Study of KPT-330 (Selinexor) in Female Patients With Advanced Gynaecologic Malignancies

Two-stage Phase 2 study in 3 separate gynecological cancer cohorts, with an additional set of participants in the ovarian cohort randomized into 2 different treatment regimens. The study is divided between a Primary Treatment Phase and a Maintenance Phase with each phase supported by a separate database.

Part 1 - Three parallel cohorts of participants with ovarian (Cohort A), endometrial (Cohort B), or cervical (Cohort C) carcinoma were enrolled.

Part 2 - Based on the observed tolerability and efficacy profile in the ongoing ovarian cohort (Cohort A), 2 additional treatment schedules will be explored to optimize the dosing schedule in a participant population with ovarian carcinoma.

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.