Study Evaluating the Efficacy and Safety of Selinexor (KPT-330) in Participants With Recurrent Gliomas

Study Overview
=================
Brief Summary
-----------------
This is an open-label, multicenter, Phase 2 study to evaluate the efficacy and safety of oral selinexor in participants with recurrent gliomas.

Detailed Description
-----------------
This is an open-label, multicenter, Phase 2 study to evaluate the efficacy and safety of oral selinexor in participants with recurrent gliomas. Initially, the study included 2 arms: an exploratory Surgical Arm (Arm A) with sequential enrollment for participants who require surgery and a medical arm (Arm B) for participants who are not eligible for surgery. Enrollment in Arm B was stopped to explore alternative dosing in Protocol Versions ≥ 4.0 to potentially improve tolerability. Four arms (Arms C, D, E, and F) were added to the Medical Arm in Protocol Version 4.0. Arms E and F were eliminated in protocol version 6.0 and no participants were ever enrolled in these arms. Participants in the primary population enrolled under Protocol Version ≥ 4.0 will be randomized to Arm C and Arm D (approximately 30 participants per arm) to explore alternative dosing to potentially improve tolerability. After screening and registration/randomization in the study, participants enrolling in Arm A or randomized to Arm C will receive 60 mg selinexor orally twice weekly. Participants randomized to Arm D will receive 80 mg selinexor orally weekly. Participants will be treated until progression of disease or the development of unacceptable toxicities. All participants will then undergo the End of Treatment (EOT) visit.

Official Title
-----------------
A Phase 2 Study Evaluating the Efficacy and Safety of Selinexor (KPT-330) in Patients With Recurrent Gliomas

Conditions
-----------------
Glioblastoma, Glioma

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


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Pathologically confirmed GBM (including all histologic variants) at first diagnosis with radiographic evidence of recurrent disease after treatment with radiotherapy and temozolomide; 18 years of age or older Participants enrolling in the medical arm (Arms B, C and D) must be on a stable or decreasing dose of corticosteroids (or none) for at least 5 days prior to the baseline MRI; Measurable disease (according to RANO guidelines) Surgical arm (Arm A) must be predicted pre-operatively to have sufficiently sized tumor to be resected and provide tissue samples for exploratory assessments. Exclusion Criteria: Markedly decreased visual acuity if attributed to other causes than GBM. Known active hepatitis A, B, or C Participants with coagulation problems and medically significant bleeding in the month prior to start of treatment (e.g., peptic ulcer, epistaxis, spontaneous bleeding). Prior history of DVT or PE is not exclusionary. Participants must not have significantly diseased or obstructed gastrointestinal tract, malabsorption, uncontrolled vomiting or diarrhea, or inability to swallow oral medications. Prior treatment with bevacizumab or other direct VEGF/ VEGFR inhibitors. For any question of the definition of a direct VEGF/VEGFR inhibitor, consult Sponsor. Arms C and D only: body surface area < 1.2 m². < 24 days from prior temozolomide, < 6 weeks from nitrosourea, < 4 weeks from other chemotherapy or investigational agents prior to start of treatment within study.

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

Sexes Eligible for Study
-----------------
All

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

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

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: Arm A: Selinexor 60 mg and Surgery<br>Participants who required surgery received up to 3 doses of oral selinexor tablets 60 milligrams (mg) twice weekly (BIW) on Day 1, Day 3 and between 2 and 48 hours prior to surgery, subsequently underwent surgery for resection of their tumor and resumed selinexor tablets 60 mg BIW after recovery, during Week 1 to 4 of each 4-week cycle, until progression of disease (PD) or development of unacceptable toxicities. | Drug: Selinexor<br>* One cycle is 28 days (4 weeks).<br>* Other names: KPT-330;|
| Experimental: Arm B: Selinexor 50 mg/m^2<br>Participants who were not eligible for surgery received selinexor tablets 50 mg per square meter (mg/m^2) BIW during Week 1 to 4 of each 4-week cycle until PD or development of unacceptable toxicities. | Drug: Selinexor<br>* One cycle is 28 days (4 weeks).<br>* Other names: KPT-330;|
| Experimental: Arm C: Selinexor 60 mg<br>Participants who were not eligible for surgery received selinexor tablets 60 mg BIW during Week 1 to 4 of each 4-week cycle until PD or development of unacceptable toxicities. | Drug: Selinexor<br>* One cycle is 28 days (4 weeks).<br>* Other names: KPT-330;|
| Experimental: Arm D: Selinexor 80 mg<br>Participants who were not eligible for surgery received selinexor tablets 80 mg once weekly (QW) during Week 1 to 4 of each 4-week cycle until PD or development of unacceptable toxicities. | Drug: Selinexor<br>* One cycle is 28 days (4 weeks).<br>* Other names: KPT-330;|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 6-Month Progression-Free Survival (PFS) Rate | The analysis of 6mPFS was performed by calculating the estimated survival probability of having PFS ≥ 6 months based on Kaplan-Meier method, where PFS was defined as the time from the start of study treatment until first documented progression based on Response Assessment in Neuro-Oncology (RANO) criteria, or death from any cause. Progressive disease occurs when either of the criteria was present: greater than or equal to (≥) 25 percentage (%) increase in T1 gadolinium enhancing disease, increase in T2/ Fluid-attenuated inversion recovery (FLAIR), detection of new lesions, or decreased clinical status. | From start of study treatment up to disease progression or death, whichever occurred first (assessed up to Month 6) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (ORR) | The ORR was determined as percentage of participants who had either complete response (CR) or partial response (PR) using the RANO criteria. CR: No T1 gadolinium enhancing disease, stable or decreasing T2/FLAIR, no new lesions, no corticosteroid use and stable, or increasing clinical status. PR: ≥50% decrease in T1 gadolinium enhancing disease, stable or decreasing T2/FLAIR, no new lesions, stable or decreased use of corticosteroids, and stable or increased clinical status. | Up to 71 months | 
| Overall Survival (OS) | The OS was calculated from the date of start of study treatment to the date of death. Participants who were still alive prior to the data cut-off for final efficacy analysis, or who dropout prior to study end, were censored on the day they were last known to be alive. The OS was estimated using Kaplan-Meier method. | From date of study treatment up to date of death (assessed up to 71 months) | 
| Progression-free Survival (PFS) | The PFS was calculated from the date of start of study treatment to the date of disease progression based on RANO criteria, or date of death should progression not have occurred. Progressive disease occurs when either of the criteria was present: ≥25% increase in T1 gadolinium enhancing disease, increased T2/FLAIR, detection of new lesions, or decreased clinical status. | From start of study treatment up to disease progression (assessed up to 71 months) | 
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) | An adverse event (AE) was defined as any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. A serious adverse event (SAE) was defined as an AE that was fatal; life threatening (places the participant at immediate risk of death); requires in-patient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; was a congenital anomaly/birth defect; and other important medical events. TEAE was defined as any AE 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. TEAEs included both serious and non-serious TEAEs. | From start of study treatment administration up to 71 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
GBM, Glioblastoma, selinexor, KPT-330, Karyopharm, brain tumor, brain cancer, Glioma, Astrocytoma, Oligodendrogliomas, Oligo-astrocytomas