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Maintenance With Selinexor/Placebo After Combination Chemotherapy in Endometrial Cancer.

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ClinicalTrials.gov Identifier: NCT03555422
Recruitment Status : Recruiting
First Posted : June 13, 2018
Last Update Posted : June 15, 2018
Sponsor:
Collaborator:
Karyopharm Therapeutics Inc
Information provided by (Responsible Party):
Universitaire Ziekenhuizen Leuven

Brief Summary:
In this study, patients with recurrent and advanced endometrial cancer with response after first or second-line chemotherapy will be randomized to maintenance therapy with 80 mg selinexor once weekly or placebo until progression.

Condition or disease Intervention/treatment Phase
Endometrial Cancer Drug: Selinexor Drug: Placebo Phase 3

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 161 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: double blind placebo controlled study
Primary Purpose: Treatment
Official Title: An Investigator-Sponsored Randomized Phase III Trial of Maintenance With Selinexor/ Placebo After Combination Chemotherapy for Patients With Advanced or Recurrent Endometrial Cancer.
Actual Study Start Date : November 22, 2017
Estimated Primary Completion Date : August 2019
Estimated Study Completion Date : January 2021

Arm Intervention/treatment
Experimental: Selinexor
oral selinexor 80 mg once weekly
Drug: Selinexor
oral medication

Placebo Comparator: Placebo
oral placebo once weekly
Drug: Placebo
oral medication




Primary Outcome Measures :
  1. Progression Free Survival [ Time Frame: 30 months after FPI ]
    Compare progression free survival (PFS) of the two treatment arms


Secondary Outcome Measures :
  1. Time to First Subsequent Therapy [ Time Frame: 30 months after FPI ]
    To compare Time to First Subsequent Therapy (TFST) of the two treatment arms

  2. PFS after consecutive treatment [ Time Frame: 30 months after FPI ]
    To compare PFS after consecutive treatment (PFS2) of the two treatment arms.. PFS2 is defined along the same timelines as PFS but accounts for the time from randomization to progression or death by any cause on any subsequent line of anticancer therapy

  3. Time to Second Subsequent Treatment [ Time Frame: 30 months after FPI ]
    To compare Time to Second Subsequent Treatment (TSST) of the two treatment arms

  4. Disease Specific Survival [ Time Frame: 30 months after FPI ]
    To compare Disease Specific Survival (DSS) of the two treatment arms. Disease Specific Survival (DSS) is defined as the time from randomization until date of death from endometrial cancer

  5. Overall Survival [ Time Frame: 30 months after FPI ]
    To compare Overall Survival (OS) of the two treatment arms. A patient's overall survival is defined as the time from randomization until date of death from any cause

  6. Disease Control Rate [ Time Frame: 30 months after FPI ]
    To compare Disease Control Rate (DCR = Complete Response (CR), Partial Response (PR) or Stable Disease (SD) for at least 12 weeks) of the two treatment arms

  7. Health-Related Quality of Life [ Time Frame: 30 months after FPI ]
    To compare Health-Related Quality of Life (HR-QoL) Outcome EORTC QLQ30 of the two treatment arms

  8. Health-Related Quality of Life [ Time Frame: 30 months after FPI ]
    To compare Health-Related Quality of Life (HR-QoL) Outcome EORTC-QLQ-EN24 of the two treatment arms

  9. Number and percentage of treatment-emergent adverse events as assessed by CTCAE v4.03 [ Time Frame: 30 months after FPI ]
    Assess the safety and tolerability of the two treatment arms by means of AE reports

  10. Actual value/changes from baseline for each clinical laboratory parameter relative to CTCAE classification ranges [ Time Frame: 30 months after FPI ]
    Assess the safety and tolerability of the two treatment arms by means of laboratory data

  11. Actual value/changes from baseline for vital signs and listing of physical examination findings [ Time Frame: 30 months after FPI ]
    Assess the safety and tolerability of the two treatment arms by means of vital signs and physical examinations


Other Outcome Measures:
  1. Progression free survival [ Time Frame: 30 months after FPI ]
    To compare PFS in the sub-populations of the two treatment arms as described under stratification factors

  2. Response Rate [ Time Frame: 30 months after FPI ]
    To compare Response Rate (RR) of the two treatment arms according to RECIST 1.1

  3. Duration of Response [ Time Frame: 30 months after FPI ]
    To compare Duration of Response (DOR) of the two treatment arms.

  4. Time to progression [ Time Frame: 30 months after FPI ]
    To compare Time to progression (TTP) of the two treatment arms

  5. Time Until Definitive Deterioration or Death [ Time Frame: 30 months after FPI ]
    To compare Time Until Definitive Deterioration or Death (TUDD) of the two treatment arms.

  6. Prognostic and predictive value of several tumor biomarkers on tumor biopsy /plasma samples as collected at the initial surgery or prior to the start and end of the treatment [ Time Frame: 30 months after FPI ]
    The specific translational research objectives are to evaluate the prognostic and predictive values of tumour biomarkers from tissue / blood samples collected at different timepoints during treatment

  7. Evaluation of ctDNA in blood samples collected predose on C1D1 and again on Day one of Cycles 1-X and end of treatment [ Time Frame: 30 months after FPI ]
    The specific translational research objectives are to evaluate the prognostic and predictive values of tumour biomarkers from tissue / blood samples collected at different timepoints during treatment



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Written informed consent in accordance with federal, local, and institutional guidelines. The patient must provide informed consent prior to the first screening procedure.
  2. Histological confirmed endometrial cancer of the endometrioid, serous, or undifferentiated type. Carcinosarcoma of the uterus is also allowed Must have received a taxane-carboplatin combination in at least one prior therapy.

    Prior second-line anthracycline based or again taxane-carboplatin is allowed. Prior Hormonal treatment is allowed.

  3. The following patients can be enrolled in the trial:

    1. Patients with stage IV disease (FIGO 2009), who have completed first-line taxane-carboplatin combination at least 12 weeks and are in partial or complete remission according to RECIST 1.1, or
    2. Patients who have relapsed after primary therapy and have completed taxane -carboplatin combination for at least 12 weeks (4 cycles of 3-or 4 weekly or 12 courses of weekly) for primary relapse and are in partial or complete remission according to RECIST 1.1, or
    3. Patients who have relapsed after primary therapy and have completed taxane-carboplatin combination for primary relapse and have received a second-line chemotherapy for at least 12 weeks for secondary relapse and are in partial or complete remission according to RECIST 1.1 on this second-line chemotherapy.

    Prior adjuvant for Stage I-III is not counted as a line of chemotherapy unless the relapse occurred within 6 months after the last adjuvant course of chemotherapy for stage I-III disease

  4. Patients must be started on study treatment between 3 and 8 weeks after completion of their final dose of the chemotherapy.
  5. Patients may have undergone primary surgery. Patients who have had complete cytoreductive surgery (i.e., no visible residual disease) prior to the last chemotherapy are not eligible.
  6. Patients may have received vaginal brachytherapy.
  7. Patients may have received external beam radiotherapy
  8. Patients may have received hormonal treatment
  9. ECOG performance status of 0-1
  10. Patients must have an adequate organ function

    • Hepatic function: total bilirubin within normal limits; ALT and AST ≤ 2.5 x ULN in pts without liver metastasis. For Pts with liver metastasis: total bilirubin within normal limits, ALT or AST ≤ 2.5 ULN
    • Coagulation parameters: International normalised ratio (INR) < 2, prothrombin time (PT) and partial thromboplastin time (PTT) < 50% of deviation of institutional ULN
    • Absolute neutrophil count (ANC) ≥ 1.0 x 109/L; platelets ≥ 100 x 109L; haemoglobin ≥ 9.0 g/dL. No blood or platelet transfusion during 4 weeks prior to randomization.Proteinuria < grade 2
    • Creatinine < 2,5 ULN or GFR > 30 ml/min (calculated using Cockroft & Gault equation, Jellife equation or measured by EDTA clearance )
    • Albumin level > 25 g/l. Intravenous albumin infusion is not allowed during the 2 weeks prior to inclusion.
  11. Life expectancy of at least 12 weeks
  12. Patients must be fit to receive experimental therapy
  13. Patient's age > 18 years
  14. Patients with preserved reproductive capacity must have a negative pregnancy test (β-HCG test in urine or serum) prior to starting study treatment. Female patients of childbearing potential must agree to use 2 methods of contraception (including 1 highly effective and 1 effective method of contraception). Effective methods of contraception must be used throughout the study and for 3 months following the last dose of study treatment.
  15. The patient should consent to the sampling of a tumor sample during the screening period of the study. If the biopsy is technically not feasible the patient remains eligible for the study so long as an archival tissue sample is available.
  16. The patient should consent to sampling for ctDNA and plasma sampling as outlined in the protocol.

Exclusion Criteria:

  1. Sarcomas, small cell carcinoma with neuroendocrine differentiation, clear cell carcinomas.
  2. Concurrent cancer therapy
  3. Previous treatment with XPO1 Inhibitor
  4. Concurrent treatment with an investigational agent or participation in another clinical trial.
  5. Patients who received any systemic anticancer therapy including investigational agents or radiation ≤3 weeks (or ≤5 half-lives of the drug [whichever is shorter]) prior to C1D1.

    Palliative radiotherapy may be permitted for symptomatic control of pain from bone metastases in extremities, provided that the radiotherapy does not involve target lesions, and the reason for the radiotherapy does not reflect progressive disease.

  6. Major injuries or surgery within the past 14 days prior to start of study treatment with and/or planned surgery during the on-treatment study period.
  7. Previous malignant disease, except patients with other malignant disease, for which the patient has been disease-free for at least three years. Concurrent other malignant disease except for curatively treated carcinoma in situ of the cervix or basal cell carcinoma of the skin.
  8. Uncontrolled (i.e., clinically unstable) infection requiring parenteral antibiotics, antivirals, or antifungals within one week prior to first dose; however, prophylactic use of these agents is acceptable even if parenteral
  9. Any life-threatening illness, medical condition or organ system dysfunction which, in the investigator's opinion, could compromise the patient's safety or compliance with the protocol.
  10. Known contraindications to selinexor.
  11. Known uncontrolled hypersensitivity to the investigational drugs, or to their excipients
  12. History of a cerebral vascular accident, transient ischemic attack or subarachnoid haemorrhage within the past 3 months.
  13. History of clinically significant haemorrhage in the past 3 months.
  14. Radiotherapy to the target lesion within the past 3 months prior to baseline imaging
  15. Persistent grade 3 or 4 toxicity from previous chemotherapy and/or radiotherapy, except alopecia.
  16. Active brain metastases (e.g. stable for <8 weeks, no adequate previous treatment with radiotherapy and/or surgery, symptomatic, requiring treatment with anti-convulsants. Corticoid therapy is allowed if administered as stable dose for at least one month before randomization).
  17. Leptomeningeal disease.
  18. Unstable cardiovascular function:

    1. Symptomatic ischemia, or
    2. Uncontrolled clinically significant conduction abnormalities (i.e., ventricular tachycardia on anti-arrhythmia are excluded; 1st degree AV block or asymptomatic LAFB/RBBB will not be excluded), or
    3. Congestive heart failure (CHF) of NYHA Class ≥3, or
    4. Myocardial infarction (MI) within 3 months
  19. Pregnancy or breastfeeding. Patients with preserved reproductive capacity, unwilling to use 2 medically acceptable methods of contraception for the duration of the trial and for 3 months afterwards.
  20. Active or chronic hepatitis C and/or B infection
  21. Patients unable to swallow tablets, patients with malabsorption syndrome, or any other GI disease or GI dysfunction that could interfere with absorption of study treatment A history of bowel obstruction requiring a nasogastric tube or intravenous infusion during the past 2 months is not allowed (except when this obstruction is caused by surgery or other non-malignant causes).
  22. Patients unwilling to comply with the protocol.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03555422


Contacts
Contact: Marijke Vanspauwen, PhD 0032342816 marijke.vanspauwen@uzleuven.be
Contact: Joke De Roover, PhD 0032347419 joke.deroover@uzleuven.be

Locations
Belgium
UZ Leuven Recruiting
Leuven, Vlaams-Brabant, Belgium, 3000
Contact: Joke De Roover, PhD    003216347419    joke.deroover@uzleuven.be   
Principal Investigator: Ignace Vergote, MD         
Sponsors and Collaborators
Universitaire Ziekenhuizen Leuven
Karyopharm Therapeutics Inc

Responsible Party: Universitaire Ziekenhuizen Leuven
ClinicalTrials.gov Identifier: NCT03555422     History of Changes
Other Study ID Numbers: ENGOT-EN5
First Posted: June 13, 2018    Key Record Dates
Last Update Posted: June 15, 2018
Last Verified: May 2018

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
Endometrial Neoplasms
Uterine Neoplasms
Genital Neoplasms, Female
Urogenital Neoplasms
Neoplasms by Site
Neoplasms
Uterine Diseases
Genital Diseases, Female