Abstract
Purpose:
Selinexor, a selective inhibitor of nuclear export, monotherapy causes nuclear accumulation of tumor-suppressor proteins and has anti-tumor activity in ovarian and endometrial cancers. The safety and tolerability of oral selinexor plus intravenous carboplatin and paclitaxel chemotherapy (selinexor + CP) was evaluated in this population.
Patients and Methods:
This phase I, 3+3 dose-escalation study assessed 4 selinexor + CP regimens. Patients in cohorts of 3, regardless of disease type, were administered 1 of 4 alternating regimens (selinexor at 30 mg/m2 or 60 mg plus CP at AUC 5 and 175 mg/m2 or 80 mg/m2, respectively) for 6–10 cycles (1 cycle=21 days), followed by selinexor maintenance. Enrolled patients with ovarian cancer had received 1 prior platinum-based therapy. Patients with endometrial cancer were chemotherapy-naive or had received 1 prior platinum-based therapy. Response was evaluated every 9 weeks.
Results:
Twenty-three patients were treated (5 serous ovarian cancer; 18 endometrial cancer, including 6 carcinosarcomas). The most common treatment-related adverse events (TRAEs) were thrombocytopenia (100%), leukopenia (91%), and hyperglycemia (87%). The most common grade 3/4 TRAEs were leukopenia (70%), neutropenia (70%), lymphopenia (61%), anemia (57%), and alanine transaminase increase (43%). One treatment-related dose-limiting toxicity (grade 3 syncope) occurred. Twelve patients achieved a partial response and 1 achieved a complete response. Responses to all four regimens were observed in ovarian and endometrial cancers.
Conclusions:
Combination selinexor + CP was safe and tolerated in advanced ovarian and endometrial cancers.
Keywords: ovarian cancer, endometrial cancer, selinexor, paclitaxel, carboplatin
Introduction
Ovarian and endometrial cancers are often initially responsive to platinum- and taxane-based chemotherapy [1–3]. However, most patients with advanced ovarian and endometrial cancers ultimately relapse, and management of recurrent disease remains challenging. Preclinical work in orthotopic mouse models of ovarian cancer has demonstrated significant anti-tumor effects of exportin 1 (XPO1/CRM1) inhibitor monotherapy, with tumor burden further decreased by the addition of paclitaxel or platinum-based chemotherapy combinations [4, 5].
XPO1 is a primary karyopherin that facilitates nuclear export of nearly all known tumor suppressor proteins (TSPs), including p53, APC/β-catenin, and FOXO [4, 6]. XPO1 also associates with kinetochores and centromeres during mitosis and controls chromosome segregation [7, 8]. Overexpression of XPO1 results in high cytoplasmic mislocalization of TSPs and of proteins regulating tumor growth; cytoplasmic XPO1 expression is also correlated with advanced tumor stage, poorly differentiated carcinomas, and worse patient outcomes [9–12].
Selinexor (KPT-330) is an orally available, covalent, and potent selective inhibitor of nuclear export (SINE) that blocks XPO1. It thus restores many TSPs and other growth-regulating proteins to the nucleus to carry out their normal functions [5]. It also inhibits the expression of DNA damage repair proteins, which could help overcome drug resistance [13, 14]. Indeed, in ovarian cancer and other malignancies, delayed DNA damage repair has been reported when selinexor is combined with DNA damage-inducing chemotherapy and radiation therapy [5, 14–16].
Recent studies have demonstrated the efficacy of selinexor monotherapy in advanced gynecologic malignancies. In a phase I basket trial (NCT01607905), patients with heavily pretreated ovarian and cervical cancers had partial responses (PRs) [17]. In a phase II study of patients with pretreated gynecologic cancer (NCT02025985), the disease control rate for ovarian, endometrial, and cervical cancers was 30%, 35%, and 24%, respectively [18]. In this trial, we evaluated the safety and preliminary efficacy of selinexor in combination with carboplatin and paclitaxel chemotherapy (CP; selinexor + CP) in advanced ovarian and endometrial cancers.
Patients and Methods
Patient selection
Eligible patients had pathologically confirmed ovarian cancer, fallopian tube or primary peritoneal cancer, or endometrial carcinoma, including carcinosarcomas. Patients with ovarian cancer histologies had recurrent disease and had received one prior first line treatment of platinum-based chemotherapy as intraperitoneal therapy; as consolidation or maintenance therapy; and/or combined with biologic or targeted agents, such as bevacizumab or PARP inhibitors. Patients with endometrial cancer histologies were either chemotherapy-naive or had received one prior first line treatment of platinum-based chemotherapy as consolidation or maintenance and/or with biologic or targeted agents. Chemotherapy-naive patients with endometrial cancer histologies who were included in the study had Stage IVB or recurrent disease. Other inclusion criteria were measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST v1.1) [19]; age ≥18 years; Eastern Cooperative Oncology Group (ECOG) Performance Status of 0–1; and adequate bone marrow, renal, hepatic, and neurologic functions. Notable exclusion criteria included prior selinexor treatment, history of intracranial metastatic disease, significant cardiovascular disease, and use of drainage gastrostomy.
Study design
This was a single-center, non-randomized, open-label phase I study that used a standard 3+3 dose-escalation design (NCT02269293). The trial assessed selinexor + CP therapy in advanced ovarian and endometrial cancers, including carcinosarcomas. The primary objectives were to evaluate the safety and tolerability and to determine the recommended phase II dose (RP2D) of selinexor in this combination therapy and population. The secondary objectives were to explore the clinical efficacy of selinexor + CP by measuring the overall response rate (ORR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS). The pharmacokinetics (PKs) of the combination therapy were also evaluated.
Patients were enrolled in cohorts of 3 at a time, regardless of disease type, to 1 of 4 alternating dosing regimens (R1–4; Table 1). After a cohort was enrolled to R4 the cycle repeated. Patients with ovarian and endometrial cancers were included at each dose level. In the absence of intolerable toxicities or other withdrawal criteria and following completion of 6–10 cycles (1 cycle=21 days) of selinexor + CP, patients continued selinexor maintenance at the same dose and schedule as that administered with chemotherapy.
Table 1.
Baseline characteristics (N=23).
| Characteristic | N (%) |
|---|---|
| Age, years | |
| Mean | 62 |
| Range | 43–77 |
| Race | |
| White | 17 (74%) |
| Black or African American | 2 (9%) |
| Asian | 2 (9%) |
| Unknown | 2 (9%) |
| No. of prior platinum-based therapies | |
| 0 | 8 (35%) |
| 1 | 14 (61%) |
| 2 | 1 (4%) |
| ECOG performance status | |
| 0 | 18 (78%) |
| 1 | 5 (22%) |
| Cancer type | |
| Endometrial cancer | 18 (78%) |
| Endometrioid grade 1 | 1 (4%) |
| Endometrioid grade 2 | 2 (9%) |
| Endometrioid grade 3 | 3 (13%) |
| Serous/high grade | 6 (26%) |
| Carcinosarcoma | 6 (26%) |
| Ovarian cancera | 5 (22%) |
| Serous | 5 (22%) |
| Stage at diagnosis | |
| Endometrial cancer | 18 (78%) |
| I | 8 (35%) |
| II | 0 |
| III | 2 (9%) |
| IV | 8 (35%) |
| Ovarian cancer | 5 (22%) |
| III | 4 (17%) |
| IV | 1 (4%) |
ECOG=Eastern Cooperative Oncology Group; No.=number.
All patients with ovarian cancer had received a platinum-based therapy ≥6 months prior.
This protocol and subsequent amendments were approved by the Memorial Sloan Kettering Cancer Center institutional review board, and all patients provided written informed consent prior to trial participation. This study was conducted in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice Guidelines.
Study treatments
The initial doses of selinexor studied were 30 mg/m2 (R1, R2) and 60 mg flat dose (R3, R4). Patients also received either (R1, R4) carboplatin at target area under the curve (AUC) 5 mg·min/mL intravenously (IV) and paclitaxel 175 mg/m2 IV over 3 hours every 3 weeks, or (R2, R3) carboplatin at AUC 5 mg·min/mL IV every 3 weeks and paclitaxel 80 mg/m2 IV over 1 hour weekly (see Table 2 for details of R1–4). For all regimens, paclitaxel IV was administered first, followed by carboplatin IV over 30 minutes in accordance with standard hospital practice. Selinexor was dosed at 30 mg/m2 on days 1, 4, 8, 11, 15 and 18 of each cycle or given as a 60 mg flat dose on days 1, 8, and 15 of each cycle. The combination selinexor + CP therapy was administered for 6 cycles, which could be extended up to 10 cycles if deemed appropriate by the treating physician. Patients continued to receive selinexor maintenance therapy after chemotherapy at the same dose and schedule as administered during combination therapy. Treatment continued until progression of disease (PD), unacceptable toxicity, or withdrawal of consent by the patient.
Table 2.
Dose level and schedules with occurrence of dose-limiting toxicity of each regimen.
| 1 | 21 | Carboplatin AUC 5 IV, Day 1 Paclitaxel 175 mg/m2 IV, Day 1 | Selinexor 30 mg/m2 orally, Day 1,4, 8, 11, 15, and 18 | 3 | 0 | |
| 2 | 21 | Carboplatin AUC 5 IV, Day 1 Paclitaxel 80 mg/m2 IV, Day 1,8,15 | Selinexor 30 mg/m2 orally, Day 1,4, 8, 11, 15, and 18 | 7 | 1 | Grade 3 syncope |
| 3 | 21 | Carboplatin AUC 5 IV, Day 1 Paclitaxel 80 mg/m2 IV, Day 1,8,15 | Selinexor 60 mg, orally, Day 1, 8, 15 | 6 | 0 | |
| 4 | 21 | Carboplatin AUC 5 IV, Day 1 Paclitaxel 175 mg/m2 IV, Day 1 | Selinexor 60 mg, orally, Day 1, 8, 15 | 7 | 0 |
AUC=area under the curve, DLT=dose-limiting toxicity
After 17 patients were enrolled, including 10 patients treated at 30 mg/m2 in R1 and R2, the protocol was amended, according to the Karyopharm Therapeutics’ (drug manufacturer) recommendation, to investigate a 60 mg flat dose of selinexor once weekly only (R3 and R4). The decision to change the dose and schedule for all patients was based on parallel studies (NCT01607892) that found the maximum concentration (Cmax) and AUC for body surface area (BSA)-based (mg/m2) and flat (mg) dosing methods were similar [20]. Additionally, there were no shown differences in toxicity profile between the dosing schedules and improved tolerability of selinexor given weekly in combination with other therapies [20].
Safety and tolerability assessments
All patients who received at least 1 dose of treatment were evaluated for safety. Adverse events (AEs) were graded according the National Cancer Institute Common Terminology Criteria for Adverse Event (CTCAE) version 4.03. Because the maximum tolerated dose (MTD) and safety profiles for patients with ovarian and endometrial cancers were expected to be similar, the enrolled patient groups were analyzed together for safety objectives. Patients were observed for dose-limiting toxicity (DLT) during cycle 1 of treatment.
Pharmacokinetic assessments
Plasma samples for PK assessment of selinexor and paclitaxel, were collected at pre-dose, 0.5, 1, 2, 4, and 21 hours post-dose on day 1 of cycle 1 and at pre-dose, 2, and 4 hours post-dose on day 1 of subsequent cycles. Carboplatin plasma samples were collected pre-dose and at 0.5, 1, and, 2 hours post-dose on day 1 of cycle 1 and at pre-dose and 2 hours post-dose on day 1 of subsequent cycles. At each time point, 2 mL of blood was collected in an EDTA tube, and plasma samples were kept frozen at −70° C until analysis.
Plasma samples were shipped frozen to Covance (Salt Lake City, Utah) for analysis. Plasma concentrations of all drugs were determined using liquid chromatography with tandem mass spectrometry, (LC/MS/MS), which is validated for measuring selinexor and is a qualified method for measuring paclitaxel and carboplatin. The selinexor method has the quantification range of 1.00 to 1000 ng/mL. Plasma concentrations of paclitaxel and carboplatin were determined within a quantification range of 50 to 20,000 ng/mL.
PK parameters were calculated by non-compartmental methodology using Phoenix WinNonlin 8.1 software (Certara). All plasma concentration values below the lower limit of quantification for the assay were treated as missing in the PK analysis, except for those occurring before the first quantifiable concentration on day 1, which were treated as zero.
Anti-tumor activity
Radiographic assessments were conducted every 9 weeks (±7 days) during treatment and then every 12 weeks until disease progression. Tumor response was measured using RECIST v1.1 guideline.
Statistical analyses
Patients were considered evaluable for the efficacy analyses if they finished at least 1 cycle of treatment and had 1 post-baseline efficacy measurement. Best overall response was analyzed as a binary endpoint, defined as complete response (CR) or PR versus stable disease (SD) and PD. The ORR was calculated with 95% exact confidence interval (CI). The DOR was summarized with descriptive statistics and was defined from time of documented response to progression. PFS was calculated from the beginning of treatment to progression, last follow-up, or death at the time of censoring. OS was calculated from the beginning of the treatment to last follow-up or death. Median PFS, 1-year PFS, median OS, and OS were estimated using the Kaplan-Meier method, while PK results were described by summary statistics at each time point that data were collected.
Results
Patient characteristics
Twenty-three patients were enrolled and treated between November 2014 and December 2017. Five patients had serous ovarian cancer and 18 patients had endometrial cancer, including 6 with carcinosarcoma. Most patients had an ECOG Performance Status of 0 (78%) and had received ≤1 platinum-based regimen (96%). Baseline characteristics are shown in Table 1.
Safety
Of the 23 evaluable patients, 1 patient experienced a grade 3 syncope DLT (in R2). A 60 mg flat dose of selinexor weekly in combination with either dosing schedule of carboplatin/paclitaxel chemotherapy was established as the RP2D. This recommendation is based on the tolerability and preliminary efficacy of selinexor, as well as on parallel studies (NCT02025985, NCT01607892) showing similar Cmax and AUC for BSA-based (mg/m2) and flat (mg) selinexor dosing [18, 20, 21].
Certain treatment-related adverse events (TRAEs) of grades 1–4 occurred in all 23 patients. A summary of TRAEs occurring in >20% of patients is shown in Table 3. Given that combination carboplatin/paclitaxel chemotherapy and selinexor each has reported hematologic toxicities, the attribution of TRAEs was related to treatment regimens not individual drugs. The most frequently reported grades 1–4 hematologic toxicities were thrombocytopenia (100%), leukopenia (100%), neutropenia (91%), and anemia (78%). AEs were managed with dose delay, dose reduction, and supportive care. The most common non-hematologic grade 3 or 4 AEs were increased alanine aminotransferase (ALT; 43%), hypokalemia (26%), and hypomagnesemia (22%).
Table 3.
Treatment-related adverse events of grades 1–4 occurring in >20% of all patients (N=23)
| Regimen 1 | Regimen 2 | Regimen 3 | Regimen 4 | All Patients | ||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Adverse Event | (N=3) | (N=7) | (N=6) | (N=7) | (N=23) | |||||
| Thrombocytopenia | 3 | 2 | 7 | 2 | 6 | 1 | 7 | 2 | 23 (100 %) | 7 (30%) |
| Leukopenia | 3 | 3 | 7 | 3 | 6 | 5 | 7 | 5 | 23 (100 %) | 16 (70%) |
| Neutropenia | 2 | 2 | 6 | 5 | 6 | 4 | 7 | 5 | 21 (91%) | 16 (70%) |
| Hyperglycemia | 3 | 0 | 7 | 2 | 6 | 2 | 4 | 0 | 20 (87%) | 4 (17%) |
| Hypomagnese mia | 2 | 0 | 5 | 1 | 6 | 4 | 6 | 0 | 19 (83%) | 5 (22%) |
| Anemia | 3 | 2 | 6 | 4 | 6 | 5 | 3 | 2 | 18 (78%) | 13 (57%) |
| Hypoalbumine mia | 2 | 0 | 5 | 0 | 5 | 0 | 6 | 1 | 18 (78%) | 1 (4%) |
| ALT increase | 2 | 0 | 5 | 3 | 6 | 5 | 5 | 2 | 18 (78%) | 10 (43%) |
| Nausea | 3 | 1 | 5 | 1 | 4 | 0 | 3 | 1 | 15 (65%) | 3 (13%) |
| Lymphopenia | 3 | 3 | 3 | 3 | 4 | 3 | 5 | 5 | 15 (65%) | 14 (61%) |
| Hyponatremia | 3 | 1 | 7 | 0 | 3 | 1 | 2 | 0 | 15 (65%) | 2 (9%) |
| Fatigue | 3 | 0 | 5 | 1 | 3 | 0 | 3 | 0 | 14 (61%) | 1 (4%) |
| Hypocalcemia | 2 | 1 | 4 | 0 | 3 | 0 | 4 | 2 | 13 (57%) | 3 (13%) |
| AST increase | 2 | 0 | 4 | 0 | 3 | 1 | 2 | 1 | 11 (48%) | 2 (9%) |
| Anorexia | 2 | 0 | 6 | 0 | 2 | 0 | 1 | 0 | 11 (48%) | 0 |
| Constipation | 2 | 0 | 3 | 0 | 2 | 0 | 4 | 0 | 11 (48%) | 0 |
| Alopecia | 0 | 0 | 5 | 0 | 2 | 0 | 3 | 0 | 10 (43%) | 0 |
| Prolonged APTT | 1 | 0 | 3 | 1 | 2 | 0 | 4 | 0 | 10 (43%) | 1 (4%) |
| Increased INR | 1 | 0 | 2 | 1 | 3 | 0 | 3 | 1 | 9 (39%) | 2 (9%) |
| Vomiting | 2 | 0 | 1 | 0 | 3 | 1 | 3 | 1 | 9 (39%) | 2 (9%) |
| Hypokalemia | 1 | 1 | 2 | 1 | 1 | 0 | 4 | 4 | 8 (35%) | 6 (26%) |
| ALP increase | 0 | 0 | 2 | 0 | 2 | 0 | 4 | 0 | 8 | 0 (35%) |
| Neuropathy | 1 | 0 | 1 | 0 | 3 | 1 | 2 | 0 | 7 (30%) | 1 (4%) |
| Weight loss | 1 | 0 | 2 | 0 | 3 | 1 | 1 | 0 | 7 (30%) | 1 (4%) |
| Diarrhea | 1 | 0 | 3 | 0 | 1 | 0 | 1 | 0 | 6 (26%) | 0 |
ALP=alkaline phosphatase, ALT=alanine transaminase, APTT= activated partial thromboplastin time; AST=aspartate aminotransferase; INR=international normalized ratio
Twelve patients (52%) reported ≥1 serious adverse event (SAE). No treatment-related deaths (grade 5) occurred but 3 non-treatment-related deaths were reported, related to progressive disease, disease-related perforation, and Bacteroides fragilis sepsis with hypoxic respiratory failure secondary to scleroderma-associated interstitial lung disease.
Other AEs included grade 3 febrile neutropenia (R1, R2, R4: n=4), grade 3 nausea (R1, R4: n=2), grade 4 anemia (R4: n=1), and grade 3 syncope (R4: n=1). Eight patients required selinexor dose reductions in the combination chemotherapy phase. Those reductions were related to thrombocytopenia or neutropenia (R2, R3: n=3 and n=1, respectively), grade 3 fatigue (R2 : n=1), grade 2 fatigue (R:, n=1), grade 3 increased ALT plus grade 3 hypokalemia (R2, R4 : n=1 and n-=1, respectively). Two patients required dose reductions of selinexor, in the maintenance phase, related to grade 2 fatigue (R3 cycle 14: n=1) and thrombocytopenia (R1 cycle 11: n=1).
Twelve of 23 patients required chemotherapy delay or reduction (52%), including both carboplatin and paclitaxel (17%; R2 and R3: n=3 and n=1, respectively), carboplatin alone (13%; R1 and R2: n=1 and n=2, respectively), and paclitaxel alone (22%; R2, R3, R4: n=1, n=2, and n=2, respectively). The most common reasons for dose delay or reduction were cytopenia and grade 2 paclitaxel-related neuropathy. One patient required dose delay because of acute kidney injury secondary to bilateral hydronephrosis which was unrelated to study treatment.
Pharmacokinetics
PK parameters of selinexor following single-dose administration on cycle 1, day 1 are listed in Supplementary Table S1. The Cmax and AUC of selinexor between 0 and 24 hours (AUC0–24) were slightly higher at the 60 mg fixed dose than with BSA-based dosing at 30 mg/m2. Patients who did not require dose reduction of selinexor in later cycles had similar plasma concentrations of the drug at 2 and 4 hours post-dosing across cycles.
In the 5 out of 10 patients treated with selinexor via BSA-based dosing at 30 mg/m2 (R1, R2), Cmax and AUC0–24 averaged at 359 ±69 ng/mL and 2759 ± 371 ng*h/mL, respectively. These Cmax and AUC values were similar to those observed in patients dosed at 30 mg/m2 in Study KCP-330–002 (Cmax=407 ±209 ng/mL, AUC0–48=3871 ±896 ng*h/mL: n=25; NCT01607905) [17]. In the 4 out of 13 patients treated with 60 mg of selinexor at fixed dose (R3, R4), Cmax and AUC0–24 averaged at 468 ±194 ng/mL and 3871 ±2225 ng*h/mL, respectively. These Cmax and AUC values were similar to those observed in patients dosed at 60 mg in Study KCP-330–003 (Cmax=547 ±169 ng/mL, AUC0−∞ =4157 ±890 ng*h/mL, n=12; NCT01896505) [22].
Paclitaxel was administered as described in the Methods. Paclitaxel Cmax and AUC0–4 averaged at 4114 ±1036 ng/mL and 9704 ±2604 ng*h/mL, respectively, in R2 and R3 patients, and averaged at 3159 ±1222 ng/mL and 3677 ±1444 ng*h/mL, respectively, in R1 and R4 patients. The AUC0–4 of paclitaxel increased almost proportionally with the dose—with a 2.6-fold increase in mean AUC with a 2.2-fold increase in dose. Carboplatin IV was administered over 0.5 hours at AUC 5 in all regimens; its Cmax and AUC0–2 averaged at 20765 ±10097 ng/mL and 22282 ±9491 ng*h/mL, respectively. In our study, the Cmax values achieved for paclitaxel and carboplatin, administered as a 3-hour infusion at 175 mg/m2 and AUC 5, respectively, were similar to those reported in other clinical trials in which these drugs were dosed as monotherapy [23].
Anti-tumor activity
Twenty patients were included in efficacy assessments, while 3 were excluded because of withdrawal of consent prior to completing cycle 1 (R2: n=1), secondary to multiple intra-abdominal abscesses and septic shock (R4: n=1), and due to organo-axial gastric volvulus (R4: n=1).
Response rates outlined by individual eligible patients are described in Table 4. ORR (CR+PR) in R1, R2, R3, and R4 were 33% (95% CI: 0.8%−91%) 100% (95% CI: 54%−100%), 83% (95% CI: 36%−100%), and 20% (95% CI: 0.5%−72%), respectively. One patient with serous ovarian cancer, in R3, achieved CR in cycle 4 and remained on selinexor treatment at study censoring. Two patients with serous ovarian cancer, in R2 and R3, respectively, achieved a PR. Ten patients with endometrial cancer achieved PR as their best response: 4 serous histology, 2 carcinosarcomas, and 4 endometrioid (n=1 endometrioid grade 1, n=1 endometrioid grade 2, n=2 endometroid grade 3). Ten patients continued to receive selinexor maintenance after completion of the selinexor + CP phase.
Table 4.
Description of best responses of patients categorized by each regimen.
| Regimen | Tissue | Histology | Relapsed/Metastatic | Best Response | |||||
|---|---|---|---|---|---|---|---|---|---|
| 1 | Ovary | HGSOC | relapsed | SD | |||||
| 1 | Endometrial | Serous | metastatic | PR | |||||
| 1 | Endometrial | Endometrioid, Grade 3 | relapsed | PD | |||||
| 2 | Ovary | HGSOC | relapsed | PR | |||||
| 2 | Endometrial | Serous | metastatic | PR | |||||
| 2 | Endometrial | Serous | relapsed | PR | |||||
| 2 | Endometrial | Carcinosarcoma | relapsed | N/A | |||||
| 2 | Endometrial | Endometrioid, Grade 3 | relapsed | PR | |||||
| 2 | Endometrial | Carcinosarcoma | relapsed | PR | |||||
| 2 | Endometrial | Endometrioid, Grade 1 | relapsed | PR | |||||
| 3 | Ovary | HGSOC | relapsed | PR | |||||
| 3 | Endometrial | Endometrioid, Grade 2 | relapsed | PR | |||||
| 3 | Ovary | HGSOC | relapsed | CR | |||||
| 3 | Endometrial | Carcinosarcoma | relapsed | PR | |||||
| 3 | Endometrial | High Grade, NOS | metastatic | PR | |||||
| 3 | Endometrial | Carcinosarcoma | metastatic | PD | |||||
| 4 | Endometrial | Serous | relapsed | SD | |||||
| 4 | Endometrial | High grade, NOS | metastatic | PR | |||||
| 4 | Endometrial | Carcinosarcoma | metastatic | PD | |||||
| 4 | Ovary | HGSOC | metastatic | N/A | |||||
| 4 | Endometrial | Endometrioid, Grade 2 | metastatic | N/A | |||||
| 4 | Endometrial | Carcinosarcoma | relapsed | PD | |||||
| 4 | Endometrial | Endometrioid, Grade 3 | metastatic | SD | |||||
HGSOC- high grade serous ovarian cancer, NOS-not otherwise specified, CR- complete response, PR- partial response, SD-stable disease, PD- progression of disease, N/A- not available
The longest median PFS of 11 months occurred in R3 (95% CI: 1.9 months – not estimable). OS was not reached for R3 and was 34.3 months for R2.
Discussion
In this phase I study, selinexor + CP had an acceptable safety profile in advanced ovarian and endometrial cancers. Attribution of toxicities to individual agents in the treatment regimens was challenging as carboplatin, paclitaxel and selinexor were administered concurrently and have some overlapping toxicities including hematological (anemia, leukopenia, thrombocytopenia), GI (nausea) and fatigue. Previous trials of selinexor monotherapy described similar toxicities[18, 22, 24]. Additionally, in both ovarian and endometrial cancers, tumor responses were seen with treatment regimens that included either dose-dense or every-3-week paclitaxel administration.
The most commonly reported TRAEs were hematologic AEs that were successfully managed with dose delays, dose reduction, and supportive care. Here we report neutropenia (70%) and leukopenia (70%) as the most common grade 3–4 hematological toxicities, both well-established toxicities of cytotoxic chemotherapy. Grade 3–4 thrombocytopenia occurred in 30% our patients. For comparison, selinexor monotherapy in solid tumor malignancies and gynecological malignancies is associated with Grade 3–4 thrombocytopenia in 17% of patients. [18, 24]. Dose reduction of selinexor occurred in 5 patients (22%) due to thrombocytopenia and neutropenia, resulting in resolution of events. Selinexor is known to induce thrombocytopenia by inhibiting the differentiation phase of early megakaryocytes and this TRAE has been previous described [25]. We suspect that concurrent administration of carboplatin and paclitaxel contributed to the increased hematological toxicity rates and potentially could have contributed to CP dose delays in patients not meeting chemotherapy treatment parameters (R2; n=4, R3; n=2), .
Constitutional symptoms such as nausea, fatigue and anorexia were experienced as well. They were typically Grade 1–2 and self-limiting and consistent with previous reports. In R2, one patient developed clinically significant grade 3 fatigue which resolved with selinexor dose reduction. Three patients (13%) had Grade 3–4 nausea whereas anorexia symptoms were mild with no Grade 3–4 events. Other important adverse events includes carboplatin hypersensitivity reactions in two patients (R2) resulting in carboplatin omission and AST and ALT elevations, with 43% of patients experiencing a Grade 3–4 ALT increase. Conservative management with dose delay and/or reduction resulted in improvement. Elevations in liver enzymes have been reported with selinexor treatment, but are generally milder, at lower frequency and more commonly seen in hematological malignancies[22, 26, 27]. The use of paclitaxel and carboplatin can also result in liver enzyme elevations and this finding warrants further investigation in future combination cytotoxic chemotherapy trials[28]. Our PK analysis suggested that co-administration of selinexor + CP had no effect on the exposure of selinexor, and no drug-to-drug interactions between selinexor and carboplatin/paclitaxel were observed.
Although this study was not designed to evaluate efficacy, responses were seen in all treatment groups and in both patients with ovarian cancer (3/5) and endometrial cancer (10/18), including 2 patients with uterine carcinosarcomas. Additionally, 2 out of 6 patients with endometrial carcinosarcomas achieved PR for approximately 9 months. Notably, although the sample size was small, the ORR in R2 was 100% (6/6), with a median PFS of 10.7 months (95% CI: 5 months – not estimable). The ORR in R3 was 83% (5/6), with a median PFS of 11 months. For comparison, in advanced endometrial cancer, combination carboplatin/paclitaxel therapy has response rates of approximately 50% [29, 30], while in platinum-sensitive ovarian cancer (NCT00002894), response rates of >60% are seen with carboplatin/paclitaxel [31, 32]. Of the 5 ovarian cancer patients, 4 had recurrent disease and were platinum sensitive. Of these 4 patients, 1 had a CR, 2 had PR and 1 had SD. Even with the small sample size, responses such as these are anticipated in platinum sensitive recurrence in ovarian cancer.
Preclinical models have suggested a synergy of selinexor with platinum chemotherapy in ovarian cancer cell lines and demonstrated the efficacy of selinexor in platinum-resistant ovarian cancer [5, 33, 34]. Furthermore, selinexor in combination with numerous chemotherapeutic agents, including topotecan, paclitaxel, cisplatin, gemcitabine, and docetaxel, has shown synergistic activity [4, 13, 15, 35]. Here, we demonstrate that selinexor in combination with carboplatin/paclitaxel chemotherapy is associated with an acceptable safety profile and has activity in patients with platinum-sensitive ovarian cancer and endometrial cancers, including carcinosarcomas. Our reported safety profile of selinexor in combination with carboplatin ad paclitaxel, generates rationale for further investigation of selinexor in advanced gynecologic malignancies, including investigating the role of selinexor maintenance therapy after carboplatin and paclitaxel treatment in a randomized phase III trial (NCT03555422).
Supplementary Material
Highlights:
Exportin 1 (XPO1/CRM1), a primary karyopherin, facilitates nuclear export of nearly all known tumor suppressor proteins.
Selinexor blocks XPO1 and has demonstrated anti-tumor activity as a monotherapy in advanced gynecological malignancies.
We evaluated the safety of selinexor with carboplatin and paclitaxel (CP) in advanced ovarian and endometrial cancers.
The recommended phase II dose of selinexor was established as a 60 mg flat dose weekly in combination with CP.
Preliminary efficacy was seen in all evaluated regimens and in both ovarian and endometrial cancer patients.
Acknowledgements:
Editorial support in manuscript preparation was provided by Hannah Rice, ELS, and Crystal Tran, BS.
Financial support: This research was supported in part through the National Institutes of Health/National Cancer Institute (NIH/NCI) Cancer Center Support Grant P30 CA008748. Dr. O’Cearbhaill is supported by NIH P01 CA190174.
Footnotes
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Conflict of Interest Statement:
C. Aghajanian reports personal fees from Tesaro, Immunogen, Clovis, Mateon Therapeutics, Eisai/Merck, Mersana Therapeutics, and Roche, as well as grants from Clovis, Genentech, AbbVie, and AstraZeneca. K. Cadoo reports travel/expenses and institutional support from AstraZeneca, institutional support from Syndax Pharmaceuticals, as well as personal fees and travel/expenses from Tessaro and personal fees from OncLive. C. F. Friedman reports steering committee funding (compensation waived, research financial support to institution) from Genentech and Merck, institutional support from Bristol Myers Squibb, and personal fees from AstraZeneca. R. N. Grisham reports personal fees from Clovis, Mateon, Regeneron, Verastem, Amgen, and Medscape, as well as grant funding from Conquer Cancer Foundation (Career Development Grant supported by Amgen). R.N. Grisham has also received academic grants from Cycle for Survival, OCRFA and Kaleidoscope of Hope. A. Iasonos reports personal fees from Mylan, Intelligencia, and Brightpath. V. Makker reports grant funding from Karyopharm for the study described (Study PI: #14–110); grant funding from Eisai, Merck, Takeda, Karyopharm, AstraZeneca, Eli Lilly, Bristol Myers Squibb, and Genentech; and personal fees from Eisai, Merck, ArQule, Karyopharm, and IBM Watson. R. E. O’Cearbhaill reports personal fees from Tesaro, GlaxoSmithKline, and Clovis, and she is a non-compensated steering committee member for the PRIMA (niraparib) study and DUO-O (olaparib) study. M. M. Rubinstein reports grant funding from Conquer Cancer Foundation/American Society of Oncology. H. Xu reports non-financial support as a full-time employee (stock options) from Karyopharm. D. Zamarin reports personal fees from Merck, Agenus, Hookipa Biotech, and Western Oncolytics, grants from Merck, sponsored travel from Genentech, and stock options from Calidi Biotherapeutics. All other authors declare no potential conflicts of interest.
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