| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated | | Selinexor/placebo will be given as maintenance therapy after combination chemotherapy for patients with p53 wild-type, advanced or recurrent endometrial cancer | |
| E.1.1.1 | Medical condition in easily understood language | | Selinexor/placebo will be given as maintenance therapy after combination chemotherapy for patients with endometrial cancer | |
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 | | E.1.2 | Level | PT | | E.1.2 | Classification code | 10014733 | | E.1.2 | Term | Endometrial cancer | | E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) | |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 | | E.1.2 | Level | PT | | E.1.2 | Classification code | 10014734 | | E.1.2 | Term | Endometrial cancer metastatic | | E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) | |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 | | E.1.2 | Level | PT | | E.1.2 | Classification code | 10014736 | | E.1.2 | Term | Endometrial cancer recurrent | | E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) | |
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial | | To evaluate the efficacy of selinexor compared to placebo as maintenance therapy | |
| E.2.2 | Secondary objectives of the trial | To compare overall survival OS in selinexor and placebo arms
To evaluate the safety and tolerability of selinexor
To compare selinexor and placebo for time to first subsequent therapy
To compare selinexor and placebo for time to second subsequent therapy
To compare selinexor and placebo for time until second progression
To assess the efficacy of selinexor compared to placebo, as assessed by a blinded independent central review (BICR)
To evaluate health-related quality of life (HR-QoL) outcomes | |
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria | 1. At least 18 years of age at the time of signing informed consent.
2. Histologically confirmed EC including: endometrioid, serous, undifferentiated, and carcinosarcoma.
3. TP53 wt assessed by NGS, evaluated by a central vendor.
4. Completed a single line, at least 12 weeks of platinum-based therapy (not including adjuvant or neoadjuvant therapy for Stage I-III disease) and achieved confirmed partial or complete response (PR or CR) by imaging, according to RECIST version 1.1. The patients should have received treatment for:
Primary Stage IV disease, defined as:
a. had a primary or later debulking surgery during first-line platinum-based therapy with R0 resection (R0 resection indicates a macroscopic complete resection of all visible tumor) and achieved CR after at least 12 weeks platinum-based therapy, OR
b. had a primary or later debulking surgery during first-line platinum-based therapy with
R1 resection (R1 resection indicates incomplete removal of all macroscopic disease) and achieved PR or CR after at least 12 weeks platinum-based chemotherapy, OR
c. had no surgery and achieved PR or CR after at least 12 weeks platinum-based chemotherapy OR
At first relapse (i.e., relapse after primary therapy including surgery and/or chemotherapy and/or immunotherapy for Stage I-IV disease), defined as:
a. had Stage I – III disease at diagnosis and received, at initial diagnosis, adjuvant chemotherapy and relapsed later. Patients should have PR or CR after at least 12 weeks of platinum-based chemotherapy compared with the start of this chemotherapy at the time of relapse,
b. had Stage I-III disease at diagnosis and did not receive adjuvant chemotherapy at initial diagnosis and relapsed later. Patients should have PR or CR after at least 12 weeks of platinum-based chemotherapy compared with the start of this chemotherapy at the time of relapse, OR
c. had Stage IV disease at diagnosis and received initially chemotherapy with or without
surgery and relapsed later. At the time of relapse, patients should have PR or CR after at
least 12 weeks of platinum-based chemotherapy compared with the start of this chemotherapy at the time of relapse.
5. Previous treatment with anti-programmed cell death protein 1(PD-1) or anti-programmed death-ligand 1(PD-L1) monoclonal antibody and concomitant biologic agents (e.g., bevacizumab, trastuzumab) is allowed.
6. Must be able to initiate study drug 3 to 8 weeks after completion of their final dose of chemotherapy.
7. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.
8. Patients must have adequate bone marrow function and organ function within 2 weeks before starting study drug as defined by the following laboratory criteria:
a. Hepatic function: total bilirubin up to <3 x upper limit of normal (ULN); alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 x ULN in patients without liver metastasis. For patients with known liver involvement of their tumor: AST and ALT ≤5 x ULN
b. Hematopoietic function within 1 week: Absolute neutrophil count (ANC) ≥1.5 x 109/L; platelet count ≥100 x 109/L; hemoglobin ≥9.0 g/dL per local laboratory results
c. Renal function: estimated creatinine clearance (CrCl) of ≥20 mL/min, calculated using the standard local formula, as applicable
9. In the opinion of the Investigator, the patient must:
a. Have a life expectancy of at least 12 weeks, and
b. Be fit to receive investigational therapy
10. Premenopausal females of childbearing potential must have a negative pregnancy test (serum β-human chorionic gonadotropin test) prior to the first dose of study drug. Female patients of childbearing potential must agree to use highly effective methods of contraception throughout the study and for 90 days following the last dose of study drug.
11. Written informed consent signed in accordance with federal, local, and institutional guidelines prior to the first screening procedure | |
| E.4 | Principal exclusion criteria | 1. Has any uterine sarcomas (carcinosarcomas – not excluded), clear cell or small cell carcinoma with neuroendocrine differentiation
2. Received a blood or platelet transfusion during the 2 weeks prior to C1D1. Patients’ hemoglobin must be assessed within 2 weeks of screening and at least 1 week post transfusion.
3. Concurrent systemic steroid therapy higher than physiologic dose (>10 mg/day of prednisone or equivalent). Systemic steroid therapy as pre-medication for taxane is allowed.
4. Insufficient time since or not recovered from procedures or anti-cancer therapy, defined as:
• Not recovered from major surgery ≤28 days prior to Day 1 dosing. Minor procedures, such as biopsies, dental work, or placement of a port or intravenous (IV) line for infusion are permitted
5. Having ongoing clinically significant anti-cancer therapy-related toxicities CTCAE Grade >1, with the exception of alopecia. In specific cases, patients whose toxicity has stabilized or with Grade 2 non-hematologic toxicities can be allowed following documented approval by the Sponsor’s Medical Monitor
6. Palliative radiotherapy within 14 days of the intended C1D1. Palliative radiotherapy may be permitted for symptomatic control of pain from bone metastases, provided that the radiotherapy does not involve target lesions, and the reason for the radiotherapy does not reflect evidence of disease progression
7. Any gastrointestinal dysfunctions that could interfere with the absorption of selinexor (e.g., bowel obstruction, inability to swallow tablets, malabsorption syndrome, unresolved nausea, vomiting, diarrhea CTCAE v 5.0 > grade 1)
8. Patients unable to tolerate two forms of antiemetics for at least 2 cycles will not be eligible for the trial.
9. Active, ongoing or uncontrolled active infection requiring parenteral antibiotics, antivirals, or antifungals within 1 week of screening
10. Serious psychiatric or medical condition that could interfere with participation in the study or in the opinion of the Investigator would make study involvement unreasonably hazardous
11. Previous treatment with an XPO1 inhibitor
12. Stable disease or PD on the post-chemotherapy scan or clinical evidence of progression prior to randomization.
13. Patients who received any systemic anticancer therapy including investigational agents ≤3 weeks (or ≤5 half-lives of the drug [whichever is shorter]) prior to C1D1.
14. Major injuries or surgery within 14 days prior to C1D1 and/or planned major surgery during the on-treatment study period
15. Other malignant disease with disease-free ≤ 3 years except: curatively treated carcinoma in situ of the cervix, basal cell carcinoma of the skin, or ductal carcinoma in situ (DCIS) of the breast
16. History of allergic reactions attributed to compounds of similar chemical or biologic composition to selinexor, or other agents used in the study
17. Active brain metastases (e.g., stable for <8 weeks, no adequate previous treatment with radiotherapy and/or surgery, symptomatic, requiring treatment with anti-convulsant therapy. Corticoid therapy is allowed if administered as stable dose for at least 1 month before randomization).
18. Females who are pregnant or lactating
19. Any other life-threatening illness, active medical condition, organ system dysfunction, or serious active psychiatric issue which, in the Investigator's opinion, could compromise the patient’s safety or the patient’s ability to remain compliant with study procedures. | |
| E.5 End points |
| E.5.1 | Primary end point(s) | Investigator assessed PFS per Response Evaluation Criteria in Solid Tumors (RECIST)
v1.1 in the ITT population (tumor protein 53 wild-type [TP53 wt] by central next generation
sequencing [NGS] testing) | |
| E.5.1.1 | Timepoint(s) of evaluation of this end point | |
| E.5.2 | Secondary end point(s) | • OS
• The safety and tolerability of study drug (selinexor and placebo) will be evaluated
based on adverse event (AE) reports, physical examination results (including vital signs), and clinical laboratory results by means of the occurrence, nature, and severity of AEs via
Common Terminology Criteria for Adverse Events (CTCAE) v. 5.0
• TFST
• TSST
• Time from randomization until the second progression event (PFS2) or death due to any
cause, whichever occurs first
• PFS, as assessed by a BICR, per RECIST v1.1
• European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life
Questionnaire EuroQol-5 Dimensions-5 Levels (EQ-5D-5L) | |
| E.5.2.1 | Timepoint(s) of evaluation of this end point | |
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 | The trial involves single site in the Member State concerned | No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 50 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned | | Canada | | Israel | | United States | | Belgium | | Czechia | | Germany | | Hungary | | Ireland | | Italy | | Spain | |
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 | Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial | | End of study will be approximately 3 years after the last patient is enrolled into the study, when the last patient in the study has withdrawn consent, has been withdrawn from the study by the Investigator, has died, or has been lost to follow-up, whichever occurs first. | |
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
