Phase 2 study of the Exportin 1 inhibitor selinexor in patients with recurrent gynecological malignancies.

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 = 66), endometrial (N = 23) or cervical (N = 25) cancer were enrolled. Median number of prior regimens for ovarian, endometrial and cervical cancer was 6 (1-11), 2 (1-5), and 3 (1-6) 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.

Safety and dose modification for patients receiving niraparib.

Background: Niraparib is a poly(ADP-ribose) polymerase inhibitor approved in the USA and Europe for maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to platinum-based chemotherapy. In the pivotal ENGOT-OV16/NOVA trial, the dose reduction rate due to treatment-emergent adverse event (TEAE) was 68.9%, and the discontinuation rate due to TEAE was 14.7%, including 3.3% due to thrombocytopenia. A retrospective analysis was carried out to identify clinical parameters that predict dose reductions. Patients and methods: All analyses were carried out on the safety population, comprising all patients who received at least one dose of study drug. Patients were analyzed according to the study drug consumed (i.e., as treated). A predictive modeling method (decision trees) was used to identify important variables for predicting the likelihood of developing grade ≥3 thrombocytopenia within 30 days after the first dose of niraparib and determine cut-off points for chosen variables. Results: Following dose modification, 200 mg was the most commonly administered dose in the ENGOT-OV16/NOVA trial. Baseline platelet count and baseline body weight were identified as risk factors for increased incidence of grade ≥3 thrombocytopenia. Patients with a baseline body weight <77 kg or a baseline platelet count <150 000/µl in effect received an average daily dose ∼200 mg (median = 207 mg) due to dose interruption and reduction. Progression-free survival in patients who were dose reduced to either 200 or 100 mg was consistent with that of patients who remained at the 300 mg starting dose. Conclusions: The analysis presented suggests that patients with baseline body weight of <77 kg or baseline platelets of <150 000/µl may benefit from a starting dose of 200 mg/day. ClinicalTrials.gov ID: NCT01847274.

Mifepristone or vacuum aspiration in termination of early pregnancy.

This trial compared the termination of early pregnancy (amenorrhoea less than 43 days) by 600 mg orally of the antiprogesteron Mifepristone to the traditional method of vacuum aspiration. Fifty women were randomly assigned to either of the treatments. All the patients treated with vacuum aspiration had a complete abortion. Three of these patients developed pelvic inflammatory diseasae (PID) after the aspiration. Another patient had the uterus perforated during the procedure, and an emergency laparotomy had to be performed. The patients in the evacuation group spent more days in bed and needed longer sick leave after the treatment than the patients in the Mifepristone group. In the Mifepristone group, six patients had incomplete abortions and all were treated by evacuation. Three of the patients developed PID after the evacuation. A decrease of 40% or more in beta hCG from the initial value to the value 1 week later were invariably associated with complete abortion. In both groups the changes in hemoglobin were insignificant and no patients needed blood transfusion or emergency evacuation. The Mifepristone treatment is a simple and safe alternative to vacuum aspiration for termination of early pregnancies.

PIP: This trial compared the termination of early pregnancy (amenorrhea less than 43 days) by 600 mg mifepristone, an antiprogesterone, to traditional method of vacuum aspiration. 50 women were randomly assigned to either of the treatments. All patients who underwent vacuum aspiration had a complete abortion. 3 of these patients developed pelvic inflammatory disease (PID) following aspiration. Another patient experienced a uterine perforation during the procedure, and an emergency laparotomy was performed. The patients in the evacuation group spent more days in bed and needed more sick leave after the treatment than the patients in the mifepristone group. In that group, 6 patients had incomplete abortions and all were treated with evacuation. 3 developed PID after the procedure. A decrease of 40% or more ion the beta-hCG from the initial value to the value 1 week later wee invariably associated with complete abortion. In both groups, the changes in hemoglobin were insignificant and no patients needed blood transfusions or emergency evacuations. The mifepristone treatment is simple and a safe alternative to vacuum aspiration for termination of early pregnancies.

Hysterosalpingography, pre- and postoperative laparoscopy in operative treatment of infertility.

The benefit of routine hysterosalpingography (HSG) and pre- and postoperative laparoscopy in diagnosing and treating anatomical infertility was investigated in 115 women. The findings at HSG and laparoscopy were compared with the diagnoses obtained by laparotomy. Laparoscopy was significantly better than HSG in detecting adhesions. Both procedures were of equal value in assessing tubal pathology. Although HSG revealed additional findings in 5 per cent of cases, none of these needed operative correction. Postoperative laparoscopy, which was performed in 70 patients, did not affect the incidence of either intra- or extra-uterine pregnancy. It is concluded that all patients should be offered diagnostic laparoscopy. HSG and second-look laparoscopy should not be used routinely.