Study of KPT-330 (Selinexor) in Female Patients With Advanced Gynaecologic Malignancies
Condition: Ovarian Carcinoma; Endometrial Carcinoma; Cervical Carcinoma
MeSH terms: Carcinoma; Endometrial Neoplasms
Intervention: Selinexor
Intervention description: Route of administration and dosage form: Oral tablet; Doses: 35 mg/m^2 BIW, 35 mg/m^2 QW, 50 mg/m^2 BIW, 50 mg/m^2 QW, 60 mg/m^2 BIW, 60 mg/m^2 QW.
Treatment cycles were 4 weeks each i.e., 28 day cycles.
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 116.0
Sex: Female
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Karyopharm; KPT-330; Selinexor; SIGN; ovarian cancer; endometrial cancer; cervical cancer; SINE™; HER2 negative

Summary:

      The primary trial objective is to determine the efficacy of KPT-330 (selinexor) in
      participants with advanced or metastatic gynaecological cancers by disease control rate
      (complete response (CR) or partial response (PR) or stable disease (SD) for at least 12
      weeks, assessed according to Response Evaluation Criteria in Solid Tumors (RECIST) version
      1.1.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.

          -  Adequate hematologic function defined as:

               -  platelets ≥125*10^9 per liter (/L)

               -  hemoglobin ≥5.59 millimoles per liter (mmol/L) or 9 grams per deciliter (g/dL)

               -  Absolute neutrophil count (ANC) ≥1.5*10^9/L

               -  White blood cells (WBC) count ≥3.0*10^9/L

               -  Up to 5 percent (%) deviation is tolerated. Transfusions and growth factors are
                  allowed.

          -  Adequate liver function defined as adequate hepatic function within 14 days prior to
             Cycle 1 Day 1: total bilirubin <2 times the upper limit of normal (ULN) (except
             participants with Gilbert's syndrome, who must have a total bilirubin of <3 times
             ULN), aspartate aminotransferase (AST) <2.0 times ULN, and alanine aminotransferase
             (ALT) <2.0 times ULN. In the case of known (radiologically and/or biopsy- documented)
             liver metastasis, AST <5.0 times ULN and ALT <5.0 times ULN is acceptable. Up to 10%
             deviation is acceptable.

          -  Renal function defined as a calculated or measured glomerular filtration rate ≥30
             milliliter per minute (mL/min).

          -  The participant has recovered to Grade less than or equal to (≤) 1 by the National
             Cancer Institute Common Terminology Criteria for Adverse Events, Version 4.03
             (NCI-CTCAE v4.03) from the effects of recent surgery, radiotherapy, chemotherapy,
             hormonal therapy, or other targeted therapies, with the exception of alopecia. The
             exceptions for such effects are allowed lab values of ≤Grade 2 specified elsewhere in
             these inclusion criteria.

          -  Life expectancy of at least 12 weeks.

          -  Able to swallow and retain oral medication.

          -  Participants must give informed consent according to the rules and regulations of the
             individual participating sites.

          -  Negative serum pregnancy test in women of childbearing potential within 14 days of
             first dose of treatment, and participants of childbearing potential must agree to use
             effective contraception during treatment up to 3 months from last dose. Fertile male
             partners must be willing and able to use effective non-hormonal means of contraception
             (barrier method of contraception in conjunction with spermicidal jelly, or surgical
             sterilization) during and for at least 6 months post-study treatment.

          -  The participant must be recovered from any prior treatment/major operation. The
             treatment/major operation must be performed at least 4 weeks prior to start of study
             drug. Palliative radiotherapy is permitted until one week prior to the start of study
             drug.

          -  Only incurable participants with histologically or cytologically proven primary tumor
             and objective documentation of disease progression on prior treatment by computerized
             tomography (CT)/ magnetic resonance imaging (MRI) may be enrolled.

          -  Ovarian, fallopian tube, or peritoneal carcinoma: both platinum refractory* and
             platinum resistant** participants, who have received ≥1 line of chemotherapy for
             relapsed disease (i.e., ≥2 lines of chemotherapy in total).

             *Platinum refractory is defined as progression during or within 4 weeks of last
             treatment with a platinum-containing therapy.

             **Platinum resistant is defined as relapse 4 weeks to <6 months after a
             platinum-containing therapy.

          -  Endometrial carcinoma: participants must have received ≥1 line of chemotherapy for
             relapsed or advanced (Stage IV, IIIc) disease.

          -  Cervical carcinoma: participants must have received ≥1 line of chemotherapy for
             relapsed or advanced (Stage IV b) disease.

          -  Carcinosarcomas (Malignant Mixed Mullerian Tumor) are allowed, but all other
             nonepithelial cancers of the ovary, fallopian tube, endometrium, or cervix are
             excluded.

          -  Participants must have either measurable disease per RECIST 1.1 or evaluable disease
             outside irradiated field on CT/MRI. For ovarian cancer: Participants must have disease
             that is measurable according to RECIST or assessable according to the Gynecological
             Cancer Intergroup (GCIG) CA-125 criterion. A rise in CA-125 or other tumor marker
             alone is not sufficient.

        Exclusion Criteria:

          -  Disease-Specific Exclusions:

               -  Evidence of complete or partial bowel obstruction.

               -  Need of Total Parenteral Nutrition.

          -  Participants who are pregnant or breast feeding.

          -  Radiation (except planned or on-going palliative radiation to bone outside of the
             region of measurable disease) ≤3 weeks prior to Cycle 1 Day 1.

          -  Chemotherapy, endocrine therapy, immunotherapy or any other systemic anti-cancer
             therapy (including investigational anti-cancer therapy) ≤3 weeks prior to Cycle 1 Day
             1.

          -  Diagnosis or recurrence of invasive cancer other than the present cancer within 3
             years (except basal or squamous cell carcinoma of the skin that has been definitively
             treated).

          -  Unstable cardiovascular function:

               -  Symptomatic ischemia, or

               -  Uncontrolled clinically significant conduction abnormalities (e.g. ventricular
                  tachycardia on anti-arrhythmics are excluded and 1st degree atrioventricular (AV)
                  block or asymptomatic left anterior fascicular block (LAFB)/ right bundle branch
                  block (RBBB) will not be excluded), or

               -  Congestive heart failure (CHF) of New York Heart Association (NYHA) Class ≥3, or
                  myocardial infarction (MI) within 3 months of Cycle 1 Day 1.

          -  Uncontrolled active infection requiring parenteral antibiotics, antivirals, or
             antifungals within one week prior to the first dose. Active infection with concurrent
             treatment is acceptable only if the participant is clinically stable.

          -  Significantly diseased or obstructed gastrointestinal tract or uncontrolled vomiting
             or diarrhea.

          -  Concurrent therapy with approved or investigational anti-cancer therapeutics.

          -  Medical, psychological, or social conditions that may interfere with the participant's
             participation in the study or evaluation of the study results.

          -  Known brain metastases unless adequately treated (surgery or radiotherapy) with no
             evidence of progression and neurologically stable off anticonvulsants and
             glucocorticoids.

          -  All non-epithelial cancers of the ovary, fallopian tube, peritoneum, endometrium or
             cervix as well as neuro-endocrine tumors are excluded.