SHIP (Selinexor in Hormone Insensitive Prostate Cancer)

Study Overview
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Brief Summary
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This is an open-label, Phase 2 clinical study of the oral Selective Inhibitor of Nuclear Export (SINE) selinexor (KPT-330) in patients with metastatic castration-resistant prostate cancer (mCRPC).

Detailed Description
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This is a Phase 2, open-label study to explore the effect of selinexor (KPT-330) therapy in patients with metastatic castration-resistant prostate cancer (mCRPC). Approximately 50 patients are planned for enrollment. Patients will receive an oral dose of selinexor on one of three dosing schedules.

Official Title
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A Phase-2, Open-Label Study of Oral Selinexor (KPT-330) in Patients With Metastatic Castration-Resistant Prostate Cancer (mCRPC)

Conditions
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Prostate Cancer

Intervention / Treatment
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* Drug: Selinexor


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically proven adenocarcinoma of the prostate with evidence for skeletal metastases on bone scan and/or CT scan. Must have received at least one agent known to impact survival (abiraterone, enzalutamide, etc.). Eastern Cooperative Oncology Group (ECOG) less than or equal to (≤ 2) or a Karnofsky Performance Status (KPS) ≥ 60%. Serum testosterone levels less than (<) 50 ng/ml. Ongoing gonadal androgen deprivation therapy with luteinising hormone-releasing hormone (LHRH) analogues or orchiectomy. Participants, who have not had an orchiectomy, must be maintained on standard dosing of LHRH analogue therapy at appropriate frequency for the duration of the study. Progression of disease despite androgen ablation shown by objective, documented evidence of disease progression (excluding prostate-specific antigen [PSA]), defined as one or both of the following: Soft tissue disease progression defined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 Bone disease progression defined by modified Prostate Cancer Clinical Trials Working Group 2 (PCWG2) with two or more new lesions or bone scan Discontinuation of all glucocorticoids prescribed to specifically treat prostate cancer (e.g., as a secondary hormonal manipulation) greater than (>) 4 weeks prior to receiving first dose of study drug. Glucocorticoids prescribed for a chronic non-cancer-related illness (e.g., asthma or chronic obstructive pulmonary disease [COPD]) that is well controlled with medical management are permissible to an equivalent of ≤ 10 milligrams (mg) prednisone daily. Laboratory requirements: White blood cell (WBC) count > 3,000/microliter (μL) Absolute neutrophil count (ANC) > 1,500/μL Hemoglobin ≥8.0 gram per deciliter (g/dL) Platelet count ≥150,000/μL Serum albumin ≥3.0 g/dL Calculated or measured creatinine clearance > 30 milliliter per minute (mL/min) A biopsy documenting prostate cancer in a target lesion (e.g., lymph node, bone lesion, or soft tissue lesion) within 3 months prior to study entry. No evidence of chronic or acute disseminated intravascular coagulation or bleeding tendency. Participant must be willing and able to comply with protocol requirements. All participants must sign an informed consent indicating that they are aware of the investigational nature of this study. Participant must be willing and able to sign an authorization for the release of their protected health information for study purposes. Exclusion Criteria: Histologic variants other than adenocarcinoma in the primary tumor. Participants who require or may be expected to require urgent treatment with docetaxel during the study (e.g., participants with visceral metastases). Abnormal hepatic function: Bilirubin > 2 times the upper limit of normal (2 x ULN) (except participants with Gilbert's syndrome [hereditary indirect hyperbilirubinemia] who must not have a total bilirubin of > 3 x ULN) Aspartate transaminase (AST) and alanine transaminase (ALT) > 2.5 x ULN (except participants with known liver involvement of their mCRPC who must not have an AST and ALT > 5 x ULN) Therapy with other hormonal therapy, including any herbal product known to decrease PSA levels (e.g., Saw Palmetto and PC-SPES) within 4 weeks prior to receiving first dose of study drug. Therapy with samarium-153, strontium-89, or radium-223 within 8 weeks prior to first dose of study drug. Uncontrolled infection or concomitant illness that is not controlled with medical management. Prior external beam radiation therapy completed < 3 weeks or single fraction of palliative radiotherapy within 14 days prior to first dose of study drug. Any currently active second malignancy, other than non-melanoma skin cancer. Participants are not considered to have a currently active malignancy, if they have completed therapy and are considered by their physician to be at least less than 30% risk of relapse over next 3 months. Active psychiatric illnesses/social situations that would limit compliance with protocol requirements. Active or uncontrolled autoimmune disease that may require corticosteroid therapy during study. Severely compromised immunological state, including known human immunodeficiency virus (HIV). Known acute or chronic hepatitis B or C. Chemotherapy and other investigational therapies (targeted or immunotherapy) will require a 3-week washout period before treatment initiation. Initiation of bisphosphonate therapy within 4 weeks prior to first dose of study treatment. Participants receiving ongoing bisphosphonate or denosumab therapy must have been on stable doses for at least 4 weeks prior to receiving first dose of study treatment. Participants on stable doses of bisphosphonates who show subsequent tumor progression may continue on this medication. Impaired cardiac function or clinically significant cardiac diseases, including any of the following: History or presence of serious uncontrolled ventricular arrhythmias or presence of uncontrolled atrial fibrillation. Clinically significant resting bradycardia (< 50 beats per minute). Any of the following within 3 months prior to study entry: myocardial infarction severe/unstable angina, Coronary Artery Bypass Graft, Grade 3 or 4 Congestive Heart Failure, Cerebrovascular Accident, Transient Ischemic Attack, or Pulmonary Embolism. Uncontrolled hypertension, as defined by a systolic blood pressure > 160 mm Hg and/or a diastolic blood pressure > 90 mm Hg with or without anti-hypertensive medication. Previous pericarditis; clinically significant pleural effusion in the previous 12 months or current ascites requiring 2 or more interventions per month. Angina at rest. Any acute toxicities due to prior chemotherapy and/or radiotherapy that have not resolved to a National Cancer Institute (NCI) common terminology criteria for adverse events (CTCAE), version 4.03 Grade of ≤ 1. Chemotherapy induced alopecia or Grade 2 neuropathy is allowed. Any condition or situation, which in the Investigator's opinion, may put the participant at significant risk, confound the study results, or interfere significantly with the participant's participation in the study. Men with a female partner of child-bearing potential, (defined as a sexually mature woman who has not undergone a hysterectomy or who has not been naturally postmenopausal for at least 12 consecutive months), who as a couple are unable or unwilling to employ two forms of highly effective contraception (e.g., male condom with spermicide, diaphragm with spermicide, intra-uterine device). Two methods of contraception must be used by participants and their partners through the study and for 3 months after the end of study treatment. Body mass index (BMI) < 1.2 m^2, in order to prevent a participant from receiving a dose of selinexor > 70 mg/m^2.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Selinexor Dosing Regimen 1<br>80 mg twice weekly for 4 weeks (8 doses per 28-day cycle) | Drug: Selinexor<br>* Comparison of different dosages and dosing schedules of drug.<br>* Other names: KPT-330;|
| Experimental: Selinexor Dosing Regimen 2<br>80 mg once weekly for 4 weeks (4 doses per 28-day cycle) | Drug: Selinexor<br>* Comparison of different dosages and dosing schedules of drug.<br>* Other names: KPT-330;|
| Experimental: Selinexor Dosing Regimen 3<br>60 mg twice weekly for 2 weeks, then 1 week off (4 doses per 21-day cycle) | Drug: Selinexor<br>* Comparison of different dosages and dosing schedules of drug.<br>* Other names: KPT-330;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Overall Clinical Benefit Response (CBR) | CBR was defined as the point estimate of the percentage of participants who had complete response (CR), partial response (PR), or stable disease (SD) at 12 weeks as per the Response Evaluation Criteria in Solid Tumors (RECIST v.1.1; soft tissue lesions). CR: Disappearance of all target lesions. PR: At least a 30 percent (%) decrease in the sum of diameters of target lesions, taken as reference the baseline sum diameter. SD: steady state of disease; non-CR or non-PR or non-progressive disease. | At 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) | PFS was defined as the time from first dose of study treatment until the disease progression or death due to any cause per RECIST v.1.1 criteria. If date of progression or death occurred after more than 1 missed study visit, participants were censored at the time of last radiologic assessment prior to the missed visit. Participants without documented progression were also censored at the time of last radiologic assessment. Participants without any post baseline assessments were censored at date of start of study therapy. | From first dose of study treatment to time of disease progression or death, censored date (up to 23 months) | 
| Percentage of Participants With Best Overall Response: RECIST v1.1 Criteria | Best overall response rate was defined as the percentage of participants who achieved best response of CR, PR as assessed by the RECIST v1.1 criteria. CR was defined as disappearance of all target lesions. PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taken as reference the baseline sum diameters. | From the date of first documented occurrence of response (CR or PR) until the date of documented progression or last disease assessment (up to 23 months) | 
| Absolute Values of Prostate Specific Antigen (PSA) Levels | PSA marker was used for the assessment of disease progression and estimated the PSA level when compared to baseline. | Baseline, Day 1 of Cycles 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 (each cycle of 28 days) and End of Treatment (30 days after last dose of study treatment) | 
| Percent Change From Baseline in Prostate Specific Antigen Levels | PSA marker was used for the assessment of disease progression and estimated the PSA level when compared to baseline. | Baseline, Day 1 of Cycles 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 (each cycle of 28 days) and End of Treatment (30 days after last dose of study treatment) | 
| Prostate Specific Antigen Response Rate | PSA response rate was defined as number of participants who achieved a ≥30% drop in PSA at 12 Weeks when compared to baseline. | Baseline up to 12 weeks | 
| Overall Survival (OS) | OS was defined as the time from first dose of study treatment until death due to any cause. Participants who were still alive prior to the data cutoff for final efficacy analysis, or who dropout prior to study end, were censored at the day they were last known to be alive. | From first dose of study treatment to death, censored date (up to 23 months) | 
| Pain Intensity Index (PPII) Total Score | Quality of life (QoL) was assessed by verbal rating of participant's pain according to present pain intensity index. Participants were asked to describe how severe their pain was at very moment. Present pain intensity was assessed on 5-point visual analog scale ranging from 0 to 5, where 0-no pain, 1-mild pain, 2-discomforting pain, 3-distressing pain, 4-horrible pain, and 5-excruciating pain. The higher scores indicated higher pain. | Baseline up to 30 days after last dose of study treatment (up to 23 months) | 
| Number of Participants With Treatment Emergent Adverse Events (TEAE) and Treatment Emergent Serious Adverse Events (TESAE) | An adverse event (AE) was defined as the appearance of (or worsening of any pre-existing) undesirable sign, symptom, or medical condition that occur after participant's signed informed consent obtained. A serious adverse event (SAE) was defined as any AE, occurring at any dose (including after the informed consent form was signed and prior to dosing) that and regardless of causality that: results in death, is life-threatening (participant was at immediate risk of death from event as it occurred), requires in-patient hospitalization (formal admission to a hospital for medical reasons) or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, results in a congenital anomaly/birth defect. TEAE was defined as any AE with onset or worsening of a pre-existing condition on or after the first administration of study treatment through 28 days following last dose or any event considered drug-related by the investigator through the end of the study. | From screening up to 23 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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castrate-resistant prostate cancer, prostate cancer, Karyopharm, KPT-330, selinexor