- Email: [email protected]
Phase 2 study of the Exportin 1 inhibitor selinexor in patients with recurrent gynecological malignancies
Gynecologic Oncology xxx (xxxx) xxx
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Gynecologic Oncology journal homepage: www.elsevier.com/locate/ygyno
Phase 2 study of the Exportin 1 inhibitor selinexor in patients with recurrent gynecological malignancies I.B. Vergote a, *, B. Lund b, U. Peen c, Z. Umajuridze d, M. Mau-Sorensen d, A. Kranich e, E. Van Nieuwenhuysen a, C. Haslund b, T. Nottrup d, S.N. Han a, N. Concin a, T.J. Unger f, Y. Chai f, N. Au f, T. Rashal f, A. Joshi f, M. Crochiere f, Y. Landesman f, J. Shah f, S. Shacham f, M. Kauffman f, M.R. Mirza f a Department of Obstetrics and Gynaecology, Division of Gynecologic Oncology, University Hospital Leuven, Leuven Cancer Institute, Leuven, Belgium, European Union b Aalborg University Hospital, Aalborg, Denmark c Herlev University Hospital, Herlev, Denmark d Department of Oncology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark e GSO Hamburg, Germany f Karyopharm Therapeutics Newton, MA, USA
h i g h l i g h t s Selinexor, an oral XPO1 inhibitor, demonstrated single-agent activity in ovarian, endometrial, and cervical cancers. Selinexor was safe and tolerable; side effects were predominantly grade 1/2. Frequently reported grade 3/4 events were thrombocytopenia, fatigue, anemia, nausea, and hyponatremia. These data support further development of selinexor in advanced gynecological malignancies.
a r t i c l e i n f o
a b s t r a c t
Article history: Received 14 July 2019 Received in revised form 24 October 2019 Accepted 8 November 2019 Available online xxx
Background: Selinexor is an oral inhibitor of the nuclear export protein Exportin 1 (XPO1) with demonstrated antitumor activity in solid and hematological malignancies. We evaluated the efficacy and safety of selinexor in heavily pretreated, recurrent gynecological malignancies. Methods: In this phase 2 trial, patients received selinexor (35 or 50 mg/m2 twice-weekly [BIW] or 50 mg/ m2 once-weekly [QW]) in 4-week cycles. Primary endpoint was disease control rate (DCR) including complete response (CR), partial response (PR) or stable disease (SD) 12 weeks. Secondary endpoints were progression-free survival (PFS), overall survival (OS) and safety. Results: 114 patients with ovarian (N ¼ 66), endometrial (N ¼ 23) or cervical (N ¼ 25) cancer were enrolled. Median number of prior regimens for ovarian, endometrial and cervical cancer was 6 (1e11), 2 (1e5), and 3 (1e6) respectively. DCR was 30% (ovarian 30%; endometrial 35%; cervical 24%), which included confirmed PRs in 8%, 9%, and 4% of patients with ovarian, endometrial, and cervical cancer respectively. Median PFS and OS for patients with ovarian, endometrial and cervical cancer were 2.6, 2.8 and 1.4 months, and 7.3, 7.0, and 5.0 months, respectively. Common Grade 3/4 adverse events (AEs) were thrombocytopenia (17%), fatigue (14%), anemia (10%), nausea (9%) and hyponatremia (9%). Patients with ovarian cancer receiving 50 mg/m2 QW had fewer high-grade AEs with similar efficacy as BIW treatment. Conclusions: Selinexor demonstrated single-agent activity and disease control in patients with heavily pretreated ovarian and endometrial cancers. Side effects were a function of dose level and treatment frequency, similar to previous reports, reversible and mitigated with supportive care. © 2019 Elsevier Inc. All rights reserved.
Keywords: XPO1 Selinexor Ovarian cancer Endometrial cancer Cervical cancer
* Corresponding author. Division of Gynecological Oncology, Department of Gynaecology and Obstetrics, Leuven Cancer Institute, Katholieke Universiteit Leuven, Herestraat 49, 3000, Leuven, Belgium, European Union. E-mail address: [email protected] (I.B. Vergote). https://doi.org/10.1016/j.ygyno.2019.11.012 0090-8258/© 2019 Elsevier Inc. All rights reserved.
Please cite this article as: I.B. Vergote et al., Phase 2 study of the Exportin 1 inhibitor selinexor in patients with recurrent gynecological malignancies, Gynecologic Oncology, https://doi.org/10.1016/j.ygyno.2019.11.012
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1. Introduction Ovarian, endometrial, and cervical malignancies lead to ~490,000 annual deaths worldwide [1]. Patients with advanced disease that has relapsed or is refractory to platinum-based therapy or radiotherapy have limited options and short survival [2]. Therefore, novel therapies are an urgent medical need for advanced gynecological malignancies. Exportin 1 (XPO1/CRM1) is nuclear export protein that mediates the transport of 200 cargo proteins through the nuclear pore complex to the cytoplasm [3]. The anti-tumor activity of TSPs requires nuclear localization, and XPO1 is the sole nuclear exporter of key tumor suppressor proteins (TSPs) such as p53, p21, BRCA1 and 2, IkB and Rb [4e6]. In addition, XPO1 transports eukaryotic initiation factor 4 e (eIF4E) in complex with oncogenic mRNAs, such as Cyclin D1, Myc, and MDM2 to the cytoplasm for their efficient translation [7,8]. In nearly all cancers studied to date, including ovarian cancer, XPO1 expression is elevated, leading to functional inactivation of TSPs and increased translation of oncoproteins [9]. Furthermore, the elevated levels are correlated with poor prognosis and reduced survival, including in ovarian cancer [5,10]. Advanced, heavily pretreated gynecologic cancers have disruptions in many TSP and oncogenic pathways [11]. Therefore, inhibition of XPO1 is an attractive therapeutic strategy that impacts multiple pathways required for cancer growth and survival. Selinexor is an oral, small-molecule inhibitor of XPO1 studied as a single agent or in combination for the treatment of hematological and solid cancers. Preclinical studies using selinexor and related Selective Inhibitor of Nuclear Export (SINE) compounds, showed nuclear retention of TSPs and oncogenic mRNAs in ovarian cancer cell lines [12]. In addition, selinexor significantly reduced the growth of patient-derived, platinum-resistant ovarian cancers in vivo and dramatically improved the OS of mice compared to vehicle treated controls [12]. In a phase I trial of selinexor in advanced solid tumors, 6 of the 13 evaluable patients with heavily pretreated ovarian or cervical cancer had a reduction in target lesion size, including 2 patients with a PR and 4 with durable disease control [13]. The recommended dose of oral selinexor based on both anti-ovarian and anti-cervical cancer activity, along with other Phase 1 studies is 60 mge80 mg on days 1 and 3 twice weekly or 80 mge100 mg once weekly [13,14]. Based on these preliminary findings, we conducted a phase 2 trial to better characterize the efficacy and safety and to determine the optimal dosing of selinexor in advanced gynecological malignancies.
full list of inclusion and exclusion criteria can be found in Supplemental Table 1. All patients were required to receive a prophylactic 5-HT3 antagonist. The protocol was approved by the institutional review board or an independent ethics committee at each participating center and was in accordance with the Declaration of Helsinki, the International Conference on HarmonisationGood Clinical Practice and local laws. All patients provided written informed consent prior to enrollment. All authors reviewed the data for accuracy, interpreted the results and collaborated in the preparation of the manuscript. 2.2. Study assessments Response assessments were by radiological (CT or MRI) and/or PET-CT imaging performed at baseline, after 6 and 12 weeks of treatment, and every 8 weeks thereafter; response assessments were based on the Response Evaluation Criteria in Solid Tumors (RECIST) guidelines (version 1.1). Patients stayed on therapy until disease progression, death, or consent withdrawal. Adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03. 2.3. Statistics
2. Methods
Sample sizes were calculated based on the Simon’s 2-stage optimal design. For each cohort in Part I, the null hypothesis that the DCR was 0.25 was tested against a one-sided alternative that the DCR was 0.50 where the first 8 patients in each cohort were considered the first stage and enrollment in the cohort would be stopped if 2 patients responded. If 3 patients responded, an additional 13 patients would be enrolled. A sample size of 21 patients in each cohort allowed for a one-sided type 1 error of 0.10 and power of 80% when the DCR was 0.50. In Part II, an additional 32 patients with ovarian cancer were enrolled in 1 of 2 treatment groups to provide 80% power to detect a difference of 40% in the proportion of patients with a given AE (10% versus 50%), at a 2sided alpha level of 20%. The primary analysis was performed by calculating the point estimate of the percentage of patients who had CR, PR, or SD 12 weeks. The difference in DCR between the 2 treatment regimens in Part II was analyzed using the Fisher’s Exact test. The secondary efficacy analyses were based on the KaplanMeier method. In the following sections, data are presented by cohort: ovarian (Part I and II), endometrial, and cervical (Part I only) and by dose (Part I vs II) for ovarian cancer.
2.1. Study design and oversight
3. Results
This was a multi-center, open-label study conducted in 2 parts. Part I evaluated selinexor in patients with ovarian, endometrial, or cervical cancer treated at 50 mg/m2 (~80 mg) BIW in 28-day cycles (8 doses per cycle). To improve tolerability based on results from Part I, the protocol was amended to include Part II to test additional dosing schedules in a more homogenous population (patients with ovarian cancer only). In Part II, patients were randomized in a 1:1 ratio using centralized randomization via an interactive webresponse system to either 35 mg/m2 (~60 mg) BIW or 50 mg/m2 (~80 mg) QW, in 28-day cycles; all of these doses had been evaluated in the Phase 1 study [13]. The primary objective was to determine the DCR. The secondary objectives were to assess overall response rate (ORR), PFS, OS, and safety and tolerability. Patients 18 years with epithelial cancers of the ovary or fallopian tube (Part I and II), endometrium or cervix (Part I only) that had no curative options, had received 1 prior line of chemotherapy, and had documented disease progression by CT/MRI were enrolled. A
3.1. Patient characteristics Between October 2014 and December 2015, 116 patients were enrolled (Fig. 1). Two patients died from cardiac events prior to receiving selinexor. As a result, 114 patients with ovarian (Part I: N ¼ 25; Part II: N ¼ 41), endometrial (N ¼ 23), or cervical (N ¼ 25) cancer were evaluable. Median age was 63 years (31e80) and prior regimens for patients with ovarian, endometrial and cervical cancer were 6 (1e11), 2 (1e5), and 3 (1e6) respectively. Nearly all patients had been previously treated with a platinum-based chemotherapy and taxane (Table 1). Median duration of treatment was 43 days (1e891). Reasons for study discontinuation included progressive disease (N ¼ 83), withdrawal of consent due to incidence or severity of AEs (N ¼ 19), withdrawal of consent due to patient’s decision (N ¼ 7), Investigator’s discretion (N ¼ 1) and death (N ¼ 2). One death was due to pneumonia and the other due to renal failure as a result of
Please cite this article as: I.B. Vergote et al., Phase 2 study of the Exportin 1 inhibitor selinexor in patients with recurrent gynecological malignancies, Gynecologic Oncology, https://doi.org/10.1016/j.ygyno.2019.11.012
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Fig. 1. Consort diagram.
disease progression, both deemed by the Investigator to be unrelated to treatment.
3.2. Efficacy Of the 114 patients that received treatment, 98 were evaluable for response. Sixteen patients were non-evaluable (NE) based on lack of adequate tumor assessments prior to withdrawal of consent and characterized as non-responders. Thirty-four of the 114 patients had SD 12 weeks or a PR for a DCR of 30% (Supplemental Table 2). In Part I, the DCR was 28% (95% CI: 12, 49) for ovarian cancer, 35% (95% CI: 16, 57) for endometrial cancer, and 24% (95% CI: 9, 45) for cervical cancer. In Part II, the DCR was 33% (95% CI: 15, 57) for 35 mg/m2 BIW and 30% (95% CI: 12, 54) for 50 mg/m2 QW. Median duration of DCR for ovarian, endometrial and cervical cancer was 6.7, 6.3 and 6.2 months, respectively. Eight patients (7%) achieved a confirmed PR, including 5 patients (8%) with ovarian cancer (Part I: 1 patient; Part II: 2 patients on 35 mg/m2 BIW and 2 patients on 50 mg/m2 QW), 2 patients (9%) with endometrial cancer, and 1 patient (4%) with cervical cancer (3 patients, 2 with ovarian cancer and 1 with endometrial cancer had an unconfirmed PR). Median duration of response for patients with a confirmed PR was 7.4 months (3.7e12.6). Of 96 patients with quantifiable baseline and on-study tumor assessments, 46 (48%) had a reduction in tumor volume (Fig. 2). Eighteen patients without adequate baseline or on-study tumor measurements were assessed as having a best overall response of
PD (N ¼ 1) based on clinical symptoms, SD < 12 weeks (N ¼ 1) or NE (N ¼ 16). Median PFS for ovarian, endometrial and cervical cancer was 2.6 (95% CI: 1.5e2.8), 2.8 (95% CI: 1.4e5.3) and 1.4 months (95% CI: 1.4e4.6), respectively (Supplemental Fig. 1A). Median PFS was not significantly different among ovarian cancer patients treated at BIW or QW schedules; 2.8 (95% CI: 1.4e4.9), 2.6 (95% CI: 1.5e3.3) and 1.5 months (95% CI: 1.4e4.6) for 35 mg/m2 BIW, 50 mg/m2 BIW and 50 mg/m2 QW respectively. (Supplemental Fig. 1B). The median OS for ovarian, endometrial and cervical cancer was 7.3 (95% CI: 4.9e9.8), 7.0 (95% CI: 3.6e11.3) and 5.0 (95% CI: 2.7e8.3), months respectively (Supplemental Fig. 1C). The apparent improvement in OS in patients treated at 35 mg/m2 BIW is likely a reflection of the small sample size and this group having a lower percentage of patients with platinumrefractory ovarian cancer (defined as progression within 28 days of last platinum dose) (14% for 35 mg/m2 BIW versus 32% for 50 mg/ m2 BIW and 35% for 50 mg/m2 QW). In the ovarian cancer cohort, serum CA 125 levels were analyzed in 50 patients. Of these, 24 (48%) patients had a decrease in levels compared with baseline (Supplemental Fig. 2). 3.3. Safety The safety profile of selinexor is summarized in Table 2. Treatment-related AEs occurring in 10% of patients were nausea (71%), fatigue (68%), decreased appetite (57%), vomiting (53%) and weight loss (48%), which were predominantly grade 1/2. Frequently
Please cite this article as: I.B. Vergote et al., Phase 2 study of the Exportin 1 inhibitor selinexor in patients with recurrent gynecological malignancies, Gynecologic Oncology, https://doi.org/10.1016/j.ygyno.2019.11.012
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I.B. Vergote et al. / Gynecologic Oncology xxx (xxxx) xxx
Table 1 Characteristics of patients at screening. Ovarian (N ¼ 66)
Endometrial (N ¼ 23)
Cervical (N ¼ 25)
Total (N ¼ 114)
Age (median, range) 65 years 75 years Ethnic Origin White North African ECOG performance status 0 1 FIGO Disease Stage I &II
63 (31e80) 22 (33%) 6 (9%)
67 (53e75) 17 (74%) 4 (17%)
53 (32e75) 5 (20%) 1 (4%)
63 (31e80) 44 (39%) 11 (10%)
66 (100%) -
23 (100%) -
24 (96%) 1 (4%)
113 (99%) 1 (1%)
33 (50%) 33 (50%)
10 (44%) 13 (57%)
14 (56%) 11 (44%)
57 (50%) 57 (50%)
3 (5%)
12 (52%)
16 (64%)
30 (26%)
III IV ND Prior lines (median, range) 1 2 3 4-6 7-9 10 Types of Prior Therapies Platinum Agent - Platinum Refractory Taxane Anthracycline Gemcitabine Bevacizumab Topo I Inhibitor PARP Inhibitor
34 (52%) 28 (42%) 1 (2%) 6 (1e11) 1 (2%) 6 (9%) 9 (14%) 33 (50%) 10 (15%) 7 (11%)
6 5 2 3 9 6 5 -
1 8 3 4 8 6 7 -
42 (37%) 41 (36%) 1 (1%) 4 (1e11) 8 (7%) 22 (19%) 22 (19%) 43 (38%) 12 (11%) 7 (6%)
66 18 66 55 33 24 18 19
22 (96%) 3 (13%) 23 (100%) 19 (83%) 3 (13%) 4 (17%) -
(100%) (27%) (100%) (83%) (50%) (36%) (27%) (29%)
reported grade 3/4 AEs were thrombocytopenia (17%), fatigue (14%), anemia (10%), nausea (9%) and hyponatremia (9%). Twenty serious adverse events (SAEs) considered at least possibly related to selinexor included 7 cases of nausea, vomiting or decreased appetite, 1 case each of anemia, discomfort, blurred vision, cataract, cognitive disorder, constipation, dehydration, haematemesis, malaise, rectal haemorrhage, thrombocytopenia, and varicella zoster infection and 2 cases of hyponatremia (Supplemental Table 3). Selinexor-related SAEs that involved major organs, febrile neutropenia or opportunistic infections were not reported. SAEs were most frequent at 50 mg/m2 BIW (15%) compared with 35 mg/m2 BIW (10%) or 50 mg/m2 QW(5%). All patients recovered from treatment-related SAEs with dose interruption and/or hospital support. Based on the available data, no major organ toxicities or cumulative toxicity was observed. Eighty-four (74%) patients required a dose reduction or interruption. In ovarian cancer cohort, the frequency of dose reductions or interruptions was numerically higher in patients treated at 50 mg/m2 BIW (80%) and 35 mg/m2 BIW (81%) compared with 50 mg/m2 QW (40%). Overall, 19 patients (17%) withdrew consent due to incidence or severity of AEs, typically nausea, vomiting, fatigue, decreased appetite or weight loss. Rates of withdrawal of consent due to AEs were numerically lower in patients treated at 50 mg/m2 QW(5%), compared with 35 mg/m2 BIW and 50 mg/m2 BIW (both 19%). 4. Discussion This is the first study to assess the efficacy of single-agent oral selinexor in a large cohort of patients with heavily pretreated, advanced gynecological malignancies. There was evidence of meaningful DCR in patients with ovarian (30%) and endometrial (35%) cancer, and to a lesser extent in patients with cervical (24%) cancer, though observed DCRs included wide confidence intervals in Part I (both below and above the prespecified 25% target).
(26%) (22%) (1e5) (13%) (39%) (26%) (22%)
(4%) (32%) (1e6) (16%) (32%) (24%) (28%)
25 (100%) 8 (32%) 23 (92%) 2 (8%) 3 (12%) 6 (24%) 4 (16%) -
113 (99%) 29 (25%) 112 (98%) 76 (67%) 39 (34%) 30 (26%) 26 (23%) 19 (17%)
Confirmed PRs were observed in all cohorts with the highest rates in endometrial (9%) and ovarian (8%) cancers. Importantly, responses and disease control were seen in patients with platinumrefractory ovarian cancer. These results are slightly lower than what was previously reported in a phase 1 study of selinexor in solid tumors, in which patients with gynecological cancers showed a combined 15% overall response rate, all partial responses, and a 46% DCR (defined as PR plus SD 16 weeks) [13]. The promising DCR of 57% that was observed in patients with cervical cancer in phase 1, however, was not seen in this study, and may be a reflection of the larger population size or poorer tolerability of the 50 mg/m2 BIW dose. While selinexor demonstrated single-agent activity in this heavily-pretreated population, increased responses may be achieved using combination therapies. Preclinical studies in cell lines and rodent models have demonstrated that selinexor potentiates the effects of radiation therapy, DNA-damaging agents, PARP inhibitors and immunotherapies to enhance apoptosis and inhibit tumor growth [12,15e19]. In tumors refractory to platinum, selinexor treatment promoted nuclear localization of TSPs, restored sensitivity to cisplatin and induced apoptosis [18,20]. An Investigator Sponsored Trial testing selinexor in combination with paclitaxel and carboplatin for the treatment of ovarian and endometrial cancer is currently ongoing (NCT02269293). To date, biomarkers predictive of response have not been identified. However, analysis of circulating tumor cells (CTC) in a subset of patients from this trial showed that those with 1CTC at baseline had more days on treatment and were more likely to meet the DCR primary endpoint compared to patients with 2 CTCs (see supplemental information) [21]. Next generation sequencing analyses to identify specific gene mutations and to profile gene expression in biopsies of selinexortreated patients are planned in future gynecological clinical trials. The safety profile of selinexor was consistent with previous clinical trials [13,22]. Most common AEs were nausea, fatigue, decreased appetite and vomiting with frequently reported grade 3
Please cite this article as: I.B. Vergote et al., Phase 2 study of the Exportin 1 inhibitor selinexor in patients with recurrent gynecological malignancies, Gynecologic Oncology, https://doi.org/10.1016/j.ygyno.2019.11.012
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Fig. 2. Maximal percent change in tumor size from screening. A. Ovarian. B. Endometrial. C. Cervical. Waterfall plots of best percent change in the sum of all target lesions from screening for 54 patients with ovarian cancer (A), 19 patients with endometrial cancer (B) and 23 patients with cervical cancer (C). Eighteen patients did not have adequate tumor measurements while on study and were considered to have PD based on clinical symptoms (1 patient), SD based on scans at follow-up (1 patient) or be NE (16 patients). * indicates platinum-refractory.
and 4 AEs being thrombocytopenia, fatigue, anemia and hyponatremia. Though most of the gastrointestinal and constitutional AEs were low grade and reversible, they were the primary reason for consent withdrawal. We hypothesize that unlike cyclic administration of more toxic chemotherapeutic agents that often lead to more severe AEs temporally related to drug administration, the continuous administration of selinexor led to low-grade AEs over longer periods that became more meaningful to the patient and require supportive care. AEs could be managed in many patients with dose modifications and supportive care, including 4e8 mg of dexamethasone BIW for decreased appetite and weight loss, platelet stimulating factors (romiplostim and eltrombopag) or blood transfusions for thrombocytopenia and prophylactic 5-HT3 antagonists for nausea. Patients required monitoring for worsening fatigue, nausea or vomiting which was managed with dose reductions or drug holidays. Of the 3 dose schedules tested in ovarian cancer, the QW schedule showed a better safety profile and improved tolerability.
In particular, the frequencies of grade 3 treatment-related thrombocytopenia, anemia and fatigue were lower with QW dosing. Furthermore, fewer dose reductions or interruptions were required at QW compared with the BIW schedules; efficacy was similar across all groups. These results are consistent with the relatively short pharmacokinetic half life of selinexor (6e8 h) but longer biologic half-life (~72 h) [22,23]. Based on the prolonged DCR, safety profile of QW versus BIW schedules and the high unmet medical need in endometrial cancer, a randomized phase 3 trial of maintenance treatment with 80 mg selinexor QW or placebo after combination chemotherapy in patients with advanced or recurrent endometrial cancer has been initiated (NCT03555422). In conclusion, oral selinexor showed moderate single-agent efficacy, particularly in patients with heavily pretreated ovarian and endometrial cancers with manageable and reversible side effects. Combination studies are ongoing.
Please cite this article as: I.B. Vergote et al., Phase 2 study of the Exportin 1 inhibitor selinexor in patients with recurrent gynecological malignancies, Gynecologic Oncology, https://doi.org/10.1016/j.ygyno.2019.11.012
(10%)
(5%)
(5%)
(25%) (15%) (5%) (5%) (5%)
(1%)
(24%) (5%) (5%) (5%) (10%) (5%)
(5%) (14%) (29%) (14%) (10%) (5%)
Data are n (%). A subject with an adverse event coding to the same System Organ Class (SOC) or Preferred Term (PT) on more than one occasion is only counted once for the SOC and PT at the highest grade. * The PT fatigue includes both fatigue and asthenia. BIW ¼ twice weekly; QW ¼ once weekly.
81 78 65 60 55 41 39 32 27 23 13 13 12 1 (1%) 1 (1%)
Grade 3
10 (9%) 16 (14%) 5 (4%) 7 (6%) 1 (1%) 11 (10%) 18 (16%) 1 (1%) 2 (2%) 9 (8%)
Grade 2
44 (39%) 43 (38%) 32 (28%) 25 (22%) 23 (20%) 30 (26%) 16 (14%) 10 (9%) 5 (4%) 12 (11%) 6 (5%) 4 (4%) 27 (24%) 19 (17%) 28 (25%) 28 (25%) 31 (27%) 4 (4%) 22 (19%) 21 (18%) 10 (9%) 7 (6%) 9 (8%) 2 (2%) 14 (70%) 15 (75%) 10 (50%) 10 (50%) 6 (30%) 4 (20%) 1 (5%) 6 (30%) 3 (15%) 3 (15%) 3 (15%) 1 (5%) 2 (10%) (5%) (5%)
1 1 1 1 2 10 (50%) 6 (30%) 6 (30%) 6 (30%) 2 (10%) 3 (15%) 1 (5%) 1 (5%) 2 (10%) 2 (10%) 1 (5%) (15%) (40%) (20%) (15%) (20%)
3 8 4 3 4 5 3 1 1 53 (73%) 48 (66%) 40 (55%) 39 (53%) 40 (55%) 29 (40%) 34 (47%) 22 (30%) 17 (23%) 15 (21%) 6 (8%) 10 (14%) 9 (12%) 1 (1%) 1 (1%) 9 (12%) 10 (14%) 4 (5%) 5 (7%) 8 (11%) 17 (23%) 1 (1%) 1 (1%) 6 (8%) 24 (33%) 29 (40%) 19 (26%) 16 (22%) 15 (21%) 21 (29%) 13 (18%) 8 (11%) 4 (5%) 8 (11%) 2 (3%) 2 (3%) 20 (27%) 9 (12%) 17 (23%) 18 (25%) 25 (34%) 3 (4%) 14 (19%) 12 (16%) 6 (8%) 4 (5%) 8 (11%) 2 (3%) 14 (67%) 15 (71%) 15 (71%) 11 (52%) 9 (43%) 8 (38%) 4 (19%) 4 (19%) 7 (33%) 6 (25%) 4 (19%) 2 (10%) 1 (5%) 5 1 1 1 2 1 1 1 10 (48%) 8 (38%) 7 (33%) 3 (14%) 6 (29%) 6 (29%) 2 (10%) 1 (5%) 1 (5%) 2 (10%) 2 (10%) 1 (5%) (19%) (10%) (33%) (33%) (10%)
4 2 7 7 2 1 3 6 3 2 1 Nausea Fatigue Decreased appetite Vomiting Weight loss Anemia Thrombocytopenia Dysgeusia Blurred vision Diarrhea Constipation Dizziness Hyponatremia
All Patients (N ¼ 114)
Grade 1 Grade 3 Grade 4 Total Grade 1 Grade 2 Grade 3 Grade 1 Grade 3 Grade 4 Total Grade 1 Grade 2
Grade 2
Grade 4 Total
50 mg/m2 QW (N ¼ 20) 50 mg/m2 BIW (N ¼ 73) 35 mg/m2 BIW (N ¼ 21) AE Term
Table 2 Treatment related adverse events occurring in 10% of patients (N ¼ 114) by dose and schedule.
(71%) (68%) (57%) (53%) (48%) (36%) (34%) (28%) (24%) (20%) (11%) (11%) (11%)
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Grade 4 Total
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Declaration of competing interest Authors I.B.V, B. L, U. P, Z.U, A.K, E.V, C.H, T.N, S.N.H, and N.C have no conflicts of interest. M.M has received a research grant from Karyopharm Therapeutics to conduct an investigator initiated trial. Authors T.J.U, Y.C, N.A, T.R, A.J, M.C, Y.L, and J.S are employees and stockholders of Karyopharm Therapecutics. S.S and M.K are board members and stockholders of Karyopharm Therapecutics. M.R.M is a scientific advisory board member of Karyopharm Therapecutics. Acknowledgements We would like to thank the patients who participated in this trial and their families, the co-investigators, nurses, and study coordinators at each of the sites. This is registered at ClinicalTrials.gov (NCT02025985). Appendix A. Supplementary data Supplementary data to this article can be found online at https://doi.org/10.1016/j.ygyno.2019.11.012. Funding This work was supported by Karyopharm Therapeutics. Author contributions Study concept and design: I.B.V, M.R.M, S.S, M.K, T.R. Acquisition of data: I.B.V, B.L, U.P, Z.U, A.K, E.V, C.H, T.N, S.N.H, N.C, M.M, M.R.M. Analysis and interpretation of data: I.B.V, M.R.M, Y.C, N.A, A.J, M.C, Y.L, T.J.U, J.S, S.S, M.K, Drafting of the manuscript: T.J.U, A.J. Critical revision of the manuscript for important intellectual content: All authors. Approval of the version of the manuscript to be published: All authors. References [1] Global Burden of Disease Cancer Collaboration, C. Fitzmaurice, C. Allen, et al., Global, regional, and national cancer incidence, mortality, years of life lost, years lived with disability, and disability-adjusted life-years for 32 cancer groups, 1990 to 2015: a systematic analysis for the global burden of disease study, JAMA Oncol. 3 (2017) 524e548. vry, E. Asselin, Chemoresistance and targeted therapies in [2] K. Brasseur, N. Ge ovarian and endometrial cancers, Oncotarget 8 (2017) 4008e4042. [3] H.Y.J. Fung, Y.M. Chook, Atomic basis of CRM1-cargo recognition, release and inhibition, Semin. Cancer Biol. 27 (2014) 52e61. [4] D.S.P. Tan, P.L. Bedard, J. Kuruvilla, et al., Promising SINEs for embargoing nuclear-cytoplasmic export as an anticancer strategy, Cancer Discov. 4 (2014) 527e537. [5] G.L. Gravina, W. Senapedis, D. McCauley, et al., Nucleo-cytoplasmic transport as a therapeutic target of cancer, J. Hematol. Oncol. 7 (85 1e9) (2014). [6] K. Parikh, S. Cang, A. Sekhri, et al., Selective inhibitors of nuclear export (SINE)–a novel class of anti-cancer agents, J. Hematol. Oncol. 7 (2014) 78. [7] I. Topisirovic, N. Siddiqui, K.L.B. Borden, The eukaryotic translation initiation factor 4E (eIF4E) and HuR RNA operons collaboratively regulate the expression of survival and proliferative genes, Cell Cycle 8 (2009) 960e961. [8] M.J. Osborne, K.L.B. Borden, The eukaryotic translation initiation factor eIF4E in the nucleus: taking the road less traveled, Immunol. Rev. 263 (2015) 210e223. [9] Cancer Genome Atlas Research Network, Integrated genomic analyses of ovarian carcinoma, Nature 474 (7353) (2011) 609e615. [10] E.N. Prendergast, L.L. Holman, A.Y. Liu, et al., Comprehensive genomic profiling of recurrent endometrial cancer: implications for selection of systemic therapy, Gynecol. Oncol. 154 (3) (2019) 461e466. [11] X. Wu, L. Peng, Y. Zhang, et al., Identification of key genes and pathways in cervical cancer by bioinformatics analysis, Int. J. Med. Sci. 16 (6) (2019) 800e812. [12] Y. Chen, S.C. Camacho, T.R. Silvers, et al., Inhibition of the nuclear export receptor XPO1 as a therapeutic target for platinum-resistant ovarian cancer, Clin. Cancer Res. 23 (2017) 1552e1563.
Please cite this article as: I.B. Vergote et al., Phase 2 study of the Exportin 1 inhibitor selinexor in patients with recurrent gynecological malignancies, Gynecologic Oncology, https://doi.org/10.1016/j.ygyno.2019.11.012
I.B. Vergote et al. / Gynecologic Oncology xxx (xxxx) xxx [13] A.R. Abdul Razak, M. Mau-Soerensen, N.Y. Gabrail, et al., First-in-Class, first-inhuman phase I study of selinexor, a selective inhibitor of nuclear export, in patients with advanced solid tumors, J. Clin. Oncol. 34 (2016) 4142e4150. [14] J. Kuruvilla, M. Savona, R. Baz, et al., Selective inhibition of nuclear export with selinexor in patients with non-Hodgkin lymphoma, Blood 129 (24) (2017) 3175e3183, 15. [15] I. Ferreiro-Neira, N.E. Torres, L.F. Liesenfeld, et al., XPO1 inhibition enhances radiation response in preclinical models of rectal cancer, Clin. Cancer Res. 22 (2016) 1663e1673. [16] P. Ranganathan, X. Yu, R. Santhanam, et al., Decitabine priming enhances the anti-leukemic effects of exportin 1 (XPO1) selective inhibitor selinexor in acute myeloid leukemia, Blood 125 (2015) 2689e2692. [17] M.R. Farren, R.C. Hennessey, R. Shakya, et al., The exportin-1 inhibitor selinexor exerts superior antitumor activity when combined with T-cell checkpoint inhibitors, Mol. Cancer Ther. 16 (2017) 417e427. [18] N.P. Arango, E. Yuca, M. Zhao, et al., Selinexor (KPT-330) demonstrates antitumor efficacy in preclinical models of triple-negative breast cancer, Breast Cancer Res. 19 (2017), 93.
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[19] H. Marijon, S. Gery, S. Elloul, et al., Selinexor, a selective inhibitor of nuclear export (SINE) compound, shows enhanced antitumor activity in combination with the PARP inhibitor, olaparib, in models of triple-negative breast cancer, Cancer Res. 75 (15) (2015). [20] M.-S. Tsai, Y.-H. Kuo, Y.-F. Chiu, et al., Down-regulation of Rad51 expression overcomes drug resistance to gemcitabine in human non-small-cell lung cancer cells, J. Pharmacol. Exp. Ther. 335 (2010) 830e840. [21] M. Crochiere, I.B. Vergote, B. Lund, et al., Circulating tumor cell number predicts time to progression in patients (TTP) with heavily pretreated gynecological cancers treated with selinexor (SEL), in: Poster Presented at: European Society for Medical Oncology Congress, 2016. Copenhagen, Denmark; Poster 886P. [22] M.M. Gounder, A. Zer, W.D. Tap, et al., Phase IB study of selinexor, a first-inclass inhibitor of nuclear export, in patients with advanced refractory bone or soft tissue sarcoma, J. Clin. Oncol. 34 (2016) 3166e3174. [23] M.L. Crochiere, E. Baloglu, B. Klebanov, et al., A method for quantification of exportin-1 (XPO1) occupancy by Selective Inhibitor of Nuclear Export (SINE) compounds, Oncotarget 7 (2) (2016) 1863e1877.
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Contents lists available at ScienceDirect
Gynecologic Oncology journal homepage: www.elsevier.com/locate/ygyno
Phase 2 study of the Exportin 1 inhibitor selinexor in patients with recurrent gynecological malignancies I.B. Vergote a, *, B. Lund b, U. Peen c, Z. Umajuridze d, M. Mau-Sorensen d, A. Kranich e, E. Van Nieuwenhuysen a, C. Haslund b, T. Nottrup d, S.N. Han a, N. Concin a, T.J. Unger f, Y. Chai f, N. Au f, T. Rashal f, A. Joshi f, M. Crochiere f, Y. Landesman f, J. Shah f, S. Shacham f, M. Kauffman f, M.R. Mirza f a Department of Obstetrics and Gynaecology, Division of Gynecologic Oncology, University Hospital Leuven, Leuven Cancer Institute, Leuven, Belgium, European Union b Aalborg University Hospital, Aalborg, Denmark c Herlev University Hospital, Herlev, Denmark d Department of Oncology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark e GSO Hamburg, Germany f Karyopharm Therapeutics Newton, MA, USA
h i g h l i g h t s Selinexor, an oral XPO1 inhibitor, demonstrated single-agent activity in ovarian, endometrial, and cervical cancers. Selinexor was safe and tolerable; side effects were predominantly grade 1/2. Frequently reported grade 3/4 events were thrombocytopenia, fatigue, anemia, nausea, and hyponatremia. These data support further development of selinexor in advanced gynecological malignancies.
a r t i c l e i n f o
a b s t r a c t
Article history: Received 14 July 2019 Received in revised form 24 October 2019 Accepted 8 November 2019 Available online xxx
Background: Selinexor is an oral inhibitor of the nuclear export protein Exportin 1 (XPO1) with demonstrated antitumor activity in solid and hematological malignancies. We evaluated the efficacy and safety of selinexor in heavily pretreated, recurrent gynecological malignancies. Methods: In this phase 2 trial, patients received selinexor (35 or 50 mg/m2 twice-weekly [BIW] or 50 mg/ m2 once-weekly [QW]) in 4-week cycles. Primary endpoint was disease control rate (DCR) including complete response (CR), partial response (PR) or stable disease (SD) 12 weeks. Secondary endpoints were progression-free survival (PFS), overall survival (OS) and safety. Results: 114 patients with ovarian (N ¼ 66), endometrial (N ¼ 23) or cervical (N ¼ 25) cancer were enrolled. Median number of prior regimens for ovarian, endometrial and cervical cancer was 6 (1e11), 2 (1e5), and 3 (1e6) respectively. DCR was 30% (ovarian 30%; endometrial 35%; cervical 24%), which included confirmed PRs in 8%, 9%, and 4% of patients with ovarian, endometrial, and cervical cancer respectively. Median PFS and OS for patients with ovarian, endometrial and cervical cancer were 2.6, 2.8 and 1.4 months, and 7.3, 7.0, and 5.0 months, respectively. Common Grade 3/4 adverse events (AEs) were thrombocytopenia (17%), fatigue (14%), anemia (10%), nausea (9%) and hyponatremia (9%). Patients with ovarian cancer receiving 50 mg/m2 QW had fewer high-grade AEs with similar efficacy as BIW treatment. Conclusions: Selinexor demonstrated single-agent activity and disease control in patients with heavily pretreated ovarian and endometrial cancers. Side effects were a function of dose level and treatment frequency, similar to previous reports, reversible and mitigated with supportive care. © 2019 Elsevier Inc. All rights reserved.
Keywords: XPO1 Selinexor Ovarian cancer Endometrial cancer Cervical cancer
* Corresponding author. Division of Gynecological Oncology, Department of Gynaecology and Obstetrics, Leuven Cancer Institute, Katholieke Universiteit Leuven, Herestraat 49, 3000, Leuven, Belgium, European Union. E-mail address: [email protected] (I.B. Vergote). https://doi.org/10.1016/j.ygyno.2019.11.012 0090-8258/© 2019 Elsevier Inc. All rights reserved.
Please cite this article as: I.B. Vergote et al., Phase 2 study of the Exportin 1 inhibitor selinexor in patients with recurrent gynecological malignancies, Gynecologic Oncology, https://doi.org/10.1016/j.ygyno.2019.11.012
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I.B. Vergote et al. / Gynecologic Oncology xxx (xxxx) xxx
1. Introduction Ovarian, endometrial, and cervical malignancies lead to ~490,000 annual deaths worldwide [1]. Patients with advanced disease that has relapsed or is refractory to platinum-based therapy or radiotherapy have limited options and short survival [2]. Therefore, novel therapies are an urgent medical need for advanced gynecological malignancies. Exportin 1 (XPO1/CRM1) is nuclear export protein that mediates the transport of 200 cargo proteins through the nuclear pore complex to the cytoplasm [3]. The anti-tumor activity of TSPs requires nuclear localization, and XPO1 is the sole nuclear exporter of key tumor suppressor proteins (TSPs) such as p53, p21, BRCA1 and 2, IkB and Rb [4e6]. In addition, XPO1 transports eukaryotic initiation factor 4 e (eIF4E) in complex with oncogenic mRNAs, such as Cyclin D1, Myc, and MDM2 to the cytoplasm for their efficient translation [7,8]. In nearly all cancers studied to date, including ovarian cancer, XPO1 expression is elevated, leading to functional inactivation of TSPs and increased translation of oncoproteins [9]. Furthermore, the elevated levels are correlated with poor prognosis and reduced survival, including in ovarian cancer [5,10]. Advanced, heavily pretreated gynecologic cancers have disruptions in many TSP and oncogenic pathways [11]. Therefore, inhibition of XPO1 is an attractive therapeutic strategy that impacts multiple pathways required for cancer growth and survival. Selinexor is an oral, small-molecule inhibitor of XPO1 studied as a single agent or in combination for the treatment of hematological and solid cancers. Preclinical studies using selinexor and related Selective Inhibitor of Nuclear Export (SINE) compounds, showed nuclear retention of TSPs and oncogenic mRNAs in ovarian cancer cell lines [12]. In addition, selinexor significantly reduced the growth of patient-derived, platinum-resistant ovarian cancers in vivo and dramatically improved the OS of mice compared to vehicle treated controls [12]. In a phase I trial of selinexor in advanced solid tumors, 6 of the 13 evaluable patients with heavily pretreated ovarian or cervical cancer had a reduction in target lesion size, including 2 patients with a PR and 4 with durable disease control [13]. The recommended dose of oral selinexor based on both anti-ovarian and anti-cervical cancer activity, along with other Phase 1 studies is 60 mge80 mg on days 1 and 3 twice weekly or 80 mge100 mg once weekly [13,14]. Based on these preliminary findings, we conducted a phase 2 trial to better characterize the efficacy and safety and to determine the optimal dosing of selinexor in advanced gynecological malignancies.
full list of inclusion and exclusion criteria can be found in Supplemental Table 1. All patients were required to receive a prophylactic 5-HT3 antagonist. The protocol was approved by the institutional review board or an independent ethics committee at each participating center and was in accordance with the Declaration of Helsinki, the International Conference on HarmonisationGood Clinical Practice and local laws. All patients provided written informed consent prior to enrollment. All authors reviewed the data for accuracy, interpreted the results and collaborated in the preparation of the manuscript. 2.2. Study assessments Response assessments were by radiological (CT or MRI) and/or PET-CT imaging performed at baseline, after 6 and 12 weeks of treatment, and every 8 weeks thereafter; response assessments were based on the Response Evaluation Criteria in Solid Tumors (RECIST) guidelines (version 1.1). Patients stayed on therapy until disease progression, death, or consent withdrawal. Adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03. 2.3. Statistics
2. Methods
Sample sizes were calculated based on the Simon’s 2-stage optimal design. For each cohort in Part I, the null hypothesis that the DCR was 0.25 was tested against a one-sided alternative that the DCR was 0.50 where the first 8 patients in each cohort were considered the first stage and enrollment in the cohort would be stopped if 2 patients responded. If 3 patients responded, an additional 13 patients would be enrolled. A sample size of 21 patients in each cohort allowed for a one-sided type 1 error of 0.10 and power of 80% when the DCR was 0.50. In Part II, an additional 32 patients with ovarian cancer were enrolled in 1 of 2 treatment groups to provide 80% power to detect a difference of 40% in the proportion of patients with a given AE (10% versus 50%), at a 2sided alpha level of 20%. The primary analysis was performed by calculating the point estimate of the percentage of patients who had CR, PR, or SD 12 weeks. The difference in DCR between the 2 treatment regimens in Part II was analyzed using the Fisher’s Exact test. The secondary efficacy analyses were based on the KaplanMeier method. In the following sections, data are presented by cohort: ovarian (Part I and II), endometrial, and cervical (Part I only) and by dose (Part I vs II) for ovarian cancer.
2.1. Study design and oversight
3. Results
This was a multi-center, open-label study conducted in 2 parts. Part I evaluated selinexor in patients with ovarian, endometrial, or cervical cancer treated at 50 mg/m2 (~80 mg) BIW in 28-day cycles (8 doses per cycle). To improve tolerability based on results from Part I, the protocol was amended to include Part II to test additional dosing schedules in a more homogenous population (patients with ovarian cancer only). In Part II, patients were randomized in a 1:1 ratio using centralized randomization via an interactive webresponse system to either 35 mg/m2 (~60 mg) BIW or 50 mg/m2 (~80 mg) QW, in 28-day cycles; all of these doses had been evaluated in the Phase 1 study [13]. The primary objective was to determine the DCR. The secondary objectives were to assess overall response rate (ORR), PFS, OS, and safety and tolerability. Patients 18 years with epithelial cancers of the ovary or fallopian tube (Part I and II), endometrium or cervix (Part I only) that had no curative options, had received 1 prior line of chemotherapy, and had documented disease progression by CT/MRI were enrolled. A
3.1. Patient characteristics Between October 2014 and December 2015, 116 patients were enrolled (Fig. 1). Two patients died from cardiac events prior to receiving selinexor. As a result, 114 patients with ovarian (Part I: N ¼ 25; Part II: N ¼ 41), endometrial (N ¼ 23), or cervical (N ¼ 25) cancer were evaluable. Median age was 63 years (31e80) and prior regimens for patients with ovarian, endometrial and cervical cancer were 6 (1e11), 2 (1e5), and 3 (1e6) respectively. Nearly all patients had been previously treated with a platinum-based chemotherapy and taxane (Table 1). Median duration of treatment was 43 days (1e891). Reasons for study discontinuation included progressive disease (N ¼ 83), withdrawal of consent due to incidence or severity of AEs (N ¼ 19), withdrawal of consent due to patient’s decision (N ¼ 7), Investigator’s discretion (N ¼ 1) and death (N ¼ 2). One death was due to pneumonia and the other due to renal failure as a result of
Please cite this article as: I.B. Vergote et al., Phase 2 study of the Exportin 1 inhibitor selinexor in patients with recurrent gynecological malignancies, Gynecologic Oncology, https://doi.org/10.1016/j.ygyno.2019.11.012
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Fig. 1. Consort diagram.
disease progression, both deemed by the Investigator to be unrelated to treatment.
3.2. Efficacy Of the 114 patients that received treatment, 98 were evaluable for response. Sixteen patients were non-evaluable (NE) based on lack of adequate tumor assessments prior to withdrawal of consent and characterized as non-responders. Thirty-four of the 114 patients had SD 12 weeks or a PR for a DCR of 30% (Supplemental Table 2). In Part I, the DCR was 28% (95% CI: 12, 49) for ovarian cancer, 35% (95% CI: 16, 57) for endometrial cancer, and 24% (95% CI: 9, 45) for cervical cancer. In Part II, the DCR was 33% (95% CI: 15, 57) for 35 mg/m2 BIW and 30% (95% CI: 12, 54) for 50 mg/m2 QW. Median duration of DCR for ovarian, endometrial and cervical cancer was 6.7, 6.3 and 6.2 months, respectively. Eight patients (7%) achieved a confirmed PR, including 5 patients (8%) with ovarian cancer (Part I: 1 patient; Part II: 2 patients on 35 mg/m2 BIW and 2 patients on 50 mg/m2 QW), 2 patients (9%) with endometrial cancer, and 1 patient (4%) with cervical cancer (3 patients, 2 with ovarian cancer and 1 with endometrial cancer had an unconfirmed PR). Median duration of response for patients with a confirmed PR was 7.4 months (3.7e12.6). Of 96 patients with quantifiable baseline and on-study tumor assessments, 46 (48%) had a reduction in tumor volume (Fig. 2). Eighteen patients without adequate baseline or on-study tumor measurements were assessed as having a best overall response of
PD (N ¼ 1) based on clinical symptoms, SD < 12 weeks (N ¼ 1) or NE (N ¼ 16). Median PFS for ovarian, endometrial and cervical cancer was 2.6 (95% CI: 1.5e2.8), 2.8 (95% CI: 1.4e5.3) and 1.4 months (95% CI: 1.4e4.6), respectively (Supplemental Fig. 1A). Median PFS was not significantly different among ovarian cancer patients treated at BIW or QW schedules; 2.8 (95% CI: 1.4e4.9), 2.6 (95% CI: 1.5e3.3) and 1.5 months (95% CI: 1.4e4.6) for 35 mg/m2 BIW, 50 mg/m2 BIW and 50 mg/m2 QW respectively. (Supplemental Fig. 1B). The median OS for ovarian, endometrial and cervical cancer was 7.3 (95% CI: 4.9e9.8), 7.0 (95% CI: 3.6e11.3) and 5.0 (95% CI: 2.7e8.3), months respectively (Supplemental Fig. 1C). The apparent improvement in OS in patients treated at 35 mg/m2 BIW is likely a reflection of the small sample size and this group having a lower percentage of patients with platinumrefractory ovarian cancer (defined as progression within 28 days of last platinum dose) (14% for 35 mg/m2 BIW versus 32% for 50 mg/ m2 BIW and 35% for 50 mg/m2 QW). In the ovarian cancer cohort, serum CA 125 levels were analyzed in 50 patients. Of these, 24 (48%) patients had a decrease in levels compared with baseline (Supplemental Fig. 2). 3.3. Safety The safety profile of selinexor is summarized in Table 2. Treatment-related AEs occurring in 10% of patients were nausea (71%), fatigue (68%), decreased appetite (57%), vomiting (53%) and weight loss (48%), which were predominantly grade 1/2. Frequently
Please cite this article as: I.B. Vergote et al., Phase 2 study of the Exportin 1 inhibitor selinexor in patients with recurrent gynecological malignancies, Gynecologic Oncology, https://doi.org/10.1016/j.ygyno.2019.11.012
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Table 1 Characteristics of patients at screening. Ovarian (N ¼ 66)
Endometrial (N ¼ 23)
Cervical (N ¼ 25)
Total (N ¼ 114)
Age (median, range) 65 years 75 years Ethnic Origin White North African ECOG performance status 0 1 FIGO Disease Stage I &II
63 (31e80) 22 (33%) 6 (9%)
67 (53e75) 17 (74%) 4 (17%)
53 (32e75) 5 (20%) 1 (4%)
63 (31e80) 44 (39%) 11 (10%)
66 (100%) -
23 (100%) -
24 (96%) 1 (4%)
113 (99%) 1 (1%)
33 (50%) 33 (50%)
10 (44%) 13 (57%)
14 (56%) 11 (44%)
57 (50%) 57 (50%)
3 (5%)
12 (52%)
16 (64%)
30 (26%)
III IV ND Prior lines (median, range) 1 2 3 4-6 7-9 10 Types of Prior Therapies Platinum Agent - Platinum Refractory Taxane Anthracycline Gemcitabine Bevacizumab Topo I Inhibitor PARP Inhibitor
34 (52%) 28 (42%) 1 (2%) 6 (1e11) 1 (2%) 6 (9%) 9 (14%) 33 (50%) 10 (15%) 7 (11%)
6 5 2 3 9 6 5 -
1 8 3 4 8 6 7 -
42 (37%) 41 (36%) 1 (1%) 4 (1e11) 8 (7%) 22 (19%) 22 (19%) 43 (38%) 12 (11%) 7 (6%)
66 18 66 55 33 24 18 19
22 (96%) 3 (13%) 23 (100%) 19 (83%) 3 (13%) 4 (17%) -
(100%) (27%) (100%) (83%) (50%) (36%) (27%) (29%)
reported grade 3/4 AEs were thrombocytopenia (17%), fatigue (14%), anemia (10%), nausea (9%) and hyponatremia (9%). Twenty serious adverse events (SAEs) considered at least possibly related to selinexor included 7 cases of nausea, vomiting or decreased appetite, 1 case each of anemia, discomfort, blurred vision, cataract, cognitive disorder, constipation, dehydration, haematemesis, malaise, rectal haemorrhage, thrombocytopenia, and varicella zoster infection and 2 cases of hyponatremia (Supplemental Table 3). Selinexor-related SAEs that involved major organs, febrile neutropenia or opportunistic infections were not reported. SAEs were most frequent at 50 mg/m2 BIW (15%) compared with 35 mg/m2 BIW (10%) or 50 mg/m2 QW(5%). All patients recovered from treatment-related SAEs with dose interruption and/or hospital support. Based on the available data, no major organ toxicities or cumulative toxicity was observed. Eighty-four (74%) patients required a dose reduction or interruption. In ovarian cancer cohort, the frequency of dose reductions or interruptions was numerically higher in patients treated at 50 mg/m2 BIW (80%) and 35 mg/m2 BIW (81%) compared with 50 mg/m2 QW (40%). Overall, 19 patients (17%) withdrew consent due to incidence or severity of AEs, typically nausea, vomiting, fatigue, decreased appetite or weight loss. Rates of withdrawal of consent due to AEs were numerically lower in patients treated at 50 mg/m2 QW(5%), compared with 35 mg/m2 BIW and 50 mg/m2 BIW (both 19%). 4. Discussion This is the first study to assess the efficacy of single-agent oral selinexor in a large cohort of patients with heavily pretreated, advanced gynecological malignancies. There was evidence of meaningful DCR in patients with ovarian (30%) and endometrial (35%) cancer, and to a lesser extent in patients with cervical (24%) cancer, though observed DCRs included wide confidence intervals in Part I (both below and above the prespecified 25% target).
(26%) (22%) (1e5) (13%) (39%) (26%) (22%)
(4%) (32%) (1e6) (16%) (32%) (24%) (28%)
25 (100%) 8 (32%) 23 (92%) 2 (8%) 3 (12%) 6 (24%) 4 (16%) -
113 (99%) 29 (25%) 112 (98%) 76 (67%) 39 (34%) 30 (26%) 26 (23%) 19 (17%)
Confirmed PRs were observed in all cohorts with the highest rates in endometrial (9%) and ovarian (8%) cancers. Importantly, responses and disease control were seen in patients with platinumrefractory ovarian cancer. These results are slightly lower than what was previously reported in a phase 1 study of selinexor in solid tumors, in which patients with gynecological cancers showed a combined 15% overall response rate, all partial responses, and a 46% DCR (defined as PR plus SD 16 weeks) [13]. The promising DCR of 57% that was observed in patients with cervical cancer in phase 1, however, was not seen in this study, and may be a reflection of the larger population size or poorer tolerability of the 50 mg/m2 BIW dose. While selinexor demonstrated single-agent activity in this heavily-pretreated population, increased responses may be achieved using combination therapies. Preclinical studies in cell lines and rodent models have demonstrated that selinexor potentiates the effects of radiation therapy, DNA-damaging agents, PARP inhibitors and immunotherapies to enhance apoptosis and inhibit tumor growth [12,15e19]. In tumors refractory to platinum, selinexor treatment promoted nuclear localization of TSPs, restored sensitivity to cisplatin and induced apoptosis [18,20]. An Investigator Sponsored Trial testing selinexor in combination with paclitaxel and carboplatin for the treatment of ovarian and endometrial cancer is currently ongoing (NCT02269293). To date, biomarkers predictive of response have not been identified. However, analysis of circulating tumor cells (CTC) in a subset of patients from this trial showed that those with 1CTC at baseline had more days on treatment and were more likely to meet the DCR primary endpoint compared to patients with 2 CTCs (see supplemental information) [21]. Next generation sequencing analyses to identify specific gene mutations and to profile gene expression in biopsies of selinexortreated patients are planned in future gynecological clinical trials. The safety profile of selinexor was consistent with previous clinical trials [13,22]. Most common AEs were nausea, fatigue, decreased appetite and vomiting with frequently reported grade 3
Please cite this article as: I.B. Vergote et al., Phase 2 study of the Exportin 1 inhibitor selinexor in patients with recurrent gynecological malignancies, Gynecologic Oncology, https://doi.org/10.1016/j.ygyno.2019.11.012
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Fig. 2. Maximal percent change in tumor size from screening. A. Ovarian. B. Endometrial. C. Cervical. Waterfall plots of best percent change in the sum of all target lesions from screening for 54 patients with ovarian cancer (A), 19 patients with endometrial cancer (B) and 23 patients with cervical cancer (C). Eighteen patients did not have adequate tumor measurements while on study and were considered to have PD based on clinical symptoms (1 patient), SD based on scans at follow-up (1 patient) or be NE (16 patients). * indicates platinum-refractory.
and 4 AEs being thrombocytopenia, fatigue, anemia and hyponatremia. Though most of the gastrointestinal and constitutional AEs were low grade and reversible, they were the primary reason for consent withdrawal. We hypothesize that unlike cyclic administration of more toxic chemotherapeutic agents that often lead to more severe AEs temporally related to drug administration, the continuous administration of selinexor led to low-grade AEs over longer periods that became more meaningful to the patient and require supportive care. AEs could be managed in many patients with dose modifications and supportive care, including 4e8 mg of dexamethasone BIW for decreased appetite and weight loss, platelet stimulating factors (romiplostim and eltrombopag) or blood transfusions for thrombocytopenia and prophylactic 5-HT3 antagonists for nausea. Patients required monitoring for worsening fatigue, nausea or vomiting which was managed with dose reductions or drug holidays. Of the 3 dose schedules tested in ovarian cancer, the QW schedule showed a better safety profile and improved tolerability.
In particular, the frequencies of grade 3 treatment-related thrombocytopenia, anemia and fatigue were lower with QW dosing. Furthermore, fewer dose reductions or interruptions were required at QW compared with the BIW schedules; efficacy was similar across all groups. These results are consistent with the relatively short pharmacokinetic half life of selinexor (6e8 h) but longer biologic half-life (~72 h) [22,23]. Based on the prolonged DCR, safety profile of QW versus BIW schedules and the high unmet medical need in endometrial cancer, a randomized phase 3 trial of maintenance treatment with 80 mg selinexor QW or placebo after combination chemotherapy in patients with advanced or recurrent endometrial cancer has been initiated (NCT03555422). In conclusion, oral selinexor showed moderate single-agent efficacy, particularly in patients with heavily pretreated ovarian and endometrial cancers with manageable and reversible side effects. Combination studies are ongoing.
Please cite this article as: I.B. Vergote et al., Phase 2 study of the Exportin 1 inhibitor selinexor in patients with recurrent gynecological malignancies, Gynecologic Oncology, https://doi.org/10.1016/j.ygyno.2019.11.012
(10%)
(5%)
(5%)
(25%) (15%) (5%) (5%) (5%)
(1%)
(24%) (5%) (5%) (5%) (10%) (5%)
(5%) (14%) (29%) (14%) (10%) (5%)
Data are n (%). A subject with an adverse event coding to the same System Organ Class (SOC) or Preferred Term (PT) on more than one occasion is only counted once for the SOC and PT at the highest grade. * The PT fatigue includes both fatigue and asthenia. BIW ¼ twice weekly; QW ¼ once weekly.
81 78 65 60 55 41 39 32 27 23 13 13 12 1 (1%) 1 (1%)
Grade 3
10 (9%) 16 (14%) 5 (4%) 7 (6%) 1 (1%) 11 (10%) 18 (16%) 1 (1%) 2 (2%) 9 (8%)
Grade 2
44 (39%) 43 (38%) 32 (28%) 25 (22%) 23 (20%) 30 (26%) 16 (14%) 10 (9%) 5 (4%) 12 (11%) 6 (5%) 4 (4%) 27 (24%) 19 (17%) 28 (25%) 28 (25%) 31 (27%) 4 (4%) 22 (19%) 21 (18%) 10 (9%) 7 (6%) 9 (8%) 2 (2%) 14 (70%) 15 (75%) 10 (50%) 10 (50%) 6 (30%) 4 (20%) 1 (5%) 6 (30%) 3 (15%) 3 (15%) 3 (15%) 1 (5%) 2 (10%) (5%) (5%)
1 1 1 1 2 10 (50%) 6 (30%) 6 (30%) 6 (30%) 2 (10%) 3 (15%) 1 (5%) 1 (5%) 2 (10%) 2 (10%) 1 (5%) (15%) (40%) (20%) (15%) (20%)
3 8 4 3 4 5 3 1 1 53 (73%) 48 (66%) 40 (55%) 39 (53%) 40 (55%) 29 (40%) 34 (47%) 22 (30%) 17 (23%) 15 (21%) 6 (8%) 10 (14%) 9 (12%) 1 (1%) 1 (1%) 9 (12%) 10 (14%) 4 (5%) 5 (7%) 8 (11%) 17 (23%) 1 (1%) 1 (1%) 6 (8%) 24 (33%) 29 (40%) 19 (26%) 16 (22%) 15 (21%) 21 (29%) 13 (18%) 8 (11%) 4 (5%) 8 (11%) 2 (3%) 2 (3%) 20 (27%) 9 (12%) 17 (23%) 18 (25%) 25 (34%) 3 (4%) 14 (19%) 12 (16%) 6 (8%) 4 (5%) 8 (11%) 2 (3%) 14 (67%) 15 (71%) 15 (71%) 11 (52%) 9 (43%) 8 (38%) 4 (19%) 4 (19%) 7 (33%) 6 (25%) 4 (19%) 2 (10%) 1 (5%) 5 1 1 1 2 1 1 1 10 (48%) 8 (38%) 7 (33%) 3 (14%) 6 (29%) 6 (29%) 2 (10%) 1 (5%) 1 (5%) 2 (10%) 2 (10%) 1 (5%) (19%) (10%) (33%) (33%) (10%)
4 2 7 7 2 1 3 6 3 2 1 Nausea Fatigue Decreased appetite Vomiting Weight loss Anemia Thrombocytopenia Dysgeusia Blurred vision Diarrhea Constipation Dizziness Hyponatremia
All Patients (N ¼ 114)
Grade 1 Grade 3 Grade 4 Total Grade 1 Grade 2 Grade 3 Grade 1 Grade 3 Grade 4 Total Grade 1 Grade 2
Grade 2
Grade 4 Total
50 mg/m2 QW (N ¼ 20) 50 mg/m2 BIW (N ¼ 73) 35 mg/m2 BIW (N ¼ 21) AE Term
Table 2 Treatment related adverse events occurring in 10% of patients (N ¼ 114) by dose and schedule.
(71%) (68%) (57%) (53%) (48%) (36%) (34%) (28%) (24%) (20%) (11%) (11%) (11%)
I.B. Vergote et al. / Gynecologic Oncology xxx (xxxx) xxx
Grade 4 Total
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Declaration of competing interest Authors I.B.V, B. L, U. P, Z.U, A.K, E.V, C.H, T.N, S.N.H, and N.C have no conflicts of interest. M.M has received a research grant from Karyopharm Therapeutics to conduct an investigator initiated trial. Authors T.J.U, Y.C, N.A, T.R, A.J, M.C, Y.L, and J.S are employees and stockholders of Karyopharm Therapecutics. S.S and M.K are board members and stockholders of Karyopharm Therapecutics. M.R.M is a scientific advisory board member of Karyopharm Therapecutics. Acknowledgements We would like to thank the patients who participated in this trial and their families, the co-investigators, nurses, and study coordinators at each of the sites. This is registered at ClinicalTrials.gov (NCT02025985). Appendix A. Supplementary data Supplementary data to this article can be found online at https://doi.org/10.1016/j.ygyno.2019.11.012. Funding This work was supported by Karyopharm Therapeutics. Author contributions Study concept and design: I.B.V, M.R.M, S.S, M.K, T.R. Acquisition of data: I.B.V, B.L, U.P, Z.U, A.K, E.V, C.H, T.N, S.N.H, N.C, M.M, M.R.M. Analysis and interpretation of data: I.B.V, M.R.M, Y.C, N.A, A.J, M.C, Y.L, T.J.U, J.S, S.S, M.K, Drafting of the manuscript: T.J.U, A.J. Critical revision of the manuscript for important intellectual content: All authors. Approval of the version of the manuscript to be published: All authors. References [1] Global Burden of Disease Cancer Collaboration, C. Fitzmaurice, C. Allen, et al., Global, regional, and national cancer incidence, mortality, years of life lost, years lived with disability, and disability-adjusted life-years for 32 cancer groups, 1990 to 2015: a systematic analysis for the global burden of disease study, JAMA Oncol. 3 (2017) 524e548. vry, E. Asselin, Chemoresistance and targeted therapies in [2] K. Brasseur, N. Ge ovarian and endometrial cancers, Oncotarget 8 (2017) 4008e4042. [3] H.Y.J. Fung, Y.M. Chook, Atomic basis of CRM1-cargo recognition, release and inhibition, Semin. Cancer Biol. 27 (2014) 52e61. [4] D.S.P. Tan, P.L. Bedard, J. Kuruvilla, et al., Promising SINEs for embargoing nuclear-cytoplasmic export as an anticancer strategy, Cancer Discov. 4 (2014) 527e537. [5] G.L. Gravina, W. Senapedis, D. McCauley, et al., Nucleo-cytoplasmic transport as a therapeutic target of cancer, J. Hematol. Oncol. 7 (85 1e9) (2014). [6] K. Parikh, S. Cang, A. Sekhri, et al., Selective inhibitors of nuclear export (SINE)–a novel class of anti-cancer agents, J. Hematol. Oncol. 7 (2014) 78. [7] I. Topisirovic, N. Siddiqui, K.L.B. Borden, The eukaryotic translation initiation factor 4E (eIF4E) and HuR RNA operons collaboratively regulate the expression of survival and proliferative genes, Cell Cycle 8 (2009) 960e961. [8] M.J. Osborne, K.L.B. Borden, The eukaryotic translation initiation factor eIF4E in the nucleus: taking the road less traveled, Immunol. Rev. 263 (2015) 210e223. [9] Cancer Genome Atlas Research Network, Integrated genomic analyses of ovarian carcinoma, Nature 474 (7353) (2011) 609e615. [10] E.N. Prendergast, L.L. Holman, A.Y. Liu, et al., Comprehensive genomic profiling of recurrent endometrial cancer: implications for selection of systemic therapy, Gynecol. Oncol. 154 (3) (2019) 461e466. [11] X. Wu, L. Peng, Y. Zhang, et al., Identification of key genes and pathways in cervical cancer by bioinformatics analysis, Int. J. Med. Sci. 16 (6) (2019) 800e812. [12] Y. Chen, S.C. Camacho, T.R. Silvers, et al., Inhibition of the nuclear export receptor XPO1 as a therapeutic target for platinum-resistant ovarian cancer, Clin. Cancer Res. 23 (2017) 1552e1563.
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