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

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.

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.

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

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

Cavg0-24h was defined as average concentration from time 0 to 24 hours.

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 the area under the concentration-time curve from time zero to infinity (extrapolated).

Apparent volume of distribution was calculated as Dose/ (kel *AUC0-inf), uncorrected for fraction absorbed, reported normalized by participant body weight (kilogram [kg]).

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

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.

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).

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.

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.

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.

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.