a rise in LFT values (this patient entered with abnormally elevated LFT values). A patient in the apixaban 20 mg group experienced an AE graded as 3 that was possibly related to study treatment. This was a lower GI bleed that the independent adjudication committee had called a major bleed (Table 2). During the treatment period, one placebo patient had DVT and non-fatal PE, and two placebo patients experienced proximal DVT. All thrombotic events were symptomatic. In addition, one subject in the apixaban 20 mg group and one subject in the placebo group had an arm DVT. Both patients had central vein catheters. Thus, there were no subjects in any apixaban group with VTE (excluding arm DVT), as compared with three (10.3%) subjects with VTE (excluding arm DVT) in the placebo group (Table 2). There were three deaths during the study period; an apixaban 5 mg patient with myeloma died of heart failure; a placebo patient with adenocarcinoma died of heart failure; and another placebo patient with squamous cell carcinoma died of progressive cancer.

Table 2.   Study outcomes
OutcomeApixaban 5 mg (n = 32)Apixaban 10 mg (n = 29)Apixaban 20 mg (n = 32)Placebo (n = 29)
n (%)95% CIn (%)95% CIn (%)95% CIn (%)95% CI
  1. AE, adverse event; CI, confidence interval; CRNM, clinically relevant non-major; DVT, deep vein thrombosis; PE, pulmonary embolism. *Considered to be related to study drug. †Adjudicated as a major bleed.

Major bleeding00.0–1100.0–122 (6.3)0.8–211 (3.4)0.1–18
CRNM bleeding1 (3.1)0.1–161 (3.4)0.1–182 (6.3)0.8–2100.0–12
Major and CRNM bleeding1 (3.1)0.1–161 (3.4)0.1–184 (12.5)3.5–291 (3.4)0.1–18
DVT ± PE00.0–1100.0–1200.0–113 (10.3)2.2–27
Grade ≥ 3 AEs*2 (6.3)0.8–2100.0–121 (3.1)†0.1–1600.0–12
All3 (9.4)2.0–251 (3.4)0.1–184 (12.5)3.5–294 (13.8)3.9–32

Biomarker data

In the statistical modeling, only the F1 + 2 biomarker provided statistically significant results. Over half of the TAT complex and about one-third of the IL-6 data were below the LLD (2.0 for both). For F1 + 2, seven observations were below the LLD (0.9) and three were above the ULD (4.8). All D-dimer data were in the measurable range, but the data were too variable to produce any meaningful results. However, the median trend lines showed similar patterns with F1 + 2 (Fig. 1). For F1 + 2, baseline levels (prior to beginning study drug) were considerably higher than those during apixaban treatment (P < 0.001), but were similar in the placebo group (P = 0.84). The apixaban treatment appeared to decrease the level of F1 + 2 when compared with placebo (P = 0.034). There was a strong linear dose–response effect over apixaban dose groups, with F1 + 2 decreasing by 1.9% (95% CI 0.7–3.1%; P = 0.004) for each milligram of drug (see Table 3 for a descriptive summary of preliminary results).

image

Figure 1.  D-Dimer and F1+2 Results.

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Table 3.   Summary of the F1 + 2 (pmol mL−1) biomarker data by visit and treatment group
GroupVisit
Baseline3–4 weeks8–9 weeks12 weeksPost-baseline†
  1. *For each group, the data are presented as follows. First row: median. Second row: median ratio relative to baseline (expressed as a percentage). Third row: number of observations. †Data from all visits excluding baseline combined.

5 mg0.31*0.240.200.260.23
79727473
3232302981
10 mg0.280.170.200.200.20
66757270
2929232678
20 mg0.280.160.160.160.16
60466157
3231262683
Placebo0.250.300.280.280.29
119129129124
2928212170

Discussion

  1. Top of page
  2. Summary.
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Addendum
  8. Disclosure of Conflict of Interests
  9. References

The use of antithrombotic agents for extended periods to prevent VTE in cancer patients can be challenging, because these patients often have complex multiorgan problems, are at increased risk for bleeding, and have an unpredictable clinical course. The usual antithrombotic agents have limitations for extended outpatient use. Recently, a new generation of antithrombotic agents has appeared which are orally administered and do not require laboratory monitoring [16]. Thus, they are attractive for long-term thromboprophylaxis in cancer patients. Before embarking on a large randomized trial to evaluate an oral FXa inhibitor, apixaban, for the prevention of VTE in cancer patients, we wanted to evaluate the feasibility of its administration in this unique patient population. When we planned this study in 2005, we had no idea of whether cancer patients on chemotherapy would be able to take the tablets for 3 months. It was well known that patients with advanced cancer were at risk for bleeding. Hence, we wanted to proceed with caution. At the same time that we were embarking on our research, the sponsor was conducting VTE prevention trials in orthopedic surgery and stroke prevention trials in patients with atrial fibrillation. There was concern that high bleeding rates in cancer patients receiving apixaban could potentially harm the broader development of apixaban.

In this phase II trial, 12 weeks of apixaban appeared to be well tolerated and acceptable for the prevention of VTE in ambulatory subjects undergoing first-line or second-line chemotherapy for advanced or metastatic cancer. This conclusion is supported by a number of observations in our data. For the 93 patients who received 5 mg or more of apixaban, the rate of major bleeding was 2.2% (95% CI 0.26%–7.5%), and there were no fatal bleeds. The incidence of patients remaining free of major or CRNM bleeding was 93.5% for the 93 patients who received apixaban. The proportions of patients remaining free of major bleeding, CRNM bleeding, VTE and grade 3 or higher AEs related to the study drug were 90.3% for apixaban and 82.8% for placebo. Finally, 78% of apixaban patients and 63% of placebo patients completed the 12 weeks of study drug. The main reason for not completing the 12 weeks was related to the underlying cancer.

It is important to recognize that the study protocol potentially selected for patients at low risk of bleeding. For example, patients with prolonged coagulation times or receiving moderate to high doses of acetylsalicylic acid or other antiplatelet agents were excluded. It was not possible to maintain logs at the study sites to record patients who fitted the inclusion criteria and were then excluded because of cost and logistics. We introduce a note of caution in extrapolating our results to a less selected population.

The trial was also designed to evaluate three doses of apixaban. Although bleeding rates were low in all three apixaban groups, there was a trend for the highest rate of bleeding in the 20-mg group. It is not possible to draw any inferences concerning apixaban dose and VTE rate. At the time of study closure, BMS had made a decision to proceed with a 5-mg total daily dose of apixaban for clinical development in VTE prevention, based on the results of trials of prophylaxis in orthopedic surgery. In our trial, patients who received the 5-mg daily dose had low rates of bleeding and VTE. Although the design of our trial precludes a formal statistical comparison between the apixaban and placebo groups for VTE rates, the results are very encouraging, with VTE rates (excluding arm DVT) of 1.1% and 13.8%, respectively. Screening for asymptomatic events by venous US and spiral CT of the chest was not performed, because we wanted to minimize logistical challenges for the patients and we did not want to disrupt their usual care.

Apixaban decreased markers of thrombin generation for all treatment doses as compared with placebo. No statistically significant dose–response effect was observed. The variability in the biomarker measurement could have been increased by the chemotherapy itself, but, because of randomization, this should have been balanced between arms. Although trends were observed, particularly with F1 + 2, the small sample size and heterogeneous population limited our ability to show significant effects.

The rate of recruitment was much slower than we had estimated. We had postulated that the target sample size of 140 patients would be accrued in < 12 months. One important reason for the slow rate was the exclusion of patients receiving bevacizumab, because of its potential to cause bleeding. During the study period, this agent was used widely in the USA for patients with metastatic colon, lung and breast cancers. Another reason for slow recruitment was that patients on other clinical trials were precluded from participation.

Our trial is the first experience of primary prophylaxis with an oral direct FXa inhibitor in ambulatory cancer patients undergoing first-line or second-line chemotherapy for advanced or metastatic cancer. This study is a step forwards in the search for a safe and tolerable prophylactic VTE regimen in cancer patients receiving chemotherapy, and provides a background for future studies.

Addendum

  1. Top of page
  2. Summary.
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Addendum
  8. Disclosure of Conflict of Interests
  9. References

The study was initially conceived by M. Levine. The trial was then designed and the protocol written jointly by the Trial Steering Committee and BMS. Data management was conducted by the Ontario Clinical Oncology Group located in Hamilton, Ontario. The analysis was performed by C. Gu and J. Julian. The manuscript was written by M. Levine and J. Julian with input from the Steering Committee and feedback from BMS.

Disclosure of Conflict of Interests

  1. Top of page
  2. Summary.
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Addendum
  8. Disclosure of Conflict of Interests
  9. References

The study was sponsored by Bristol-Myers Squibb and Pfizer Inc.

References

  1. Top of page
  2. Summary.
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Addendum
  8. Disclosure of Conflict of Interests
  9. References
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