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

Study Overview
=================
Brief 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.

Detailed Description
-----------------
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.

Official Title
-----------------
A Phase II, Open-label Study of Efficacy and Safety of the Selective Inhibitor of Nuclear Export/SINE™ Compound KPT-330 (Selinexor) in Patients With Advanced Gynaecologic Malignancies

Conditions
-----------------
Ovarian Carcinoma, Endometrial Carcinoma, Cervical Carcinoma

Intervention / Treatment
-----------------
* Drug: Selinexor


Participation Criteria
=================
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.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1: Cohort A-Ovarian carcinoma: Selinexor up to 60 mg/m^2 BIW<br>Participants with ovarian carcinoma who were platinum refractory or platinum resistant and had received at least one line of chemotherapy for relapsed disease received a dose of 50 milligram per meter square (mg/m^2) of selinexor oral tablets twice weekly (BIW) (doses at least 36 hours apart) with light meal and 120 milliliters (mL) of water in a 4-week treatment cycles. After 12 weeks of treatment, a dose of 60 mg/m^2 of selinexor oral tablets BIW were administrated if the participants had no major toxicity. During dose reduction, participants received a minimum dose of 35 mg/m^2 once weekly (QW). This treatment continued until progression of disease (PD) or unacceptable toxicity or any discontinuation criteria or withdrawal of consent by the participant, or non-compliance by the participant with protocol requirements. | Drug: Selinexor<br>* 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.<br>* Other names: XPOVIO;|
| Experimental: Part 1: Cohort B-Endometrial carcinoma: Selinexor up to 60 mg/m^2 BIW<br>Participants with endometrial carcinoma who had received at least one line of chemotherapy for relapsed or advanced (Stage IVb, IIIc) disease received a dose of 50 mg/m^2 of selinexor oral tablets BIW (doses at least 36 hours apart) with light meal and 120 mL of water in a 4-week treatment cycles. After 12 weeks of treatment, a dose of 60 mg/m^2 of selinexor oral tablets BIW were administrated if the participants had no major toxicity. During dose reduction, participants received a minimum dose of 35 mg/m^2 QW. This treatment continued until PD or unacceptable toxicity or any discontinuation criteria or withdrawal of consent by the participant, or non-compliance by the participant with protocol requirements. | Drug: Selinexor<br>* 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.<br>* Other names: XPOVIO;|
| Experimental: Part 1: Cohort C-Cervical carcinoma: Selinexor up to 60 mg/m^2 BIW<br>Participants with cervical carcinoma who had received at least one line of chemotherapy for relapsed or advanced (Stage IV) disease received a dose of 50 mg/m^2 of selinexor oral tablets BIW (doses at least 36 hours apart) with light meal and 120 mL of water in a 4-week treatment cycles. After 12 weeks of treatment, a dose of 60 mg/m^2 of selinexor oral tablets BIW were administrated if the participants had no major toxicity. During dose reduction, participants received a minimum dose of 35 mg/m^2 QW. This treatment continued until PD or unacceptable toxicity or any discontinuation criteria or withdrawal of consent by the participant, or non-compliance by the participant with protocol requirements. | Drug: Selinexor<br>* 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.<br>* Other names: XPOVIO;|
| Experimental: Part 2: Cohort A-Ovarian carcinoma Schedule 1: Selinexor up to 50 mg/m^2 BIW<br>Participants with ovarian carcinoma who were platinum refractory or platinum resistant and had received at least one line of chemotherapy for relapsed disease received a dose of 35 mg/m^2 of selinexor oral tablets BIW (doses at least 36 hours apart) with light meal and 120 mL of water in a 4-week treatment cycles. After 6 weeks of treatment, a dose of 50 mg/m^2 of selinexor oral tablets BIW were administrated if the participants had no major toxicity. During dose reduction, participants received a minimum dose of 35 mg/m^2 QW. This treatment continued until PD or unacceptable toxicity or any discontinuation criteria or withdrawal of consent by the participant, or non-compliance by the participant with protocol requirements. | Drug: Selinexor<br>* 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.<br>* Other names: XPOVIO;|
| Experimental: Part 2: Cohort A-Ovarian carcinoma Schedule 2: Selinexor up to 60 mg/m^2 QW<br>Participants with ovarian carcinoma who were platinum refractory or platinum resistant and had received at least one line of chemotherapy for relapsed disease received a dose of 50 mg/m^2 of selinexor oral tablets QW (doses at least 5 days apart) with light meal and 120 mL of water in a 4-week treatment cycles. After 6 weeks of treatment, a dose of 60 mg/m^2 of selinexor oral tablets QW were administrated if the participants had no major toxicity. During dose reduction, participants received a minimum dose of 35 mg/m^2 QW. This treatment continued until PD or unacceptable toxicity or any discontinuation criteria or withdrawal of consent by the participant, or non-compliance by the participant with protocol requirements. | Drug: Selinexor<br>* 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.<br>* Other names: XPOVIO;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Disease Control Response According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) | Disease Control Rate (DCR) was defined as the point estimate of the percentage of participants who had complete response (CR), partial response (PR), or stable disease (SD) for at least 12 weeks, assessed according to RECIST v1.1. CR was defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to less than (<) 10 millimeters (mm). PR was defined as at least a 30 percent (%) decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. Participants without documented disease progression were censored on the date of last radiologic assessment. | Baseline up to 30 days after last dose administration, assessed after 6 weeks and 12 weeks (approximately 35 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Overall Response According to RECIST v1.1 | Overall Response Rate (ORR) was defined as the point estimate of the percentage of participants who had CR or PR, assessed according to RECIST v1.1. CR was defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) had reduction in short axis to <10 mm. PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. | Baseline up to the date of progression or recurrence (approximately 35 months) | 
| Percentage of Participants With Disease Control According to Gynecological Cancer Intergroup (GCIG) Response Criteria | DCR was defined as the point estimate of the percentage of participants who had CR, PR, or SD for at least 12 weeks, assessed according to GCIG response criteria (RECIST v1.1 and CA-125). | Baseline up to 30 days after last dose administration, assessed after 6 weeks and 12 weeks (approximately 35 months) | 
| Percentage of Participants With Overall Response According to GCIG Response Criteria | ORR was defined as the point estimate of the percentage of participants who had CR or PR, assessed according to GCIG response criteria (RECIST v1.1 and CA-125). | Baseline up to the date of progression or recurrence (approximately 35 months) | 
| Progression-free Survival (PFS) According to RECIST v1.1 | PFS was defined as the time from date of start of study therapy to the date of tumor disease progression (i.e., radiological only) or date of death due to any cause. Participants without documented disease progression were censored at the time of last radiologic assessment. Participants without any post baseline assessments were censored at date of start of study therapy. | From start of study drug administration until PD or discontinuation from the study or death, whichever occurred first (approximately 35 months) | 
| Overall Survival (OS) | OS was defined as time from the date of start of study therapy to the date of death due to any cause. Participants who were alive at the time of the analysis or were lost to follow-up were censored at the day they were last known to be alive. Kaplan-Maier method was used for estimation. | From start of study treatment up to the date of death, assessed every 3 months (approximately 35 months) | 
| Percentage of Participants Who Survived at 12 and 24 Months | OS rate was reported as the percentage of participants who were alive at 12 and 24 months. OS was defined as time from the date of start of study therapy to the date of death due to any cause. Participants who were alive at the time of the analysis or are lost to follow-up were censored at the day they were last known to be alive. Survival rate were estimated by Kaplan-Maier method. | 12 and 24 months | 
| Number of Participants With Treatment-emergent Adverse Events (TEAE) and Treatment-emergent Serious Adverse Events (TESAE) According to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), Version 4.03 | An adverse event (AE) was defined as any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product, whether or not it is considered related to the medicinal product. A serious adverse event (SAE) was defined as an AE that meets one or more of the mentioned criteria, i.e., fatal, life threatening (places the participants at immediate risk of death), required in-patient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, congenital anomaly/birth defect, or important medical events. TEAE was defined as any AE (serious/non-serious) with onset or worsening of a pre-existing condition on or after the first administration of study medication through 30 days following last dose or any event considered drug-related by the investigator through the end of the study. | From start of study treatment up to 30 days after the last dose administration (approximately 35 months) | 
| Number of Participants With Treatment-emergent Adverse Events by Severity According to National Cancer Institute Common Terminology Criteria for Adverse Events NCI CTCAE, Version 4.03 | AE: any unfavorable and unintended sign, symptom, or disease temporally associated with use of medicinal product, whether or not it is considered related to medicinal product. TEAE: any AE (serious/non-serious) with onset or worsening of a pre-existing condition on or after the first administration of study drug through 30 days following last dose or any event considered drug-related by investigator through end of study. As per NCI-CTCAE version 4.03, Grade 1: asymptomatic or mild symptoms, clinical or diagnostic observations only, intervention not indicated; Grade 2: moderate, minimal, local or noninvasive intervention indicated, limiting age-appropriate instrumental activities of daily life (ADL); Grade 3: severe or medically significant but not immediately life-threatening, hospitalization or prolongation of existing hospitalization indicated, disabling, limiting self-care ADL; Grade 4: life-threatening consequence, urgent intervention indicated; Grade 5: death related to AE. | From start of study treatment up to 30 days after the last dose administration (approximately 35 months) | 
| Quality of Life (QoL): Change From Baseline European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (EORTC QLQC30) Scores | EORTC QLQC30: Disease specific indication that rates overall QoL in cancer participants. It consists of 30 general questions from 3 domains; 1) global health status, 2) functioning scales (physical, emotional, cognitive, social and role functioning), 3) symptom scales (fatigue, nausea, vomiting, pain, dyspnoea, insomnia, appetite loss, constipation, diarrhea, financial difficulty). Out of 30 questions, 28 questions were scored using scale of 1 to 4, represented answers of 'not at all', 'a little', 'quite a bit', and 'very much'; remaining 2 questions contributed to global health status were scored on scale of 1 to 7, represented range of 'very poor' to 'excellent' that evaluated overall health and QoL. All scales and single-item measures range from 0 to 100, where higher score represented higher response level. Higher score for functional scale, global health status and symptom scale represented high level of functioning, high QoL, and high level of symptoms or problems, respectively. | Baseline, End of treatment (EOT) i.e., 30 days after last dose of study drug administration (up to 31 months) | 
| Number of Participants With Individual Clinically Significant Abnormalities in Laboratory Tests | Clinically significant laboratory tests abnormalities were analyzed and reported for this outcome measure. | From start of study treatment up to 30 days after the last dose administration (approximately 35 months) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Karyopharm, KPT-330, Selinexor, SIGN, ovarian cancer, endometrial cancer, cervical cancer, SINE™, HER2 negative