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Clinical trial for assessing the safety of edoxaban with chemotherapy to the patients with gynecologic cancer-associated thrombosis by measuring its blood concentration (EGCAT study)

EGCAT study (EGCAT study)

16

Participants were included if they were 20 years of age or older and under 85 years of age, histologically diagnosed with ovarian or advanced uterine corpus cancer, and were having venous thromboembolism or pulmonary embolism confirmed by hematological test (D-dimer) and imaging studies (lower limb venous ultrasound and/or contrast-enhanced computed tomography). Patients with cervical and vulvar cancers were not included in this study because of different treatment strategies such as radiotherapy and concurrent chemoradiotherapy. After the primary surgeries were performed and the existence of malignancy was histologically confirmed, written informed consents were obtained before the initial postoperative adjuvant chemotherapy. As the remaining tumors may affect the hypercoagulability of patients, those who underwent suboptimal surgeries were excluded. Patients who were expected to survive at least six months from the time of consent were included. Patients with performance status more than 2, impaired renal function, abnormal liver function, weight < 40 kg, active bleeding or high risk of bleeding, uncontrolled hypertension, history of hypersensitivity to DOACs, pregnant or lactating, taking antiplatelet agents, history of venous thrombosis, complications of acute bacterial endocarditis, and history or treatment of atrial fibrillation were excluded from the study.The median age of the patients was 57 (range; 45-77) years, and the mean BMI was 22.1 (range; 17.7-29.0). Among those, 12 patients had ovarian cancer and 4 had uterine corpus cancer. In 12 ovarian cancer patients, 1 was serous carcinoma, 4 were endometrioid carcinoma, 6 were clear cell carcinoma, and 1 was mixed carcinoma (endometriod/serous). In 4 uterine corpus cancer, 3 were endometroid carcinoma and 1 was carcinosarcoma. Eight patients were diagnosed as early stage (Stage I-II), and the others were as advanced stages (Stage III-IV). Twelve cases had VTE only and the other 4 had PE in addition to VTE. Based on body weight of the patients, 3 patients received 60mg edoxaban, and the other 13 received 30mg edoxaban. None had any histories of previous thrombosis or thrombotic predisposition. All patients strictly adhered to edoxaban medication during the study.

After written informed consents were obtained followed by the primary surgeries, patients were treated with oral edoxaban 30mg or 60mg (Daiichi-Sankyo, Tokyo, Japan) tablet daily after breakfast based on their weight and renal function. Patients with ovarian cancer patients were planned to receive 6 cycles of carboplatin (AUC=5) plus paclitaxel (175mg/m2) and/or bevacizumab (15mg/kg), and those with advanced uterine corpus cancer were planned to receive 6 cycles of carboplatin (AUC=4), paclitaxel (150mg/m2) and epirubicin (50mg/m2) . Since the pharmacokinetics study of edoxaban revealed that the steady state of blood concentration is achieved after 3 days of the treatment , the planned postoperative chemotherapies were started more than 3 days after the administration of edoxaban. Through the chemotherapy period, blood samples were collected six times . On the first day of chemotherapy, patients had the 1st blood draw just before taking edoxaban after breakfast (Timing 1; Ctrough day1). Since it is known that single oral doses of edoxaban result in peak plasma concentrations within 1.0-2.0 h of administration , a 2nd blood draw was performed two hours after the administration of edoxaban under physician supervision and defined as Cmax day1 (Timing 2). Thereafter, the patients received the initial chemotherapy as described above. The 3rd and 4th blood draws were performed at the same time on the next day and defined as Ctrough day2 (Timing 3) and Cmax day2 (Timing 4), respectively. The 5th and 6th blood samples were taken on the next day after the last cycle of chemotherapy in order to assess the long-term effects of chemotherapy and defined as Ctrough day2* (Timing 5) and Cmax day2* (Timing 6), respectively. Using these blood samples, in addition to the plasma concentration of edoxaban, blood coagulation tests including prothrombin time-international normalized ratio (PT-INR), activated partial thromboplastin time (APTT), and Factor Xa concentration were analyzed.

There were no adverse events including bleeding or recurrent thrombosis within 6 months of the study entry. Outside the set observation period, there were one case of hemorrhage and one case of recurrent thrombosis. One case presented intermittent epistaxis that was quickly stopped by pressure, so oral edoxaban was not discontinued. In one patient with recurrent thrombus, thrombus in lower the inferior vena cava was observed 9 months after the administration of edoxaban, and anticoagulation therapy was switched from edoxaban to heparin.

%change of trough concentrations of edoxaban during chemotherapies including paclitaxel. The primary endpoint of this study was whether the trough concentration of edoxaban were affected by the administration of chemotherapy including paclitaxel. Among 16 patients enrolled, the plasma samples were able to be collected after the initial chemotherapy from 15 cases, and after the last chemotherapy from 8 cases. The mean values of Ctrough day1 (at timing 1), Cmax day1 (at timing 2), Ctrough day2 (at timing 3), Cmax day2 (at timing 4), Ctrough day2* (at timing 5), and Cmax day2* (at timing 6) were 17.7+-10.9 ng/ml, 216.6+-119.9 ng/ml, 20.0+-15.6 ng/ml, 257.1+-123.6 ng/ml, 14.3+-7.8 ng/ml , and 222.4+-119.6 ng/ml, respectively. In 12 ovarian cancer patients, the mean values of Ctrough day1 (at timing 1) was 14.9+-6.2 ng/ml and Ctrough day2 (at timing 3) was 15.2+-7.4 ng/ml. In 4 uterine corpus cancer patients, Ctrough day1 (at timing 1) was 26.8+-16.6 ng/ml and Ctrough day2 (at timing 3) was 33.1+-25.2 ng/ml. Those trough concentration were not significantly different by tumor types , indicating those were not different by the regimen of chemotherapy. Totally, the trough concentration of edoxaban was changed from 17.7+-10.9 ng/ml to 20.0+-15.6 ng/ml after the initial chemotherapy including paclitaxel (n=15), and the mean percent change in edoxaban concentration was 14.5% (95% confidence interval <CI>, -6.4 to inf; P = 0.12) with SD of 45.9% contrary to expectations , indicating that the trough concentrations of edoxaban, which represents excretion capacity, were not significantly increased by chemotherapy including paclitaxel. In 8 cases whose blood samples were collected at timing 1, 3, and 5, the trough concentration of edoxaban was changed from 21.6+-13.3 ng/ml to 14.3+-7.8 ng/ml , and the mean percent change in edoxaban concentration was -22.0% (95% CI, -52.7 to inf; p= 0.89) with its SD of 45.9% , showing that the trough concentrations of edoxaban were not significantly affected by multiple cycles of chemotherapy.AUC values which reflect the actual body exposure to edoxaban two hours after the administration were calculated on day1 (before the first chemotherapy), day2 (after the first chemotherapy) and day2*(after the last chemotherapy) from 8 cases whose blood samples were collected at all timings. Average AUC values on day1, day2 and day2* were 238.2+-115.6 ng*h/ml, 277.1+-133.5 ng*h/ml, and 229.8+-118.2 ng*h/ml, respectively. Those AUC values were not significantly affected by multiple cycles of chemotherapies (p=0.325) . Among 2 cases who received 60mg edoxaban, average AUC values on day1, day2 and day2* were 330.0+-257.3 ng*h/ml, 501.7+-160.2 ng*h/ml, and 418.0+-90.9 ng*h/ml, respectively . Among 6 cases who received 30mg edoxaban, average AUC values on day1, day2 and day2* were 184.8+-101.6 ng*h/ml, 235.7+-62.9 ng*h/ml, and 176.2+-49.9 ng*h/ml, respectively . In both doses, AUC values which reflect the actual body exposure to edoxaban were not altered by chemotherapies. %changes of active Factor Xa concentration, PT-INR and APTT during the chemotherapy including paclitaxel. While active factor Xa concentration was 0.102+-0.080 E-06 M before taking edoxaban (timing 1) and 0.124+-.095 E-06 M two hours after edoxaban administration (timing 2) (n=16). On one day after the initial chemotherapy, that was 0.113+-0.102 E-06 M before taking edoxaban (timing 3) and 0.145+-0.116 E-06 M two hours after edoxaban administration (timing 4) (n=15). On one day after the last chemotherapy, that was 0.133+-0.173 E-06 M before taking edoxaban (timing 5) and 0.104+-0.08 E-06 M two hours after edoxaban administration (timing 6) (n=8). In 8 cases whose blood samples were collected from all timings, those values were not significantly altered during the study period (p=0.359) . While PT-INR was 1.05+-0.05 before taking edoxaban was (timing 1) and 1.47+-0.27 two hours after edoxaban administration (timing 2) (n=16). On one day after the initial chemotherapy, that was 1.07+-0.24 before taking edoxaban was (timing 3) and 1.30+-0.15 two hours after edoxaban administration (timing 4) (n=15). On one day after the last chemotherapy, that was 1.05+-0.06 before taking edoxaban (timing 5) and 1.29+-0.18 two hours after edoxaban administration (timing 6) (n=8). While PT-INR values were increased two hours after the edoxaban administration (p=0.036), those returned to the similar level on the next day. In 8 cases whose blood samples were collected from all timings, PT-INR values were not affected by chemotherapies . While APTT was 29.5+-3.0 sec. before taking edoxaban was (timing 1) and 34.4+-4.2 sec. two hours after edoxaban administration (timing 2) (n=16). On one day after the initial chemotherapy, that was 27.7+-3.3 sec. before taking edoxaban (timing 3) and 31.1+-3.7 sec. two hours after edoxaban administration (timing 4) (n=15). On one day after the last chemotherapy, that was 26.8+-3.3 sec. before taking edoxaban (timing 5) and 30.1+-4.7 sec. two hours after edoxaban administration (timing 6) (n=8). While APTT values were slightly extended two hours after the edoxaban administration (p=0.035), those returned to the similar level on the next day. In comparison with timing 1 and 5, APTT values slightly shortened (p=0.041); however, there were no other differences among timings. In cancer associated thrimbosis (CAT) patients with ovarian or uterine corpus cancer who are taking oral edoxaban, no significant increase in trough concentration of edoxaban was observed when they received chemotherapy including paclitaxel for the cure of cancer. Our findings suggested the safety of edoxaban usage during the treatment of gynecological cancers.

In CAT patients with ovarian or uterine corpus cancer who are taking oral edoxaban, no significant increase in trough concentration of edoxaban was observed when they received chemotherapy, suggesting the safety of edoxaban usage during the treatment of gynecological cancers.

April. 28, 2023

No

none

https://jrct.niph.go.jp/latest-detail/jRCTs051190024

Sawada Kenjiro

Osaka University Hospital

2-15 Yamadaoka,Suita,Osaka,Japan

daasawada@gyne.med.osaka-u.ac.jp

Tadashi Oride

Osaka University Hospital

2-15 Yamadaoka,Suita,Osaka,Japan

+81-6-6879-3351

t.oride@gyne.med.osaka-u.ac.jp

Complete

April. 01, 2019

Interventional

single arm study

open(masking not used)

no treatment control/standard of care control

single assignment

treatment purpose

1. Pathohistologically diagnosed with ovarian or uterus corpus cancer
2. Confirmed venous thrombosis in hematology test (D-dimer) and image test (lower limb venous ultrasound and/or contrast-enhanced computed tomography)
3. Female subjects with age more than or equal to 20 years and less than 85 years
4. First line chemotherapy after operation
5. Any chemotherapies of following were selected
TC( Paclitaxel plus Carboplatin)
Dose dense TC
TC pulse Bevacizumab
TEC (Paclitaxel plus Epirubicin pulse Carboplatin)
6. An Eastern Cooperative Oncology Group Performance Status of 0 to 2 at the time of informed consent
7. Life expectancy more than 6 months from the time of informed consent
8. Able to consent this study by oneself and provide written informed consent

1. Creatinine clearance (Cockcroft-Gault) less than 30mL/min
2. Concurrent transaminase (AST or ALT more than and equal to 80U/L) and total bilirubin (more than and equal to 1.8 mg/dL) elevation in the absence of a clinical explanation
3. Body weight less than 40kg
4. Active bleeding on the day of informed consent or with particularly high bleeding risk
5. Patients with uncontrollable high blood pressure (systolic blood pressure more than and equal to 170mmHg or diastolic blood pressure more than and equal to110mmHg in the case of using antihypertensive drug)
6. History of allergy to Direct oral anticoagulants (DOACs)
7. Patients who are pregnant, breastfeeding, or with wish for a baby
8. Treatment with aspirin in a dosage of more than or equal to 100mg per day or dual antiplatelet therapy (any 2 antiplatelet agents including aspirin plus any other oral or intravenous antiplatelet drug) anticipated to continue during study
9. History of venous thrombosis
10. Patients with complications of acute bacterial endocarditis
11. Patients with history of atrial fibrillation or complications of atrial fibrillation
12. Considered ineligible for other reasons by the investigators

Female

Cancer-associated thrombosis

Medicate and additional hematology tests

Cancer-associated thrombosis, Direct oral anticoagulant

Variations in edoxaban plasma concentration before and after chemotherapy (rate difference)

1. Variations in edoxaban plasma concentration in the sixth cycles of chemotherapy (rate difference)
2. Variations in edoxaban plasma concentration before and after chemotherapy (AUC 0-2)
3. Variations in the level of Xa activity, APTT and PT-INR (rate difference or difference)
4. Recurrent venous thrombosis or bleeding during 6 months after registration in this study
5. Recurrent venous thrombosis during 6 months after starting this study after registration in this study

+81-662108324

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