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A phase II study of apatinib in patients with recurrent epithelial ovarian cancer
YGYNO-976993; No. of pages: 5; 4C: Gynecologic Oncology xxx (2017) xxx–xxx
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A phase II study of apatinib in patients with recurrent epithelial ovarian cancer Mingming Miao a, Guanming Deng a, Sujuan Luo a, Jiajia Zhou a, Le Chen a, Jun Yang a, Jie He a, Junjun Li b, Jing Yao c, Shanmei Tan d, Jie Tang a,⁎,1 a
Department of Gynecologic Oncology, Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, PR China Department of Pathology, Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, PR China Department of Obstetric Gynecology, First People's Hospital of Loudi, Loudi, PR China d Department of Obstetric Gynecology, First People's Hospital of Huaihua, Huaihua, PR China b c
H I G H L I G H T S • • • • •
Apatinib is an oral, novel antiangiogenical VEGFR2 tyrosine kinase inhibitor. Platinum resistant, recurrent, pretreated EOC responded positively to apatinib. ORR is 41.4%, and DCR is 68.9% in this trial. mPFS is 5.1 months, and mOS is 14.5 months in this trial. The toxicity of apatinib is controllable and tolerable.
a r t i c l e
i n f o
Article history: Received 14 October 2017 Received in revised form 8 December 2017 Accepted 10 December 2017 Available online xxxx
a b s t r a c t Objective. Antiangiogenic treatments have been implicated to play a major role in epithelial ovarian cancer (EOC). Apatinib, a novel oral antiangiogenic agent targeting vascular endothelial growth factor receptor (VEGFR2), is currently being studied in different tumor types and is already used in gastric adenocarcinoma. This study was performed to assess the efficacy and safety of apatinib in patients with recurrent, pretreated EOC. © 2017 Elsevier Inc. All rights reserved.
Keywords: Epithelial ovarian cancer Platinum-resistant Recurrence Antiangiogenic treatment Target therapy Apatinib
Patients and methods Patients with recurrent, platinum-resistant, pre-treated EOC who failed available standard chemotherapy were enrolled. Apatinib was administered as 500 mg daily. Primary objective is the overall response rate (ORR) according to MASS criteria. Secondary objectives are progression free survival (PFS), overall survival (OS), disease control rate
⁎ Corresponding author at: Department of Gynecologic Oncology, Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410006, PR China. E-mail address: [email protected] (J. Tang). 1 Address: 283 Tongzipo Road, Yuelu District, Changsha, Hunan 410013, PR China.
(DCR), safety and tolerability. The treatment duration is until disease progression or intolerability of apatinib. Results 29 eligible patients were enrolled in this multicenter, open-label, single arm study and received apatinib for a median of 36.8 weeks (range 13–64.8 weeks). Median follow-up time was 12 months. 28 patients were eligible for efficacy analysis. ORR is 41.4% (95% confidence interval (CI), 23.3%–59.4%). DCR is 68.9% (95% CI, 52.1%–85.8%). Median PFS is 5.1 months (95% CI, 3.8 m–6.5 m). Median OS is 14.5 months (95% CI, 12.4 m–16.4 m). The most common treatment-related adverse events (AEs) were hand-foot syndrome (51.7%), hypertension (34.6%),
https://doi.org/10.1016/j.ygyno.2017.12.013 0090-8258/© 2017 Elsevier Inc. All rights reserved.
Please cite this article as: M. Miao, et al., A phase II study of apatinib in patients with recurrent epithelial ovarian cancer, Gynecol Oncol (2017), https://doi.org/10.1016/j.ygyno.2017.12.013
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M. Miao et al. / Gynecologic Oncology xxx (2017) xxx–xxx
nausea and vomiting (31.0%). 3 patients had no significant toxicity. 9 patients experienced grade 3 treatment-related AEs.
including chemotherapy and target therapy for recurrent platinum resistant EOC are limited, and the efficacy is poor (response rate is b 30%).
Conclusions
2. Materials and methods
Apatinib 500 mg daily p.o. is a feasible treatment in patients with recurrent, platinum-resistant, pretreated EOC. Multi-center prospective studies enrolling more patients are needed.
2.1. Patients
1. Background Ovarian carcinoma is the most deadly gynecologic malignancy in women worldwide [1]. The vast majority of ovarian carcinomas are epithelial ovarian cancer (EOC), occurring in about 70% of ovarian cancer cases. Ovarian cancer's early stages (I/II) are difficult to diagnose because most symptoms are nonspecific and thus of little use in diagnosis. As a result, it often goes undetected until it spreads within the pelvis and abdomen in later stages (III/IV) [2]. Despite improved surgical skills and a highly initial response to the chemotherapy of paclitaxel plus carboplatin, about 75% of patients with advanced ovarian carcinoma develop a tumor relapse within 2 years [2]. After recurrence, only approximately 30% of platinum-sensitive patients respond to second-line chemotherapy while those with platinum-resistant disease are only 10–25%. The overall survival rate at 5 years is 40–50% and 75% of patients die of recurrent disease [2]. Thus, identification and development of novel agents with limited toxicity that target the mechanisms of tumor growth and metastasis are needed. Angiogenesis involves the formation of new blood vessels to feed tumors and plays an important role in the development and progression of cancer. VEGFR family mainly involves three kinds of trans-membrane proteins (VEGFR-1, VEGFR-2 and VEGFR-3) characterized by a tyrosine kinase activity [3]. Among these receptors, VEGFR-2 is the most important mediator of the VEGF-induced angiogenic signaling [4,5]. More and more evidences support the assumption of VEGF/VEGFR as target molecules for the treatment of the ovarian cancer. Bevacizumab is a recombinant humanized monoclonal IgG1 antibody that targets vascular endothelial growth factor-A (VEGF-A), and is approved in the treatment of ovarian cancer, both as a single-agent drug and in combination with cytotoxic chemotherapy. It has been published that the addition of bevacizumab to standard chemotherapy is used as a front-line treatment of advanced ovarian cancer [6]. In addition, combination of bevacizumab with chemotherapy improves response rate in recurrent ovarian cancer (platinum-sensitive and platinum-resistant disease), but still not ideal [6,7]. Apatinib is an oral, novel angiogenesis inhibitor targeting the intracellular ATP binding site of VEGFR2 with a binding affinity 10 times that of vatalanib or sorafenib, and prevents phosphorylation and subsequent downstream signaling. By inhibiting VEGFR2, apatinib may decrease tumor micro-vessel density and slow or stop the tumor growth and development [8]. Apatinib has been licensed by the Food and Drug Administration of the Peoples Republic of China (CFDA) for advanced gastric adenocarcinoma and adenocarcinoma of the gastroesophageal junction and is on the market in China [9,10]. The randomized, double-Blind, placebo-controlled phase III trial of Apatinib in patients with chemotherapy-refractory advanced or metastatic adenocarcinoma of the stomach or gastroesophageal junction was published in Journal of Clinical Oncology in 2016 [10]. These data show that apatinib significantly improved OS and PFS with an acceptable safety profile in patients with advanced gastric cancer refractory to two or more lines of prior chemotherapy. It seems that apatinib can circumvents cancer cell resistance to other antineoplastic agents, which has been also approved in several Phase II/III studies, including in soft tissue sarcoma, breast, lung cancer and liver cancer [10,11]. The aim of this trail is to assess the efficacy and safety of apatinib as a single agent in patients with recurrent platinum-resistant EOC who failed available standard chemotherapy since the available treatments
Patients with recurrent, platinum-resistant, pre-treated EOC who failed available standard chemotherapy were enrolled in this multicenter phase Π trial. This study was approved by the ethics committee of Hunan Caner Hospital. Every patient signed a consent form prior to enrolment and must be willing to comply with treatment and follow up assessments and procedures. In detail, patients included in the study must meet all the following criteria: 1) 18 years b the age of female subjects b 70 years. 2) Histologically or cytologically confirmed diagnosis of epithelial ovarian cancer, cancer of the fallopian tube, or peritoneal cancer. 3) Definition of relapse: demonstration of measurable tumor according to MASS criteria [12] by an imaging procedure ± CA-125 N twice of the upper laboratory normal value. 4) Patients must have failed at least 2 available standard chemotherapy regimens ± secondary cytoreductive surgery when relapse. 5) Adequate hematologic, coagulation, hepatic, renal, and cardiac function, with an Eastern Cooperative Oncology Group (ECOG) performance status 0–2.6) Adequate contraception. 7) Able to swallow and retain oral medication. 8) A life expectancy of at least 12 weeks. Patients will be excluded from the study for any of the following reasons: 1) Diagnosis of any second malignancy within the last 5 years except basal cell or squamous cell skin cancer or in situ carcinoma of the cervix uteri. 2) History or clinical evidence of central nervous system (CNS) metastases or leptomeningeal carcinomatosis. 3) Clinically significant gastrointestinal abnormalities which might interfere with oral dosing. 4) History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 28 days prior to beginning study treatment. 5) History of any one or more of the following cardiovascular conditions within the past 6 months: Cardiac angioplasty or stenting, myocardial infarction, unstable angina, symptomatic peripheral vascular disease, coronary artery by-pass graft surgery, class II, III or IV congestive heart failure as defined by the New York Heart Association (NYHA), history of cerebrovascular accident, pulmonary embolism or untreated deep venous thrombosis (DVT) within the past 6 months. 6) Macroscopic hematuria. 7) Evidence of active bleeding or bleeding diathesis. 8) Uncontrolled hypertension. 9) Urine protein ≥++ and confirmed N 1.0 g by the 24 h quantity. 10) Pregnancy or lactation period. 2.2. Drug administration Apatinib was provided by Jiangsu Hengrui Medicine Co., Ltd. A starting dose of apatinib was administered 250 mg p.o. twice daily. Dose reduction was allowed to 250 mg daily if patients experienced grade 3 hematologic adverse events or grade 3 hypertension, hand and foot syndrome, proteinuria or other grade 3/4 adverse events which investigators considered dose reduction necessary. Patient discontinued oral administration of apatinib if they experienced disease progression, unacceptable toxicity after dose of reduction, or toxicity requiring cumulative dose interruption of N 14 days or twice in an initiating treatment cycle. 2.3. Study design and assessments This is a multicenter, open-label, single-arm, phase II study performed at three centers in China. This trial has been designed by the study initiators at the Department of Gynecologic Oncology at the Hunan cancer Hospital and under cooperation with the Department of Gynecology and Obstetrics of First People's Hospital of Loudi, and the Department of Gynecology and Obstetrics of First People's Hospital of Huaihua. The final protocol was approved by the ethics committee of
Please cite this article as: M. Miao, et al., A phase II study of apatinib in patients with recurrent epithelial ovarian cancer, Gynecol Oncol (2017), https://doi.org/10.1016/j.ygyno.2017.12.013
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the Hunan cancer Hospital, China. The overall coordination is performed by the Department of Gynecologic Oncology at the Hunan cancer Hospital. This department is also responsible for the overall trial management, database management, quality assurance including monitoring and reporting. The primary endpoint of phase II is the overall response rate (ORR) according to MASS criteria. Secondary end points include progression free survival (PFS), overall survival (OS), disease control rate (DCR), and toxicity. PFS is defined to be the time from registration to the date of disease progression. OS is defined to be the time from registration to the date of death. ORR is defined as the proportion of eligible patients who achieve a confirmed CR or PR by MASS criteria evaluated by the investigators. DCR is defined as the proportion of patients who achieve CR, PR and SD for at least 8 weeks. Radiologic assessments of disease were conducted by contrast-enhanced CT (CECT) at baseline and every 2 months thereafter until progression. Serum CA-125 levels were assessed at base line and every month thereafter until progression [13]. The baseline examinations should be performed within 2 weeks before start of treatment, including general well-being according to ECOG, physical examination, documentation of measurable tumor lesions by contrast-enhanced CT, CA-125, pregnancy test and blood count, blood chemistry obligatory. Adverse events (AEs) were assessed and graded in accordance with the Common Terminology Criteria for AEs version 4.0. The safety evaluation was done every month and continued until 28 days after the last dose of apatinib or recovery to grade 1 or 0 from any acute toxicities associated with apatinib. Patients who experienced hand-foot syndromes were treated with topical interventions, such as corticosteroids, keratolytics, moisturizers, or phototherapy. 5HT3 receptor antagonists, such as ondansetron and palonosetron were used in preventing nausea and vomiting. G-CSF was given when patients suffered neutropenia. Patients with hypertension could be controlled by angiotensin receptor blocker or calcium antagonists. Follow-up investigations will be done every month with the aim of determining the time of tumor progression until death or lost is met. The following examinations will be performed every month: survival status, physical examination, assessment of ECOG performance, determination of tumor progression, CA-125 tumor marker, and further anticancer treatment, quality of life (EORTC-QLQ C 30 and Ovar 28). 2.4. Statistical analysis We used a Simon's optimal two-stage design [14] to test the null hypothesis that the proportion of patients achieving an overall response in the study was 10% or lower versus the alternative hypothesis that it was 40% or higher, with a type I error of 0.05 and 80% power. We established that a sample size of 15 patients evaluable for the primary endpoint was needed. Assuming a 20% dropout rate, final accrual number was 18. The safety and survival analysis was based on the intention-to-treat population. Patients who received at least one month of apatinib were included in the survival and safety analysis. PFS and OS were estimated using Kaplan-Meier method. The Statistical Package for the Social Sciences software (SPSS) version 16.0 was used for all statistical analyses.
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Table 1 Patients' characteristics. Characteristics
No. %
Median age, range (years) ECOG status 0 1 FIGO stage IIIA IIIB IIIC IV Tumor grade Well differentiated Moderately differentiated Poorly differentiated Platinum-resistant recurrence Yes No Previous BV Yes No Number of prior chemotherapy regimens 2 3 ≥3 Dose reduction Yes No
51.3 (37, 67) 19 (65.5%) 10 (34.5%) 2 (6.9%) 1 (3.4%) 22 (75.9%) 4 (13.8%) 3 (10.3%) 6 (20.7%) 20 (69.0%) 18 (62.1%) 11 (37.9%) 2 (6.9%) 27 (93.1%) 10 (34.5%) 6 (20.7%) 13 (44.8%) 9 (31.0%) 20 (69.0%)
Abbreviations: ECOG, Eastern Cooperative Oncology Group; FIGO, International Federation Gynecology Obstetrics; BV, bevacizumab.
not shown). Detailed patients' characteristics at baseline are shown in Table 1. 3.2. Efficacy and survival analysis At time of analysis, 28 patients were eligible for response evaluations because one case died at the end of the first month of treatment before clinical evaluated, which was not considered as treatment-related death or caused by disease progression and was analysed as a disease progression case (Table 2). In the overall series, 12 partial responses but none of complete response have been registered, with an ORR of 41.4% (95% CI, 23.3%–59.4%). Median response duration was 7.3 months (range = 2.6– 11.7), and 3 out of 8 patients (37.5%) had a response duration ≥6 months. 8 patients (28.6%) experienced stable disease (median duration: 5.8 months, range = 2.8–8.8), and 6 of them (75%) had a response duration ≥6 months. DCR was achieved in 20 cases (68.9%, 95% CI, 52.1%–85.8%). A total of 19 patients (65.5%) progressed during treatment. As of October 2017, follow up data were available for all patients. Median follow up duration was 12 months (range = 3–19.4 months). In the whole series, median PFS was 5.1 months (95% CI, 3.8 m– 6.5 m). There was no difference in PFS curve according to number of previous chemotherapy lines (data not shown) (Fig. 1A). 17 patients were still alive at the time of analysis and median OS was 14.5 months (95% CI, 12.4 m–16.4 m; Fig. 1B). 3.3. Toxicities
3. Results 3.1. Patient characteristics A total of 29 patients were enrolled. 26 patients (89.7%) presented with FIGO stage IIIC disease. Median age at diagnosis of recurrence was 51.5 years (range = 37–67). Median number of previous regimens was 3.6 (range = 2–8); in particular, 65.5% of patients had received ≥3 previous lines, and 27.6% of patients had received ≥5 prior treatments before apatinib was administered. Number of previous chemotherapy lines did not influence clinical response to treatment (P N 0.05, data
Toxicities encountered in the study were exhibited in Table 3. Treatment discontinued in 25 patients at the last follow-up time. 19 (82.6%) Table 2 Patients' response n (%).
ORR DCR
CR
PR
SD
PD
NE
0 (0) 12 (41.4%) 20 (68.9%)
12 (41.4%)
8 (27.6%)
8 (27.6%)
1 (3.4%)
Please cite this article as: M. Miao, et al., A phase II study of apatinib in patients with recurrent epithelial ovarian cancer, Gynecol Oncol (2017), https://doi.org/10.1016/j.ygyno.2017.12.013
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Fig. 1. Kaplan-Meier curves of PFS and OS. Kaplan-Meier curves of PFS (A) and OS (B). mPFS = 5.1 months (95% CI, 3.8 m–6.5 m), mOS = 14.5 months (95% CI, 12.4 m–16.4 m). PFS: progression free survival; OS: overall survival; mPFS: median progression free survival; mOS: median overall survival.
patients discontinued because of disease progression, 2 (8.7%) because of adverse events (1 for hand-foot syndrome grade 3 and 1 for hypertension grade 3) and 2 (8.7%) because of death. Patients received apatinib for a median of 36.8 weeks (range 13–64.8 weeks). 11 patients (39.3%) required dose interruption during at least one month. 9 patients (32.1%) experienced dose reduction during treatment because of severe hand-foot syndrome and hypertension. 3 patients had no significant toxicity. Most adverse reactions were mild and easily controlled (grade 1 to 2). Overall, the grade 1 and 2 adverse reactions accounted for 58.6% (17/29) of the total adverse events. No grade four adverse events were observed in the trial. The most common treatment-related AEs of all grade were hand-foot syndrome (51.7%), hypertension (34.6%), nausea and vomiting (31.0%), pain (24.1%), transaminase increased (17.2%), neutropenia (13.8%), thrombocytopenia (10.3%) and fatigue(6.8%). 9 patients (31.1%) experienced grade 3 treatment-related AEs (5 for hand-foot syndrome, 3 for hypertension, 1 for neutropenia). 4. Discussion Evidence indicates that targeting VEGFR signaling is a promising therapeutic strategy in ovarian cancer, involving blockage of VEGF/ VEGFR pathway either binding to VEGF or interfering with certain domains of VEGFR. Recently, many VEGFR-2 inhibitors such as sorafenib [15], vandetanib [16,17], cediranib [18–20], and sunitinib [21] have been developed. The aim of this trial is to elucidate the therapeutic potential and tolerability of the new antiangiogenically active tyrosinekinase inhibitor apatinib orally taken as a single agent in patients with advanced recurrent EOC. This is the first clinical trial report of recurrent EOC patients who failed the first and second lines of chemotherapy, responding positively to apatinib. Indeed, in this trial, it gives ORR 41.4% at the dose of apatinib 500 mg p.o. per day, which is significantly higher than figures reported for other drugs used in a similar setting. Ferrandina et al. evaluated the efficacy and safety of metronomic oral cyclophosphamide (MOC) in 54 heavily treated, relapsed ovarian cancer patients [22].
Table 3 Adverse events according to CTCAE 4.0. Adverse event
Grade 1 (n, %)
Grade 2 (n, %)
Grade 3 (n, %)
Total
Hand-foot syndrome Hypertension Nausea and vomiting Pain Transaminase increased Neutropenia Thrombocytopenia Fatigue Diarrhea and constipation Anorexia
4 (13.8%) 3 (10.4%) 5 (17.2%) 5 (17.2%) 3 (10.4%) 3 (10.4%) 2 (6.8%) 1 (3.4%) – –
6 (20.7%) 4 (13.8%) 4 (13.8%) 2 (6.8%) 2 (6.8%) 1 (3.4%) 1 (3.4%) 1 (3.4%) 1 (3.4%) 1 (3.4%)
5 (17.2%) 3 (10.4%) – – – – 1 (3.4%) – – –
15 (51.7%) 10 (34.6%) 9 (31.0%) 7 (24.1%) 5 (17.2%) 4 (13.8%) 4 (13.8%) 2 (6.8%) 1 (3.4%) 1 (3.4%)
79.6% of patients had received ≥2 previous lines before starting MOC. The ORR was 20.4% and DCR was 40.8%. In our study both the ORR and DCR are higher, and the median PFS (5.1 months) is longer than the data in the trail reported by Ferrandina (PFS was 4 months). In another phase II study performed by Francesco et al., EOC patients were administered with oral celecoxib (400 mg/day) in combination with intravenous carboplatin (AUC5, q28). The response rate was 28.9% [23]. Weekly topotecan and docetaxel regimen was also evaluated in heavily treated EOC patients, the ORR and DCR was 25% and 38%, respectively [24]. The median PFS is 5.1 months in this study, which is similar compared to other standard treatment regimens in advanced recurrent EOC. Kudoh et al. conducted a preliminary study to investigate effects of combination of bevacizumab and pegylated liposomal doxorubicin (PLD) for heavily pretreated patients with recurrent ovarian cancer [25]. Thirty patients were treated with weekly 2 mg/kg bevacizumab and 10 mg/m2 PLD (3 weeks on, 1 week off). The overall response rate was 33%. Clinical benefit rate was 73%. Median progression-free survival was 6 months (range: 2–20 months) as reported. Patients with platinum resistant recurrent ovarian cancer were administered with 1000 mg/m2 gemcitabine on days 1, 8 and 15 by D'Agostino, G et al. [26]. An overall clinical benefit was observed in 53.7% of patients. Thirteen patients (31.7%) had a time-to-progression exceeding 24 weeks. In the present trial, apatinib exhibited its antitumor ability after the EOC patients were resistant to the drugs in the first and second lines of chemotherapy. Apatinib circumvents cancer cell resistance to other antineoplastic agents based on the mechanism of reversing the P-glycoprotein (ABCB1)-and ABCG2-mediated multidrug resistance in drug-resistant solid tumor cells by inhibiting their transport function [11]. Its in vitro IC50 value for 50% enzymatic inhibition has been lower than other recently-developed anti-VEGFR agents such as sunitinib (0.001 vs. 0.005, respectively) [27,28]. Apatinib has also been approved to treat chemotherapy-refractory advanced gastric cancer and adenocarcinoma of the gastroesophageal junction for Chinese patients by CFDA. In a randomized, double-blind, placebo-controlled phase III trial, 267 patients with advanced or metastatic adenocarcinoma of the stomach or gastroesophageal junction who had failed two or more prior lines of chemotherapy from 32 centers in China were enrolled. Median OS was significantly improved in apatinib group compared with the placebo group (6.5 months v 4.7 months, P = 0.0149). Apatinib also significantly prolonged median PFS (2.6 months v 1.8 months, P b 0.001) [10]. In generally, the toxicity of apatinib was controllable and tolerable. The most frequently observed AEs of apatinib in this study were handfoot syndrome (51.7%), hypertension (34.6%), and nausea and vomiting (31.0%), which were similar to those reported in metastatic gastric cancer and breast cancer [8,9,29]. About half of the patients exposed to apatinib developed hand-foot syndrome grade 2 or higher. This was the most prominent reason for dose reduction and treatment discontinuation in this trial. But hand-foot syndrome and proteinuria could recover rapidly and be well tolerated after dose interruption or
Please cite this article as: M. Miao, et al., A phase II study of apatinib in patients with recurrent epithelial ovarian cancer, Gynecol Oncol (2017), https://doi.org/10.1016/j.ygyno.2017.12.013
M. Miao et al. / Gynecologic Oncology xxx (2017) xxx–xxx
reduction. Hemotologic toxicities including neutropenia, thrombocytopenia and transaminase increased were mild to moderate. 34.6% patients experienced grade 3 adverse events. No grade 4 AEs have been observed in this trial. Hypertension could also be well controlled by using angiotensin receptor blocker with or without calcium antagonists besides dose interruption or reduction. In conclusion, recurrent EOC is probably incurable and remains a challenge for clinical practitioners. However, this trial approves that apatinib may contribute to achieve clinical benefits with an acceptable safety profile for patients with recurrent, platinum-resistant EOC. Apatinib may mark a major clinical benefit as a new, additive and presumably well manageable oral treatment option to the existing therapies and give time and quality of life to EOC patients. However, our data are limited representative due to the low number of cases. The definite efficacy of apatinib and the correct sequence of the treatment warrant further evaluation involving large-scale clinical trials. Conflict of interest The authors declare that they have no competing interests. All authors filled in a conflict of interest form. Acknowledgement We thank all of our patients for participation in this study. This study was supported by a Grant from National Natural Science Foundation of China (No. 81101996), a Grant from the Planned Science and Technology Project of Hunan Province, China (No. 2014FJ2015), and a Grant from Chinese Anti-Cancer Association (No. 29). References [1] L.A. Torre, F. Bray, R.L. Siegel, J. Ferlay, J. Lortettieulent, A. Jemal, Global cancer statistics, 2012, CA Cancer J. Clin. 65 (2015) 87–108. [2] T. Korkmaz, S. Seber, G. Basaran, Review of the current role of targeted therapies as maintenance therapies in first and second line treatment of epithelial ovarian cancer; in the light of completed trials, Crit. Rev. Oncol. Hematol. 98 (2016) 180–188. [3] W.A. Spannuth, A.K. Sood, R.L. Coleman, Angiogenesis as a strategic target for ovarian cancer therapy, Nat. Clin. Pract. Oncol. 5 (2008) 194. [4] S. Banerjee, M. Dowsett, A. Ashworth, L.A. Martin, Mechanisms of disease: angiogenesis and the management of breast cancer, Nat. Clin. Pract. Oncol. 4 (2007) 536–550. [5] D.J. Hicklin, L.M. Ellis, Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis, J. Clin. Oncol. 23 (2005) 1011. [6] R.A. Burger, M.W. Sill, B.J. Monk, B.E. Greer, J.I. Sorosky, Phase II trial of bevacizumab in persistent or recurrent epithelial ovarian cancer or primary peritoneal cancer: a Gynecologic Oncology Group Study, J. Clin. Oncol. 25 (2007) 5165. [7] F.H. Pujade-Lauraine, B. Weber, A. Reuss, A.G.K. Poveda, Errata: Bevacizumab combined with chemotherapy for platinum-resistant recurrent ovarian cancer: the AURELIA open-label randomized phase III trial, J. Clin. Oncol. 32 (2014) 1302–1308 2014; 32. [8] L. Jin, X. Zhao, C. Lei, H. Guo, F. Lv, K. Jia, et al., Safety and pharmacokinetics of novel selective vascular endothelial growth factor receptor-2 inhibitor YN968D1 in patients with advanced malignancies, BMC Cancer 10 (2010) 529. [9] J. Li, S. Qin, J. Xu, W. Guo, J. Xiong, Y. Bai, et al., Apatinib for chemotherapy-refractory advanced metastatic gastric cancer: results from a randomized, placebo-controlled, parallel-arm, phase II trial, J. Clin. Oncol. 31 (2013) 3219.
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A phase II study of apatinib in patients with recurrent epithelial ovarian cancer Mingming Miao a, Guanming Deng a, Sujuan Luo a, Jiajia Zhou a, Le Chen a, Jun Yang a, Jie He a, Junjun Li b, Jing Yao c, Shanmei Tan d, Jie Tang a,⁎,1 a
Department of Gynecologic Oncology, Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, PR China Department of Pathology, Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, PR China Department of Obstetric Gynecology, First People's Hospital of Loudi, Loudi, PR China d Department of Obstetric Gynecology, First People's Hospital of Huaihua, Huaihua, PR China b c
H I G H L I G H T S • • • • •
Apatinib is an oral, novel antiangiogenical VEGFR2 tyrosine kinase inhibitor. Platinum resistant, recurrent, pretreated EOC responded positively to apatinib. ORR is 41.4%, and DCR is 68.9% in this trial. mPFS is 5.1 months, and mOS is 14.5 months in this trial. The toxicity of apatinib is controllable and tolerable.
a r t i c l e
i n f o
Article history: Received 14 October 2017 Received in revised form 8 December 2017 Accepted 10 December 2017 Available online xxxx
a b s t r a c t Objective. Antiangiogenic treatments have been implicated to play a major role in epithelial ovarian cancer (EOC). Apatinib, a novel oral antiangiogenic agent targeting vascular endothelial growth factor receptor (VEGFR2), is currently being studied in different tumor types and is already used in gastric adenocarcinoma. This study was performed to assess the efficacy and safety of apatinib in patients with recurrent, pretreated EOC. © 2017 Elsevier Inc. All rights reserved.
Keywords: Epithelial ovarian cancer Platinum-resistant Recurrence Antiangiogenic treatment Target therapy Apatinib
Patients and methods Patients with recurrent, platinum-resistant, pre-treated EOC who failed available standard chemotherapy were enrolled. Apatinib was administered as 500 mg daily. Primary objective is the overall response rate (ORR) according to MASS criteria. Secondary objectives are progression free survival (PFS), overall survival (OS), disease control rate
⁎ Corresponding author at: Department of Gynecologic Oncology, Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410006, PR China. E-mail address: [email protected] (J. Tang). 1 Address: 283 Tongzipo Road, Yuelu District, Changsha, Hunan 410013, PR China.
(DCR), safety and tolerability. The treatment duration is until disease progression or intolerability of apatinib. Results 29 eligible patients were enrolled in this multicenter, open-label, single arm study and received apatinib for a median of 36.8 weeks (range 13–64.8 weeks). Median follow-up time was 12 months. 28 patients were eligible for efficacy analysis. ORR is 41.4% (95% confidence interval (CI), 23.3%–59.4%). DCR is 68.9% (95% CI, 52.1%–85.8%). Median PFS is 5.1 months (95% CI, 3.8 m–6.5 m). Median OS is 14.5 months (95% CI, 12.4 m–16.4 m). The most common treatment-related adverse events (AEs) were hand-foot syndrome (51.7%), hypertension (34.6%),
https://doi.org/10.1016/j.ygyno.2017.12.013 0090-8258/© 2017 Elsevier Inc. All rights reserved.
Please cite this article as: M. Miao, et al., A phase II study of apatinib in patients with recurrent epithelial ovarian cancer, Gynecol Oncol (2017), https://doi.org/10.1016/j.ygyno.2017.12.013
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nausea and vomiting (31.0%). 3 patients had no significant toxicity. 9 patients experienced grade 3 treatment-related AEs.
including chemotherapy and target therapy for recurrent platinum resistant EOC are limited, and the efficacy is poor (response rate is b 30%).
Conclusions
2. Materials and methods
Apatinib 500 mg daily p.o. is a feasible treatment in patients with recurrent, platinum-resistant, pretreated EOC. Multi-center prospective studies enrolling more patients are needed.
2.1. Patients
1. Background Ovarian carcinoma is the most deadly gynecologic malignancy in women worldwide [1]. The vast majority of ovarian carcinomas are epithelial ovarian cancer (EOC), occurring in about 70% of ovarian cancer cases. Ovarian cancer's early stages (I/II) are difficult to diagnose because most symptoms are nonspecific and thus of little use in diagnosis. As a result, it often goes undetected until it spreads within the pelvis and abdomen in later stages (III/IV) [2]. Despite improved surgical skills and a highly initial response to the chemotherapy of paclitaxel plus carboplatin, about 75% of patients with advanced ovarian carcinoma develop a tumor relapse within 2 years [2]. After recurrence, only approximately 30% of platinum-sensitive patients respond to second-line chemotherapy while those with platinum-resistant disease are only 10–25%. The overall survival rate at 5 years is 40–50% and 75% of patients die of recurrent disease [2]. Thus, identification and development of novel agents with limited toxicity that target the mechanisms of tumor growth and metastasis are needed. Angiogenesis involves the formation of new blood vessels to feed tumors and plays an important role in the development and progression of cancer. VEGFR family mainly involves three kinds of trans-membrane proteins (VEGFR-1, VEGFR-2 and VEGFR-3) characterized by a tyrosine kinase activity [3]. Among these receptors, VEGFR-2 is the most important mediator of the VEGF-induced angiogenic signaling [4,5]. More and more evidences support the assumption of VEGF/VEGFR as target molecules for the treatment of the ovarian cancer. Bevacizumab is a recombinant humanized monoclonal IgG1 antibody that targets vascular endothelial growth factor-A (VEGF-A), and is approved in the treatment of ovarian cancer, both as a single-agent drug and in combination with cytotoxic chemotherapy. It has been published that the addition of bevacizumab to standard chemotherapy is used as a front-line treatment of advanced ovarian cancer [6]. In addition, combination of bevacizumab with chemotherapy improves response rate in recurrent ovarian cancer (platinum-sensitive and platinum-resistant disease), but still not ideal [6,7]. Apatinib is an oral, novel angiogenesis inhibitor targeting the intracellular ATP binding site of VEGFR2 with a binding affinity 10 times that of vatalanib or sorafenib, and prevents phosphorylation and subsequent downstream signaling. By inhibiting VEGFR2, apatinib may decrease tumor micro-vessel density and slow or stop the tumor growth and development [8]. Apatinib has been licensed by the Food and Drug Administration of the Peoples Republic of China (CFDA) for advanced gastric adenocarcinoma and adenocarcinoma of the gastroesophageal junction and is on the market in China [9,10]. The randomized, double-Blind, placebo-controlled phase III trial of Apatinib in patients with chemotherapy-refractory advanced or metastatic adenocarcinoma of the stomach or gastroesophageal junction was published in Journal of Clinical Oncology in 2016 [10]. These data show that apatinib significantly improved OS and PFS with an acceptable safety profile in patients with advanced gastric cancer refractory to two or more lines of prior chemotherapy. It seems that apatinib can circumvents cancer cell resistance to other antineoplastic agents, which has been also approved in several Phase II/III studies, including in soft tissue sarcoma, breast, lung cancer and liver cancer [10,11]. The aim of this trail is to assess the efficacy and safety of apatinib as a single agent in patients with recurrent platinum-resistant EOC who failed available standard chemotherapy since the available treatments
Patients with recurrent, platinum-resistant, pre-treated EOC who failed available standard chemotherapy were enrolled in this multicenter phase Π trial. This study was approved by the ethics committee of Hunan Caner Hospital. Every patient signed a consent form prior to enrolment and must be willing to comply with treatment and follow up assessments and procedures. In detail, patients included in the study must meet all the following criteria: 1) 18 years b the age of female subjects b 70 years. 2) Histologically or cytologically confirmed diagnosis of epithelial ovarian cancer, cancer of the fallopian tube, or peritoneal cancer. 3) Definition of relapse: demonstration of measurable tumor according to MASS criteria [12] by an imaging procedure ± CA-125 N twice of the upper laboratory normal value. 4) Patients must have failed at least 2 available standard chemotherapy regimens ± secondary cytoreductive surgery when relapse. 5) Adequate hematologic, coagulation, hepatic, renal, and cardiac function, with an Eastern Cooperative Oncology Group (ECOG) performance status 0–2.6) Adequate contraception. 7) Able to swallow and retain oral medication. 8) A life expectancy of at least 12 weeks. Patients will be excluded from the study for any of the following reasons: 1) Diagnosis of any second malignancy within the last 5 years except basal cell or squamous cell skin cancer or in situ carcinoma of the cervix uteri. 2) History or clinical evidence of central nervous system (CNS) metastases or leptomeningeal carcinomatosis. 3) Clinically significant gastrointestinal abnormalities which might interfere with oral dosing. 4) History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 28 days prior to beginning study treatment. 5) History of any one or more of the following cardiovascular conditions within the past 6 months: Cardiac angioplasty or stenting, myocardial infarction, unstable angina, symptomatic peripheral vascular disease, coronary artery by-pass graft surgery, class II, III or IV congestive heart failure as defined by the New York Heart Association (NYHA), history of cerebrovascular accident, pulmonary embolism or untreated deep venous thrombosis (DVT) within the past 6 months. 6) Macroscopic hematuria. 7) Evidence of active bleeding or bleeding diathesis. 8) Uncontrolled hypertension. 9) Urine protein ≥++ and confirmed N 1.0 g by the 24 h quantity. 10) Pregnancy or lactation period. 2.2. Drug administration Apatinib was provided by Jiangsu Hengrui Medicine Co., Ltd. A starting dose of apatinib was administered 250 mg p.o. twice daily. Dose reduction was allowed to 250 mg daily if patients experienced grade 3 hematologic adverse events or grade 3 hypertension, hand and foot syndrome, proteinuria or other grade 3/4 adverse events which investigators considered dose reduction necessary. Patient discontinued oral administration of apatinib if they experienced disease progression, unacceptable toxicity after dose of reduction, or toxicity requiring cumulative dose interruption of N 14 days or twice in an initiating treatment cycle. 2.3. Study design and assessments This is a multicenter, open-label, single-arm, phase II study performed at three centers in China. This trial has been designed by the study initiators at the Department of Gynecologic Oncology at the Hunan cancer Hospital and under cooperation with the Department of Gynecology and Obstetrics of First People's Hospital of Loudi, and the Department of Gynecology and Obstetrics of First People's Hospital of Huaihua. The final protocol was approved by the ethics committee of
Please cite this article as: M. Miao, et al., A phase II study of apatinib in patients with recurrent epithelial ovarian cancer, Gynecol Oncol (2017), https://doi.org/10.1016/j.ygyno.2017.12.013
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the Hunan cancer Hospital, China. The overall coordination is performed by the Department of Gynecologic Oncology at the Hunan cancer Hospital. This department is also responsible for the overall trial management, database management, quality assurance including monitoring and reporting. The primary endpoint of phase II is the overall response rate (ORR) according to MASS criteria. Secondary end points include progression free survival (PFS), overall survival (OS), disease control rate (DCR), and toxicity. PFS is defined to be the time from registration to the date of disease progression. OS is defined to be the time from registration to the date of death. ORR is defined as the proportion of eligible patients who achieve a confirmed CR or PR by MASS criteria evaluated by the investigators. DCR is defined as the proportion of patients who achieve CR, PR and SD for at least 8 weeks. Radiologic assessments of disease were conducted by contrast-enhanced CT (CECT) at baseline and every 2 months thereafter until progression. Serum CA-125 levels were assessed at base line and every month thereafter until progression [13]. The baseline examinations should be performed within 2 weeks before start of treatment, including general well-being according to ECOG, physical examination, documentation of measurable tumor lesions by contrast-enhanced CT, CA-125, pregnancy test and blood count, blood chemistry obligatory. Adverse events (AEs) were assessed and graded in accordance with the Common Terminology Criteria for AEs version 4.0. The safety evaluation was done every month and continued until 28 days after the last dose of apatinib or recovery to grade 1 or 0 from any acute toxicities associated with apatinib. Patients who experienced hand-foot syndromes were treated with topical interventions, such as corticosteroids, keratolytics, moisturizers, or phototherapy. 5HT3 receptor antagonists, such as ondansetron and palonosetron were used in preventing nausea and vomiting. G-CSF was given when patients suffered neutropenia. Patients with hypertension could be controlled by angiotensin receptor blocker or calcium antagonists. Follow-up investigations will be done every month with the aim of determining the time of tumor progression until death or lost is met. The following examinations will be performed every month: survival status, physical examination, assessment of ECOG performance, determination of tumor progression, CA-125 tumor marker, and further anticancer treatment, quality of life (EORTC-QLQ C 30 and Ovar 28). 2.4. Statistical analysis We used a Simon's optimal two-stage design [14] to test the null hypothesis that the proportion of patients achieving an overall response in the study was 10% or lower versus the alternative hypothesis that it was 40% or higher, with a type I error of 0.05 and 80% power. We established that a sample size of 15 patients evaluable for the primary endpoint was needed. Assuming a 20% dropout rate, final accrual number was 18. The safety and survival analysis was based on the intention-to-treat population. Patients who received at least one month of apatinib were included in the survival and safety analysis. PFS and OS were estimated using Kaplan-Meier method. The Statistical Package for the Social Sciences software (SPSS) version 16.0 was used for all statistical analyses.
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Table 1 Patients' characteristics. Characteristics
No. %
Median age, range (years) ECOG status 0 1 FIGO stage IIIA IIIB IIIC IV Tumor grade Well differentiated Moderately differentiated Poorly differentiated Platinum-resistant recurrence Yes No Previous BV Yes No Number of prior chemotherapy regimens 2 3 ≥3 Dose reduction Yes No
51.3 (37, 67) 19 (65.5%) 10 (34.5%) 2 (6.9%) 1 (3.4%) 22 (75.9%) 4 (13.8%) 3 (10.3%) 6 (20.7%) 20 (69.0%) 18 (62.1%) 11 (37.9%) 2 (6.9%) 27 (93.1%) 10 (34.5%) 6 (20.7%) 13 (44.8%) 9 (31.0%) 20 (69.0%)
Abbreviations: ECOG, Eastern Cooperative Oncology Group; FIGO, International Federation Gynecology Obstetrics; BV, bevacizumab.
not shown). Detailed patients' characteristics at baseline are shown in Table 1. 3.2. Efficacy and survival analysis At time of analysis, 28 patients were eligible for response evaluations because one case died at the end of the first month of treatment before clinical evaluated, which was not considered as treatment-related death or caused by disease progression and was analysed as a disease progression case (Table 2). In the overall series, 12 partial responses but none of complete response have been registered, with an ORR of 41.4% (95% CI, 23.3%–59.4%). Median response duration was 7.3 months (range = 2.6– 11.7), and 3 out of 8 patients (37.5%) had a response duration ≥6 months. 8 patients (28.6%) experienced stable disease (median duration: 5.8 months, range = 2.8–8.8), and 6 of them (75%) had a response duration ≥6 months. DCR was achieved in 20 cases (68.9%, 95% CI, 52.1%–85.8%). A total of 19 patients (65.5%) progressed during treatment. As of October 2017, follow up data were available for all patients. Median follow up duration was 12 months (range = 3–19.4 months). In the whole series, median PFS was 5.1 months (95% CI, 3.8 m– 6.5 m). There was no difference in PFS curve according to number of previous chemotherapy lines (data not shown) (Fig. 1A). 17 patients were still alive at the time of analysis and median OS was 14.5 months (95% CI, 12.4 m–16.4 m; Fig. 1B). 3.3. Toxicities
3. Results 3.1. Patient characteristics A total of 29 patients were enrolled. 26 patients (89.7%) presented with FIGO stage IIIC disease. Median age at diagnosis of recurrence was 51.5 years (range = 37–67). Median number of previous regimens was 3.6 (range = 2–8); in particular, 65.5% of patients had received ≥3 previous lines, and 27.6% of patients had received ≥5 prior treatments before apatinib was administered. Number of previous chemotherapy lines did not influence clinical response to treatment (P N 0.05, data
Toxicities encountered in the study were exhibited in Table 3. Treatment discontinued in 25 patients at the last follow-up time. 19 (82.6%) Table 2 Patients' response n (%).
ORR DCR
CR
PR
SD
PD
NE
0 (0) 12 (41.4%) 20 (68.9%)
12 (41.4%)
8 (27.6%)
8 (27.6%)
1 (3.4%)
Please cite this article as: M. Miao, et al., A phase II study of apatinib in patients with recurrent epithelial ovarian cancer, Gynecol Oncol (2017), https://doi.org/10.1016/j.ygyno.2017.12.013
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Fig. 1. Kaplan-Meier curves of PFS and OS. Kaplan-Meier curves of PFS (A) and OS (B). mPFS = 5.1 months (95% CI, 3.8 m–6.5 m), mOS = 14.5 months (95% CI, 12.4 m–16.4 m). PFS: progression free survival; OS: overall survival; mPFS: median progression free survival; mOS: median overall survival.
patients discontinued because of disease progression, 2 (8.7%) because of adverse events (1 for hand-foot syndrome grade 3 and 1 for hypertension grade 3) and 2 (8.7%) because of death. Patients received apatinib for a median of 36.8 weeks (range 13–64.8 weeks). 11 patients (39.3%) required dose interruption during at least one month. 9 patients (32.1%) experienced dose reduction during treatment because of severe hand-foot syndrome and hypertension. 3 patients had no significant toxicity. Most adverse reactions were mild and easily controlled (grade 1 to 2). Overall, the grade 1 and 2 adverse reactions accounted for 58.6% (17/29) of the total adverse events. No grade four adverse events were observed in the trial. The most common treatment-related AEs of all grade were hand-foot syndrome (51.7%), hypertension (34.6%), nausea and vomiting (31.0%), pain (24.1%), transaminase increased (17.2%), neutropenia (13.8%), thrombocytopenia (10.3%) and fatigue(6.8%). 9 patients (31.1%) experienced grade 3 treatment-related AEs (5 for hand-foot syndrome, 3 for hypertension, 1 for neutropenia). 4. Discussion Evidence indicates that targeting VEGFR signaling is a promising therapeutic strategy in ovarian cancer, involving blockage of VEGF/ VEGFR pathway either binding to VEGF or interfering with certain domains of VEGFR. Recently, many VEGFR-2 inhibitors such as sorafenib [15], vandetanib [16,17], cediranib [18–20], and sunitinib [21] have been developed. The aim of this trial is to elucidate the therapeutic potential and tolerability of the new antiangiogenically active tyrosinekinase inhibitor apatinib orally taken as a single agent in patients with advanced recurrent EOC. This is the first clinical trial report of recurrent EOC patients who failed the first and second lines of chemotherapy, responding positively to apatinib. Indeed, in this trial, it gives ORR 41.4% at the dose of apatinib 500 mg p.o. per day, which is significantly higher than figures reported for other drugs used in a similar setting. Ferrandina et al. evaluated the efficacy and safety of metronomic oral cyclophosphamide (MOC) in 54 heavily treated, relapsed ovarian cancer patients [22].
Table 3 Adverse events according to CTCAE 4.0. Adverse event
Grade 1 (n, %)
Grade 2 (n, %)
Grade 3 (n, %)
Total
Hand-foot syndrome Hypertension Nausea and vomiting Pain Transaminase increased Neutropenia Thrombocytopenia Fatigue Diarrhea and constipation Anorexia
4 (13.8%) 3 (10.4%) 5 (17.2%) 5 (17.2%) 3 (10.4%) 3 (10.4%) 2 (6.8%) 1 (3.4%) – –
6 (20.7%) 4 (13.8%) 4 (13.8%) 2 (6.8%) 2 (6.8%) 1 (3.4%) 1 (3.4%) 1 (3.4%) 1 (3.4%) 1 (3.4%)
5 (17.2%) 3 (10.4%) – – – – 1 (3.4%) – – –
15 (51.7%) 10 (34.6%) 9 (31.0%) 7 (24.1%) 5 (17.2%) 4 (13.8%) 4 (13.8%) 2 (6.8%) 1 (3.4%) 1 (3.4%)
79.6% of patients had received ≥2 previous lines before starting MOC. The ORR was 20.4% and DCR was 40.8%. In our study both the ORR and DCR are higher, and the median PFS (5.1 months) is longer than the data in the trail reported by Ferrandina (PFS was 4 months). In another phase II study performed by Francesco et al., EOC patients were administered with oral celecoxib (400 mg/day) in combination with intravenous carboplatin (AUC5, q28). The response rate was 28.9% [23]. Weekly topotecan and docetaxel regimen was also evaluated in heavily treated EOC patients, the ORR and DCR was 25% and 38%, respectively [24]. The median PFS is 5.1 months in this study, which is similar compared to other standard treatment regimens in advanced recurrent EOC. Kudoh et al. conducted a preliminary study to investigate effects of combination of bevacizumab and pegylated liposomal doxorubicin (PLD) for heavily pretreated patients with recurrent ovarian cancer [25]. Thirty patients were treated with weekly 2 mg/kg bevacizumab and 10 mg/m2 PLD (3 weeks on, 1 week off). The overall response rate was 33%. Clinical benefit rate was 73%. Median progression-free survival was 6 months (range: 2–20 months) as reported. Patients with platinum resistant recurrent ovarian cancer were administered with 1000 mg/m2 gemcitabine on days 1, 8 and 15 by D'Agostino, G et al. [26]. An overall clinical benefit was observed in 53.7% of patients. Thirteen patients (31.7%) had a time-to-progression exceeding 24 weeks. In the present trial, apatinib exhibited its antitumor ability after the EOC patients were resistant to the drugs in the first and second lines of chemotherapy. Apatinib circumvents cancer cell resistance to other antineoplastic agents based on the mechanism of reversing the P-glycoprotein (ABCB1)-and ABCG2-mediated multidrug resistance in drug-resistant solid tumor cells by inhibiting their transport function [11]. Its in vitro IC50 value for 50% enzymatic inhibition has been lower than other recently-developed anti-VEGFR agents such as sunitinib (0.001 vs. 0.005, respectively) [27,28]. Apatinib has also been approved to treat chemotherapy-refractory advanced gastric cancer and adenocarcinoma of the gastroesophageal junction for Chinese patients by CFDA. In a randomized, double-blind, placebo-controlled phase III trial, 267 patients with advanced or metastatic adenocarcinoma of the stomach or gastroesophageal junction who had failed two or more prior lines of chemotherapy from 32 centers in China were enrolled. Median OS was significantly improved in apatinib group compared with the placebo group (6.5 months v 4.7 months, P = 0.0149). Apatinib also significantly prolonged median PFS (2.6 months v 1.8 months, P b 0.001) [10]. In generally, the toxicity of apatinib was controllable and tolerable. The most frequently observed AEs of apatinib in this study were handfoot syndrome (51.7%), hypertension (34.6%), and nausea and vomiting (31.0%), which were similar to those reported in metastatic gastric cancer and breast cancer [8,9,29]. About half of the patients exposed to apatinib developed hand-foot syndrome grade 2 or higher. This was the most prominent reason for dose reduction and treatment discontinuation in this trial. But hand-foot syndrome and proteinuria could recover rapidly and be well tolerated after dose interruption or
Please cite this article as: M. Miao, et al., A phase II study of apatinib in patients with recurrent epithelial ovarian cancer, Gynecol Oncol (2017), https://doi.org/10.1016/j.ygyno.2017.12.013
M. Miao et al. / Gynecologic Oncology xxx (2017) xxx–xxx
reduction. Hemotologic toxicities including neutropenia, thrombocytopenia and transaminase increased were mild to moderate. 34.6% patients experienced grade 3 adverse events. No grade 4 AEs have been observed in this trial. Hypertension could also be well controlled by using angiotensin receptor blocker with or without calcium antagonists besides dose interruption or reduction. In conclusion, recurrent EOC is probably incurable and remains a challenge for clinical practitioners. However, this trial approves that apatinib may contribute to achieve clinical benefits with an acceptable safety profile for patients with recurrent, platinum-resistant EOC. Apatinib may mark a major clinical benefit as a new, additive and presumably well manageable oral treatment option to the existing therapies and give time and quality of life to EOC patients. However, our data are limited representative due to the low number of cases. The definite efficacy of apatinib and the correct sequence of the treatment warrant further evaluation involving large-scale clinical trials. Conflict of interest The authors declare that they have no competing interests. All authors filled in a conflict of interest form. Acknowledgement We thank all of our patients for participation in this study. This study was supported by a Grant from National Natural Science Foundation of China (No. 81101996), a Grant from the Planned Science and Technology Project of Hunan Province, China (No. 2014FJ2015), and a Grant from Chinese Anti-Cancer Association (No. 29). References [1] L.A. Torre, F. Bray, R.L. Siegel, J. Ferlay, J. Lortettieulent, A. Jemal, Global cancer statistics, 2012, CA Cancer J. Clin. 65 (2015) 87–108. [2] T. Korkmaz, S. Seber, G. Basaran, Review of the current role of targeted therapies as maintenance therapies in first and second line treatment of epithelial ovarian cancer; in the light of completed trials, Crit. Rev. Oncol. Hematol. 98 (2016) 180–188. [3] W.A. Spannuth, A.K. Sood, R.L. Coleman, Angiogenesis as a strategic target for ovarian cancer therapy, Nat. Clin. Pract. Oncol. 5 (2008) 194. [4] S. Banerjee, M. Dowsett, A. Ashworth, L.A. Martin, Mechanisms of disease: angiogenesis and the management of breast cancer, Nat. Clin. Pract. Oncol. 4 (2007) 536–550. [5] D.J. Hicklin, L.M. Ellis, Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis, J. Clin. Oncol. 23 (2005) 1011. [6] R.A. Burger, M.W. Sill, B.J. Monk, B.E. Greer, J.I. Sorosky, Phase II trial of bevacizumab in persistent or recurrent epithelial ovarian cancer or primary peritoneal cancer: a Gynecologic Oncology Group Study, J. Clin. Oncol. 25 (2007) 5165. [7] F.H. Pujade-Lauraine, B. Weber, A. Reuss, A.G.K. Poveda, Errata: Bevacizumab combined with chemotherapy for platinum-resistant recurrent ovarian cancer: the AURELIA open-label randomized phase III trial, J. Clin. Oncol. 32 (2014) 1302–1308 2014; 32. [8] L. Jin, X. Zhao, C. Lei, H. Guo, F. Lv, K. Jia, et al., Safety and pharmacokinetics of novel selective vascular endothelial growth factor receptor-2 inhibitor YN968D1 in patients with advanced malignancies, BMC Cancer 10 (2010) 529. [9] J. Li, S. Qin, J. Xu, W. Guo, J. Xiong, Y. Bai, et al., Apatinib for chemotherapy-refractory advanced metastatic gastric cancer: results from a randomized, placebo-controlled, parallel-arm, phase II trial, J. Clin. Oncol. 31 (2013) 3219.
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Please cite this article as: M. Miao, et al., A phase II study of apatinib in patients with recurrent epithelial ovarian cancer, Gynecol Oncol (2017), https://doi.org/10.1016/j.ygyno.2017.12.013