Safety Study of the Selective Inhibitor of Nuclear Export (SINE) KPT-330 in Patients With Advanced Hematological Cancer

Study Overview
=================
Brief Summary
-----------------
The purpose of this research study is to find out more information relating to the highest dose of KCP-330 that can be given safely and side effects it may cause, to examine how the body affects KCP-330 concentrations in the blood (pharmacokinetics or PK), to examine the effects of KCP-330 on the body (pharmacodynamics or PDn) and to obtain information on its effectiveness in treating cancer.

Official Title
-----------------
A Phase I Study of the Safety, Pharmacokinetics and Pharmacodynamics of Escalating Doses of the Selective Inhibitor of Nuclear Export/SINE™ Compound KPT-330 in Patients With Advanced Hematological Malignancies

Conditions
-----------------
Hematological Malignancies

Intervention / Treatment
-----------------
* Drug: KPT-330


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria Malignancies that are refractory to or intolerant of established therapy known to provide clinical benefit. Patients must not be candidates for anti-tumor regimes known to provide clinical benefit. All patients must have evidence of progressive disease on study entry. Previously untreated patients who are not chemotherapy candidates on Arm 2 may have advanced disease (without clear progression). There is no upper limit on the number of prior treatments provided that all inclusion criteria are met, and exclusion criteria are not met. Exclusion Criteria Radiation, chemotherapy, or immunotherapy or any other anticancer therapy ≤2 weeks prior to cycle 1 day 1 and mitomycin C and radioimmunotherapy 6 weeks prior to cycle 1 day 1. Patients with active graft versus host disease after allogeneic stem cell transplantation. At least 3 months must have elapsed since completion of allogeneic stem cell transplantation except for patients with AML, where at least 2 months must have elapsed; Known active hepatitis A, B, or C infection; or known to be positive for HCV RNA or HBsAg (HBV surface antigen); Patients with active CNS malignancy. Asymptomatic small lesions are not considered active. Treated lesions may be considered inactive if they are stable for at least 3 months. Patient with malignant cells in their cerebrospinal fluid (CSF) without CNS symptom may be included. Significantly diseased or obstructed gastrointestinal tract or uncontrolled vomiting or diarrhea. Grade ≥2 peripheral neuropathy at baseline (within 14 days prior to cycle 1 day 1). Macular degeneration, uncontrolled glaucoma, or markedly decreased visual acuity. In the opinion of the investigator, patients who are significantly below their ideal body weight.

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: selinexor<br> | Drug: KPT-330<br> <br> * Other names: Selinexor;|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs) | An adverse event (AE) was any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product during the course of a study and which does not necessarily have to have a causal relationship with this treatment. An Serious adverse event (SAE) was an AE resulting in any of the following outcomes: death; life-threatening event; required or prolonged inpatient hospitalization; persistent or significant disability/incapacity; congenital anomaly. TEAEs are any untoward medical incidence in a participant during administered study treatment, whether or not these events were related to study treatment. | From first dose of study drug administration to end of treatment (up to 27 months) | 
| Recommended Phase 2 Dose (RP2D) of Selinexor | Recommended Phase 2 dose was determined by maximum tolerated dose (MTD). MTD was defined as the next lower dose level below the one in which > 1 of 3 participants or ≥ 2 of 6 participants experienced dose-limiting toxicity (DLT), provided that that dose level is ≤25% lower than the highest dose tested. If the projected MTD was >25% lower than the highest dose tested, then an additional cohort of ≥3 participants were added at a dose that was intermediate between the intolerable dose and the next lower dose. | From first dose of study drug administration to end of treatment (up to 27 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Observed Plasma Concentration (Cmax) of Selinexor | Cmax was defined as the maximum observed concentration, taken directly from the plasma concentration. | 0 (pre-dose), 0.5, 1, 2, 4, 8, 24 and 48 hours post-dose on Day 1, 8 of Cycle 1 and Days 15, 16 or 17 of Cycle 2 | 
| Time to Maximum Observed Concentration (Tmax) of Selinexor | Tmax was defined as time of first observation of Cmax, taken directly from the plasma concentration data. | 0 (pre-dose), 0.5, 1, 2, 4, 8, 24 and 48 hours post-dose on Day 1, 8 of Cycle 1 and Days 15, 16 or 17 of Cycle 2 | 
| Average Concentration From Time 0 to 24 Hours (Cavg0-24h) of Selinexor | Cavg0-24h was defined as average concentration from time 0 to 24 hours. | 0 (pre-dose), 0.5, 1, 2, 4, 8, 24 and 48 hours post-dose on Day 1, 8 of Cycle 1 and Days 15, 16 or 17 of Cycle 2 | 
| Area Under the Concentration-Time Curve From Time 0 to t (AUC0-t) of Selinexor | AUC0-t was defined as area under the concentration-time curve from time zero to the last non-zero concentration. | 0 (pre-dose), 0.5, 1, 2, 4, 8, 24 and 48 hours post-dose on Day 1, 8 of Cycle 1 and Days 15, 16 or 17 of Cycle 2 | 
| Area Under the Concentration-Time Curve From Time 0 Extrapolated to Infinity (AUC0-inf) of Selinexor | AUC0-inf was defined as the area under the concentration-time curve from time zero to infinity (extrapolated). | 0 (pre-dose), 0.5, 1, 2, 4, 8, 24 and 48 hours post-dose on Day 1, 8 of Cycle 1 and Days 15, 16 or 17 of Cycle 2 | 
| Apparent Volume of Distribution Uncorrected for Fraction Absorbed (Vd/F) of Selinexor | Apparent volume of distribution was calculated as Dose/ (kel *AUC0-inf), uncorrected for fraction absorbed, reported normalized by participant body weight (kilogram [kg]). | 0 (pre-dose), 0.5, 1, 2, 4, 8, 24 and 48 hours post-dose on Day 1, 8 of Cycle 1 and Days 15, 16 or 17 of Cycle 2 | 
| Apparent Total Body Clearance, Uncorrected for Fraction Absorbed (Cl/F) of Selinexor | Cl/F was calculated as Dose/AUC0-inf, uncorrected for fraction absorbed, reported normalized by participant body weight (kg). | 0 (pre-dose), 0.5, 1, 2, 4, 8, 24 and 48 hours post-dose on Day 1, 8 of Cycle 1 and Days 15, 16 or 17 of Cycle 2 | 
| Terminal Half-Life (t½) of Selinexor | t½ was, calculated as ln(2)/kel, where kel is elimination rate constant, calculated using linear regression on the terminal portion of the log-linear concentration versus time curve. | 0 (pre-dose), 0.5, 1, 2, 4, 8, 24 and 48 hours post-dose on Day 1, 8 of Cycle 1 and Days 15, 16 or 17 of Cycle 2 | 
| Number of Participants With Overall Response of Selinexor | Objective response for each malignancy was defined using the disease response criteria by malignancy; For NHL (including DLBCL, PTCL, and CTCL), objective response included complete response (CR) and partial response (PR). For MM, objective response included stringent complete response (sCR), CR, very good partial response (VGPR), and PR. For WM, objective response included CR, VGPR, and PR. For CLL, ALL, and AML, objective response included complete remission and Partial remission. For CML, objective response includes complete cytogenic response, and complete hematologic response (CHR). | From first dose of study drug administration to end of treatment (up to 27 months) | 
| Duration of Response | Duration of response was defined as the time from the first occurrence of objective response to first documented evidence of disease recurrence or progression. Participants without evidence of progression were censored at time of last evaluable disease assessment. Objective response was defined as any response of partial response/remission or better for all malignancies; for AML, a response of morphologic leukemia-free state is also included for ORR. Duration of response was calculated by Kaplan-Meier method. | From first dose of study drug administration to end of treatment (up to 27 months) | 
| Progression-free Survival | Progression-free survival (PFS) was calculated from the date of first dose of study drug to first documented evidence of disease recurrence or progression or death due to any cause. Participants who were last known to be alive and without evidence of progression were censored at time of last evaluable disease assessment. If date of progression or death occurred after more than 1 missed disease assessment interval, participants were censored at the time of last evaluable disease assessment prior to the missed assessment. | Cycle 1 Day 1 to End of Treatment (up to 27 months) | 
| Duration of at Least Stable Disease | Duration of at least stable disease was defined as the time from the date of first dose of study drug to first documented evidence of disease recurrence or progression. Participants without evidence of progression were censored at time of last evaluable disease assessment. | Cycle 1 Day 1 to End of Treatment (up to 27 months) | 
| Overall Survival | Overall Survival was calculated from the date of first dose of study drug to date of death due to any cause. Participants who were last known to be alive were censored at time of last contact. Overall survival was calculated by Kaplan-Meier method. | Cycle 1 Day 1 to End of Treatment (up to 27 months) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Selinexor, KPT-330, Multiple Myeloma, non-Hodgkin Lymphoma, Chronic Lymphocytic Leukemia, Waldenström's macroglobulinemia, Peripheral T-Cell Lymphoma, Cutaneous T-Cell Lymphoma, Chronic Myelocytic Leukemia, Acute Lymphoblastic Leukemia