Safety Study of KPT-330 (Selinexor) in Patients With Advanced or Metastatic Solid Tumor Cancer

An Adverse Event (AE) was defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. TEAE was defined as an adverse event with an onset that occurs after receiving study drug. A serious adverse event (SAE) was defined as an AE that meets one or more of the mentioned criteria; is fatal, life threatening, required in-patient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, congenital anomaly/birth defect, or important medical events. Number of participants with TEAEs and TESAEs were reported.

An AE was defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. TEAE was defined as an adverse event with an onset that occurs after receiving study drug. A treatment-related AE was any untoward medical occurrence in a clinical investigation participant administered a medicinal product; the event had a causal relationship with the treatment or usage.

An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. 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. A treatment related AE was any untoward medical occurrence in a clinical investigation participant administered a product or medical device; the event had a causal relationship with the treatment or usage.

Evaluation of DLTs was only conducted in participants who participated in the Dose-escalation Phase. A DLT was defined as any of the following, considered possibly related to drug administration, occurring in the first 28 days (or 21 days for participants on Schedule 8) at the target dose (ie, for Schedule 2 this meant the first 4 weeks after the 12 mg/m2 run-in week): Missed selinexor doses due to drug-related toxicities, discontinuation of a participant due to a toxicity that was at least possibly related to study drug before completing Cycle 1.

The RP2D was the maximum tolerated dose (MTD) or less. MTD was defined as the next lower dose level below the one in which >1 of 3 participants or ≥2 of 6 participants experienced DLT, provided that dose level was ≤25 percent (%) lower than the highest (intolerable) dose tested. If the projected MTD was >25% lower than the highest dose tested, then an additional cohort of ≥3 participants was added at a dose that was intermediate between the intolerable dose and the next lower dose.

Cmax was defined as maximum observed concentration, taken directly from the plasma concentration data.

Tmax was defined as time of first observation of Cmax, taken directly from the plasma concentration data.

AUC0-t was defined as area under the concentration-time curve from time zero to the last non-zero concentration.

AUC0-inf was defined as area under the concentration-time curve from time zero to infinity (extrapolated). It was calculated as AUC0-t + Ct/kel, where: Ct = the last observed non-zero concentration and Kel = elimination rate constant.

t1/2 was defined as elimination half-life, it was calculated as ln(2)/kel, where In = natural logarithm and kel = elimination rate constant.

CL/F was calculated as Dose/AUC0-inf, uncorrected for fraction absorbed; reported normalized by participant body weight (kilogram).

Vd/F was calculated as Dose/(kel * AUC0-inf), uncorrected for fraction absorbed; reported normalized by participant body weight (kilogram).

BOR is response recorded from start of treatment until disease progression/recurrence. Best lesion response was defined by Recist Criteria V1 (for target and non-target lesions) and RANO criteria (for glioblastoma multiforme): complete response (CR)- disappearance of all target lesions. Any pathological lymph nodes (target/non target) must have reduction in short axis to less than (<) 10 mm; partial response (PR)- at least 30% decrease in sum of diameters of target lesions, taking as reference the baseline sum longest diameter; stable disease (SD)- steady state of disease. Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD; progressive disease (PD): at least 20% increase in sum of diameters of measured lesions taking as references smallest sum of diameters recorded since treatment started. In addition to relative increase of 20%, sum must also demonstrate an absolute increase of at least 5 mm, or appearance of one or more new lesions.

Objective response rate (ORR) was determined as percentage of participants who had either CR or PR, as defined by RECIST v1.1 (for solid tumors). CR was defined as disappearance of all target lesions. Any pathological lymph nodes (target/non target) must have reduction in short axis to <10 mm and PR was defined as at least 30% decrease in sum of diameters of target lesions. ORR was calculated as a proportion and included a 2 sided 95% CI using the exact (Clopper-Pearson) method.

Duration of stable disease was defined as the time from the date of first dose to first documented radiologic evidence of disease recurrence or progression, as defined by RECIST v1.1 (for solid tumors) or RANO criteria (for GBM and AnaA).

Progression-free survival was calculated from the date of first dose of study treatment to first documented evidence of disease recurrence or progression or death due to any cause. Patients who are last known to be alive and without evidence of progression will be censored at time of last evaluable disease assessment. If date of progression or death occurred after more than 1 missed disease assessment interval, patients are censored at the time of last evaluable disease assessment prior to the missed assessment. Progressive disease was defined as at least a 20% increase in the sum of diameters of measured lesions taking as references the smallest sum of diameters recorded since the treatment started. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. Appearance of one or more new lesions also constituted progressive disease.

OS was calculated from the date of first dose to date of death. 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. The OS was calculated using the Kaplan-Meier method.