Solid Tumor
Conditions
Keywords
Selinexor, KPT-330, Squamous Cell Carcinoma, Glioblastoma multiforme, Adenocarcinoma, Melanoma, Colorectal cancer, Gynecological cancer, Castrate-resistant Prostate Cancer, Other solid tumors
Brief summary
Phase 1 study to evaluate the safety and tolerability of selinexor and determine the Recommended Phase 2 Dose (RP2D) of selinexor for advanced or metastatic solid tumor malignancies.
Detailed description
This is a phase 1a and phase 1b, open-label, dose-escalation study to evaluate the safety and tolerability of selinexor and determine the RP2D in patients with solid tumor malignancies.
Interventions
DRUGSelinexor
Participants in this study will receive selinexor orally at dose levels specified for their respective dose cohorts. Dosing will begin at 3 mg/m\^2 twice a week and will escalate until the MTD or RP2D is determined. Cycles will be repeated in 4-week (28 days for schedule 1 to 7) and 3-week (21 days for schedule 8) intervals until progression of disease, unacceptable toxicity, or another discontinuation criterion is met. In the case of toxicity, dose adjustment will be permitted.
DRUGAcetaminophen
Oral 500 mg (in Cycle 1, Week 1) to 1000 mg (in Cycle 1, Week 2 and onwards) of acetaminophen will be administered 1 hour prior to each selinexor dose up to 8 doses per cycle (28 days per cycle)
Sponsors
Karyopharm Therapeutics Inc
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Dose Escalation Phase: Patients with advanced or metastatic solid tumors for which no standard therapy is available. For Schedule 6 only: patients with colorectal cancer with liver metastasis. Dose Expansion Phase: Previously treated, metastatic or advanced recurrent malignancy with 1 of the following diagnoses, which has been confirmed histologically or cytologically: * Up to 12 patients with metastatic colorectal cancer with a history of progression or recurrence following prior fluoropyrimidine, irinotecan and platinum containing regimens as well as bevacizumab. In addition, patients with Kras wild type tumor must have received at least one EGFR blocker. * Up to 6 patients with histological or cytological documentation of advanced ovarian, fallopian tube, or primary peritoneal carcinoma with a history of progression or recurrence following at least one prior platinum and one taxane based chemotherapy * Up to 12 patients with incurable Squamous cell cancers as follows: 1. A minimum of 4 Squamous Non-Small Cell Lung Cancer (Sq-NSCLC) 2. A minimum of 4 Squamous Cell Carcinomas of the Head and Neck (Sq-HNC) 3. Squamous Cell Carcinoma of the Cervix (SqCC) All patient with Squamous Cell Carcinomas should have a documented history of progression or recurrence following at least one prior platinum based chemotherapy or chemotherapy/radiation containing regimen * Up to 6 patients with castration-resistant prostate cancer (CRPC) that was pathologically confirmed as adenocarcinoma of the prostate and with evidence of metastatic disease on bone scan or other imaging. Patient must have progressive disease after at least one hormonal treatment and one cytotoxic therapy e.g. with docetaxel, mitoxantrone. * Up to 12 patients with unresectable metastatic melanoma whose disease progressed on at least 1 prior systemic anticancer regimen (chemotherapy, biological or immunotherapy, or targeted therapy). Enrollment to this cohort may have been stopped before reaching 12 patients once the dose-escalation portion of the study was completed. * Approximately 6 patients with advanced or metastatic solid tumors were to be enrolled on Schedule 8 at a starting dose of 35 mg/m\^2 to assess general tolerability and activity of selinexor. 2. Dose Escalation Phase: Patients have exhausted, or be deemed to not benefit from, further conventional therapy and have evidence of progressive disease on study entry. Both Dose Escalation and Expansion Phases: There is no upper limit on the number of prior treatments provided that all inclusion criteria are met and
Exclusion criteria
are not met. Hormone ablation therapy is considered an anticancer regimen. Radiation and surgery are not considered anticancer regimes.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) | From start of study drug administration to 30 days after last dose of study treatment (maximum duration of 45 months) | 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. |
| Number of Participants With Treatment-related Treatment-emergent Adverse Events | From start of study drug administration to 30 days after last dose of study treatment (maximum duration of 45 months) | 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. |
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) Greater Than or Equal to Grade 3, Based on National Cancer Institute Common Terminology Criteria (NCI-CTCAE), Version 4.03 | From start of study drug administration to 30 days after last dose of study treatment (maximum duration of 45 months) | 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. |
| Number of Participants Who Experienced Dose Limiting Toxicity (DLT) | Cycle 1 only (28-day cycle) | 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. |
| Recommended Phase 2 Dose (RP2D) | From start of study drug administration to 30 days after last dose of study treatment (maximum duration of 45 months) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Apparent Total Body Clearance (CL/F) of Selinexor | Cycle1, Day1: Pre-dose, 30, 60, 120, 240, 480 minutes | CL/F was calculated as Dose/AUC0-inf, uncorrected for fraction absorbed; reported normalized by participant body weight (kilogram). |
| Apparent Volume of Distribution of Selinexor (Vd/F) | Cycle1, Day1: Pre-dose, 30, 60, 120, 240, 480 minutes | Vd/F was calculated as Dose/(kel \* AUC0-inf), uncorrected for fraction absorbed; reported normalized by participant body weight (kilogram). |
| Number of Participants With Best Overall Response (BOR) | Up to maximum duration of 45 months | 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. |
| Maximum Observed Plasma Concentration (Cmax) of Selinexor | Cycle1, Day1: Pre-dose, 30, 60, 120, 240, 480 minutes | Cmax was defined as maximum observed concentration, taken directly from the plasma concentration data. |
| Duration of Stable Disease (SD) | From first dose of study drug administration to first documented evidence of disease recurrence or progression (maximum duration of 45 months) | 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 (PFS) | From start of study drug administration until PD or discontinuation from the study or death (maximum duration of 45 months) | 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. |
| Overall Survival (OS) | From first dose of study drug administration to date of death (maximum duration of 45 months) | 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. |
| Percentage of Participants With Objective Response | Up to maximum duration of 45 months | 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. |
| Time of Maximum Observed Concentration in Plasma (Tmax) of Selinexor | Cycle1, Day1: Pre-dose, 30, 60, 120, 240, 480 minutes | Tmax was defined as time of first observation of Cmax, taken directly from the plasma concentration data. |
| Area Under the Concentration Time Curve From the Time of Dosing to Time in Plasma (AUC0-t) of Selinexor | Cycle1, Day1: Pre-dose, 30, 60, 120, 240, 480 minutes | AUC0-t was defined as area under the concentration-time curve from time zero to the last non-zero concentration. |
| Area Under the Concentration Time Curve From the Time of Dosing Extrapolated to Infinity (AUC0-inf) of Selinexor | Cycle1, Day1: Pre-dose, 30, 60, 120, 240, 480 minutes | 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. |
| Elimination Half-Life (t1/2) of Selinexor | Cycle1, Day1: Pre-dose, 30, 60, 120, 240, 480 minutes | t1/2 was defined as elimination half-life, it was calculated as ln(2)/kel, where In = natural logarithm and kel = elimination rate constant. |
Countries
Canada, Denmark, United States
Participant flow
Recruitment details
The study was conducted at six centers in United States, Canada, and Denmark from 18 June 2012 and 15 March 2016.
Pre-assignment details
A total of 192 participants were enrolled, of which 191 participants started study (1 participant reported missing malignancy), 189 participants received at least 1 dose of study drug.
Participants by arm
| Arm | Count |
|---|---|
| Arm A (Colorectal Cancer) Participants with colorectal cancer with liver metastasis received oral selinexor as a single agent in eight schedules- Schedule 1: ≤12 milligrams per meter square (mg/m\^2) 3 times weekly (TIW) during Weeks 1 and 3, BIW during Weeks 2 and 4 up to 10 doses/cycle (28 days/cycle); Schedule 2: \>12 mg/m\^2 TIW during Weeks 1 and 3, BIW in Weeks 2 and 4 up to 10 doses/cycle (28 days/cycle); Schedule 3: ≥30 mg/m\^2 BIW(Days 1 and 3) up to 8 doses/cycle (28 days/cycle); Schedule 4: ≥20 mg/m\^2 BIW (Days 1 and 2) up to 8 doses/cycle (28 days/cycle); Schedule 5: ≥35 mg/m\^2 BIW (Days 1 and 4) up to 8 doses (28 days/cycle); Schedule 6: ≥20 mg/m\^2 BIW (Days 1 and 4) after 500 mg (Cycle 1, Week 1) to 1000 mg (Cycle 1, Week 2 onwards) acetaminophen (given 1 hour prior to each selinexor dose) up to 8 doses/cycle(28 days/cycle); Schedule 7: ≥50 mg/m\^2 once weekly (QW) up to 4 doses/cycle (28 days per cycle); Schedule 8: ≥45 mg/m\^2 BIW (Days 1 and 3) up to 4 doses/cycle (21 days/cycle), until disease progression, death, or unacceptable toxicity. | 59 |
| Arm B (Gynecological Cancer) Participants with gynecological cancer received oral selinexor as a single agent in eight schedules, Schedule 1: ≤12 mg/m\^2 TIW during Weeks 1 and 3, BIW during Weeks 2 and 4 up to 10 doses/cycle (28 days/cycle); Schedule 2: \>12 mg/m\^2 TIW during Weeks 1 and 3, BIW in Weeks 2 and 4 up to 10 doses/cycle (28 days/cycle); Schedule 3: ≥30 mg/m\^2 BIW (Days 1 and 3) up to 8 doses/cycle (28 days/cycle); Schedule 4: ≥20 mg/m\^2 BIW (Days 1 and 2) up to 8 doses/cycle (28 days/cycle); Schedule 5: ≥35 mg/m\^2 BIW (Days 1 and 4) up to 8 doses (28 days/cycle); Schedule 7: ≥50 mg/m\^2 QW up to 4 doses/cycle (28 days per cycle); Schedule 8: ≥45 mg/m\^2 BIW (Days 1 and 3) up to 4 doses/cycle (21 days/cycle), until disease progression, death, or unacceptable toxicity. | 20 |
| Arm C (Squamous Cell Cancer) Participants with squamous cell cancer received oral selinexor as a single agent in eight schedules, Schedule 1: ≤12 mg/m\^2 TIW during Weeks 1 and 3, BIW during Weeks 2 and 4 up to 10 doses/cycle (28 days/cycle); Schedule 2: \>12 mg/m\^2 TIW during Weeks 1 and 3, BIW in Weeks 2 and 4 up to 10 doses/cycle (28 days/cycle); Schedule 3: ≥30 mg/m\^2 BIW (Days 1 and 3) up to 8 doses/cycle (28 days/cycle); Schedule 4: ≥20 mg/m\^2 BIW (Days 1 and 2) up to 8 doses/cycle (28 days/cycle); Schedule 5: ≥35 mg/m\^2 BIW (Days 1 and 4) up to 8 doses (28 days/cycle); Schedule 7: ≥50 mg/m\^2 QW up to 4 doses/cycle (28 days per cycle); Schedule 8: ≥45 mg/m\^2 BIW (Days 1 and 3) up to 4 doses/cycle (21 days/cycle), until disease progression, death, or unacceptable toxicity. | 21 |
| Arm D (Castrate-resistant Prostate Cancer) Participants with CRPC received oral selinexor as a single agent in eight schedules, Schedule 1: ≤12 mg/m\^2 TIW during Weeks 1 and 3, BIW during Weeks 2 and 4 up to 10 doses/cycle (28 days/cycle); Schedule 2: \>12 mg/m\^2 TIW during Weeks 1 and 3, BIW in Weeks 2 and 4 up to 10 doses/cycle (28 days/cycle); Schedule 3: ≥30 mg/m\^2 BIW (Days 1 and 3) up to 8 doses/cycle (28 days/cycle); Schedule 4: ≥20 mg/m\^2 BIW (Days 1 and 2) up to 8 doses/cycle (28 days/cycle); Schedule 5: ≥35 mg/m\^2 BIW (Days 1 and 4) up to 8 doses (28 days/cycle); Schedule 7: ≥50 mg/m\^2 QW up to 4 doses/cycle (28 days per cycle); Schedule 8: ≥45 mg/m\^2 BIW (Days 1 and 3) up to 4 doses/cycle (21 days/cycle), until disease progression, death, or unacceptable toxicity. | 21 |
| Arm E (Glioblastoma Multiforme) Participants with GBM received oral selinexor as a single agent in eight schedules, Schedule 1: ≤12 mg/m\^2 TIW during Weeks 1 and 3, BIW during Weeks 2 and 4 up to 10 doses/cycle (28 days/cycle); Schedule 2: \>12 mg/m\^2 TIW during Weeks 1 and 3, BIW in Weeks 2 and 4 up to 10 doses/cycle (28 days/cycle); Schedule 3: ≥30 mg/m\^2 BIW (Days 1 and 3) up to 8 doses/cycle (28 days/cycle); Schedule 4: ≥20 mg/m\^2 BIW (Days 1 and 2) up to 8 doses/cycle (28 days/cycle); Schedule 5: ≥35 mg/m\^2 BIW (Days 1 and 4) up to 8 doses (28 days/cycle); Schedule 7: ≥50 mg/m\^2 QW up to 4 doses/cycle (28 days per cycle); Schedule 8: ≥45 mg/m\^2 BIW (Days 1 and 3) up to 4 doses/cycle (21 days/cycle), until disease progression, death, or unacceptable toxicity. | 6 |
| Arm F (Melanoma) Participants with melanoma received oral selinexor as a single agent in eight schedules, Schedule 1: ≤12 mg/m\^2 TIW during Weeks 1 and 3, BIW during Weeks 2 and 4 up to 10 doses/cycle (28 days/cycle); Schedule 2: \>12 mg/m\^2 TIW during Weeks 1 and 3, BIW in Weeks 2 and 4 up to 10 doses/cycle (28 days/cycle); Schedule 3: ≥30 mg/m\^2 BIW (Days 1 and 3) up to 8 doses/cycle (28 days/cycle); Schedule 4: ≥20 mg/m\^2 BIW (Days 1 and 2) up to 8 doses/cycle (28 days/cycle); Schedule 5: ≥35 mg/m\^2 BIW (Days 1 and 4) up to 8 doses (28 days/cycle); Schedule 7: ≥50 mg/m\^2 QW up to 4 doses/cycle (28 days per cycle); Schedule 8: ≥45 mg/m\^2 BIW (Days 1 and 3) up to 4 doses/cycle (21 days/cycle), until disease progression, death, or unacceptable toxicity. | 15 |
| Arm G (Other Solid Tumors) Participants with other solid tumors received oral selinexor as a single agent in eight schedules, Schedule 1: ≤12 mg/m\^2 TIW during Weeks 1 and 3, BIW during Weeks 2 and 4 up to 10 doses/cycle (28 days/cycle); Schedule 2: \>12 mg/m\^2 TIW during Weeks 1 and 3, BIW in Weeks 2 and 4 up to 10 doses/cycle (28 days/cycle); Schedule 3: ≥30 mg/m\^2 BIW (Days 1 and 3) up to 8 doses/cycle (28 days/cycle); Schedule 4: ≥20 mg/m\^2 BIW (Days 1 and 2) up to 8 doses/cycle (28 days/cycle); Schedule 5: ≥35 mg/m\^2 BIW (Days 1 and 4) up to 8 doses (28 days/cycle); Schedule 7: ≥50 mg/m\^2 QW up to 4 doses/cycle (28 days per cycle); Schedule 8: ≥45 mg/m\^2 BIW (Days 1 and 3) up to 4 doses/cycle (21 days/cycle), until disease progression, death, or unacceptable toxicity. | 47 |
| Total | 189 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 |
|---|---|---|---|---|---|---|---|---|
| Overall Study | Death | 1 | 1 | 1 | 1 | 0 | 0 | 3 |
| Overall Study | Disease progression | 44 | 16 | 15 | 11 | 6 | 7 | 21 |
| Overall Study | Incidence or severity of AEs | 5 | 1 | 1 | 3 | 0 | 2 | 8 |
| Overall Study | Investigator discretion | 0 | 0 | 0 | 0 | 0 | 1 | 0 |
| Overall Study | Non-compliance with study procedures | 0 | 0 | 0 | 0 | 0 | 0 | 1 |
| Overall Study | Other | 1 | 0 | 0 | 0 | 0 | 0 | 1 |
| Overall Study | Other treatments become available | 1 | 0 | 0 | 0 | 0 | 0 | 1 |
| Overall Study | Randomized but not treated | 1 | 0 | 0 | 0 | 1 | 1 | 0 |
| Overall Study | Withdrawal by participant | 7 | 2 | 4 | 6 | 0 | 4 | 12 |
Baseline characteristics
| Characteristic | Arm A (Colorectal Cancer) | Arm G (Other Solid Tumors) | Arm F (Melanoma) | Arm E (Glioblastoma Multiforme) | Arm D (Castrate-resistant Prostate Cancer) | Arm C (Squamous Cell Cancer) | Arm B (Gynecological Cancer) | Total |
|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 59.8 years STANDARD_DEVIATION 11.35 | 57.7 years STANDARD_DEVIATION 12.67 | 67.7 years STANDARD_DEVIATION 11.04 | 56.0 years STANDARD_DEVIATION 14.94 | 68.7 years STANDARD_DEVIATION 7.69 | 59.2 years STANDARD_DEVIATION 7.39 | 55.0 years STANDARD_DEVIATION 12.54 | 60.2 years STANDARD_DEVIATION 11.82 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 3 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 6 Participants |
| Race (NIH/OMB) Black or African American | 10 Participants | 5 Participants | 1 Participants | 0 Participants | 2 Participants | 4 Participants | 0 Participants | 22 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 0 Participants | 0 Participants | 3 Participants |
| Race (NIH/OMB) White | 45 Participants | 41 Participants | 14 Participants | 6 Participants | 16 Participants | 17 Participants | 18 Participants | 157 Participants |
| Sex: Female, Male Female | 25 Participants | 14 Participants | 4 Participants | 3 Participants | 0 Participants | 9 Participants | 20 Participants | 75 Participants |
| Sex: Female, Male Male | 34 Participants | 33 Participants | 11 Participants | 3 Participants | 21 Participants | 12 Participants | 0 Participants | 114 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk |
|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 59 / 59 | 20 / 20 | 21 / 21 | 21 / 21 | 6 / 6 | 15 / 15 | 46 / 47 |
| serious Total, serious adverse events | 30 / 59 | 13 / 20 | 9 / 21 | 8 / 21 | 2 / 6 | 5 / 15 | 24 / 47 |
Outcome results
Primary
Number of Participants Who Experienced Dose Limiting Toxicity (DLT)
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.
Time frame: Cycle 1 only (28-day cycle)
Population: DLT Evaluable Population included all participants enrolled to the study during the dose-escalation phase who met the inclusion/exclusion criteria on first day of dosing and completed at least 1 cycle of therapy or experienced a DLT during the first cycle. As pre-specified in the study Protocol data were not collected per dose level. The limited data available based on cancer stratification as pre-specified in the protocol is presented.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm A (Colorectal Cancer) | Number of Participants Who Experienced Dose Limiting Toxicity (DLT) | 1 Participants |
| Arm B (Gynecological Cancer) | Number of Participants Who Experienced Dose Limiting Toxicity (DLT) | 0 Participants |
| Arm C (Squamous Cell Cancer) | Number of Participants Who Experienced Dose Limiting Toxicity (DLT) | 0 Participants |
| Arm D (Castrate-resistant Prostate Cancer) | Number of Participants Who Experienced Dose Limiting Toxicity (DLT) | 0 Participants |
| Arm E (Glioblastoma Multiforme) | Number of Participants Who Experienced Dose Limiting Toxicity (DLT) | 0 Participants |
| Arm F (Melanoma) | Number of Participants Who Experienced Dose Limiting Toxicity (DLT) | 1 Participants |
| Arm G (Other Solid Tumors) | Number of Participants Who Experienced Dose Limiting Toxicity (DLT) | 2 Participants |
Primary
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 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.
Time frame: From start of study drug administration to 30 days after last dose of study treatment (maximum duration of 45 months)
Population: Safety population included all participants who received at least one dose of selinexor. As pre-specified in the study Protocol data were not collected per dose level. The limited data available based on cancer stratification as pre-specified in the protocol is presented.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm A (Colorectal Cancer) | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) | Participants with TEAEs | 59 Participants |
| Arm A (Colorectal Cancer) | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) | Participants with TESAEs | 30 Participants |
| Arm B (Gynecological Cancer) | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) | Participants with TEAEs | 20 Participants |
| Arm B (Gynecological Cancer) | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) | Participants with TESAEs | 13 Participants |
| Arm C (Squamous Cell Cancer) | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) | Participants with TEAEs | 21 Participants |
| Arm C (Squamous Cell Cancer) | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) | Participants with TESAEs | 9 Participants |
| Arm D (Castrate-resistant Prostate Cancer) | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) | Participants with TEAEs | 21 Participants |
| Arm D (Castrate-resistant Prostate Cancer) | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) | Participants with TESAEs | 8 Participants |
| Arm E (Glioblastoma Multiforme) | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) | Participants with TEAEs | 6 Participants |
| Arm E (Glioblastoma Multiforme) | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) | Participants with TESAEs | 2 Participants |
| Arm F (Melanoma) | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) | Participants with TEAEs | 15 Participants |
| Arm F (Melanoma) | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) | Participants with TESAEs | 5 Participants |
| Arm G (Other Solid Tumors) | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) | Participants with TEAEs | 46 Participants |
| Arm G (Other Solid Tumors) | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) | Participants with TESAEs | 24 Participants |
Primary
Number of Participants With Treatment-emergent Adverse Events (TEAEs) Greater Than or Equal to Grade 3, Based on National Cancer Institute Common Terminology Criteria (NCI-CTCAE), Version 4.03
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.
Time frame: From start of study drug administration to 30 days after last dose of study treatment (maximum duration of 45 months)
Population: Safety population included all participants who received at least one dose of selinexor. As pre-specified in the study Protocol data were not collected per dose level. The limited data available based on cancer stratification as pre-specified in the protocol is presented.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm A (Colorectal Cancer) | Number of Participants With Treatment-emergent Adverse Events (TEAEs) Greater Than or Equal to Grade 3, Based on National Cancer Institute Common Terminology Criteria (NCI-CTCAE), Version 4.03 | 50 Participants |
| Arm B (Gynecological Cancer) | Number of Participants With Treatment-emergent Adverse Events (TEAEs) Greater Than or Equal to Grade 3, Based on National Cancer Institute Common Terminology Criteria (NCI-CTCAE), Version 4.03 | 17 Participants |
| Arm C (Squamous Cell Cancer) | Number of Participants With Treatment-emergent Adverse Events (TEAEs) Greater Than or Equal to Grade 3, Based on National Cancer Institute Common Terminology Criteria (NCI-CTCAE), Version 4.03 | 16 Participants |
| Arm D (Castrate-resistant Prostate Cancer) | Number of Participants With Treatment-emergent Adverse Events (TEAEs) Greater Than or Equal to Grade 3, Based on National Cancer Institute Common Terminology Criteria (NCI-CTCAE), Version 4.03 | 17 Participants |
| Arm E (Glioblastoma Multiforme) | Number of Participants With Treatment-emergent Adverse Events (TEAEs) Greater Than or Equal to Grade 3, Based on National Cancer Institute Common Terminology Criteria (NCI-CTCAE), Version 4.03 | 4 Participants |
| Arm F (Melanoma) | Number of Participants With Treatment-emergent Adverse Events (TEAEs) Greater Than or Equal to Grade 3, Based on National Cancer Institute Common Terminology Criteria (NCI-CTCAE), Version 4.03 | 11 Participants |
| Arm G (Other Solid Tumors) | Number of Participants With Treatment-emergent Adverse Events (TEAEs) Greater Than or Equal to Grade 3, Based on National Cancer Institute Common Terminology Criteria (NCI-CTCAE), Version 4.03 | 35 Participants |
Primary
Number of Participants With Treatment-related Treatment-emergent Adverse Events
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.
Time frame: From start of study drug administration to 30 days after last dose of study treatment (maximum duration of 45 months)
Population: Safety population included all participants who received at least one dose of selinexor. As pre-specified in the study Protocol data were not collected per dose level. The limited data available based on cancer stratification as pre-specified in the protocol is presented.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm A (Colorectal Cancer) | Number of Participants With Treatment-related Treatment-emergent Adverse Events | Participants with Treatment-related TEAEs | 59 Participants |
| Arm A (Colorectal Cancer) | Number of Participants With Treatment-related Treatment-emergent Adverse Events | Participants with Treatment-related TESAEs | 6 Participants |
| Arm B (Gynecological Cancer) | Number of Participants With Treatment-related Treatment-emergent Adverse Events | Participants with Treatment-related TEAEs | 19 Participants |
| Arm B (Gynecological Cancer) | Number of Participants With Treatment-related Treatment-emergent Adverse Events | Participants with Treatment-related TESAEs | 2 Participants |
| Arm C (Squamous Cell Cancer) | Number of Participants With Treatment-related Treatment-emergent Adverse Events | Participants with Treatment-related TEAEs | 20 Participants |
| Arm C (Squamous Cell Cancer) | Number of Participants With Treatment-related Treatment-emergent Adverse Events | Participants with Treatment-related TESAEs | 1 Participants |
| Arm D (Castrate-resistant Prostate Cancer) | Number of Participants With Treatment-related Treatment-emergent Adverse Events | Participants with Treatment-related TEAEs | 21 Participants |
| Arm D (Castrate-resistant Prostate Cancer) | Number of Participants With Treatment-related Treatment-emergent Adverse Events | Participants with Treatment-related TESAEs | 4 Participants |
| Arm E (Glioblastoma Multiforme) | Number of Participants With Treatment-related Treatment-emergent Adverse Events | Participants with Treatment-related TEAEs | 6 Participants |
| Arm E (Glioblastoma Multiforme) | Number of Participants With Treatment-related Treatment-emergent Adverse Events | Participants with Treatment-related TESAEs | 1 Participants |
| Arm F (Melanoma) | Number of Participants With Treatment-related Treatment-emergent Adverse Events | Participants with Treatment-related TEAEs | 14 Participants |
| Arm F (Melanoma) | Number of Participants With Treatment-related Treatment-emergent Adverse Events | Participants with Treatment-related TESAEs | 1 Participants |
| Arm G (Other Solid Tumors) | Number of Participants With Treatment-related Treatment-emergent Adverse Events | Participants with Treatment-related TEAEs | 45 Participants |
| Arm G (Other Solid Tumors) | Number of Participants With Treatment-related Treatment-emergent Adverse Events | Participants with Treatment-related TESAEs | 9 Participants |
Primary
Recommended Phase 2 Dose (RP2D)
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.
Time frame: From start of study drug administration to 30 days after last dose of study treatment (maximum duration of 45 months)
Population: Safety Population included all participants who received at least one dose of selinexor. The data in terms of dose was reported as combined data for participants from all arms, pre-specified in protocol. Here, 'Overall number of participants analyzed' signifies participants with available data for the outcome measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A (Colorectal Cancer) | Recommended Phase 2 Dose (RP2D) | 35 mg/m^2 |
Secondary
Apparent Total Body Clearance (CL/F) of Selinexor
CL/F was calculated as Dose/AUC0-inf, uncorrected for fraction absorbed; reported normalized by participant body weight (kilogram).
Time frame: Cycle1, Day1: Pre-dose, 30, 60, 120, 240, 480 minutes
Population: PK population consisted of all participants who received selinexor, and had evaluable PK for at least one dosing occasion. Data for the PK parameters were planned and analyzed based on doses and % coefficient of variation was not evaluable for arms with single participant. Here, 'Overall number of participants analyzed' signifies participants with available data for the outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Arm A (Colorectal Cancer) | Apparent Total Body Clearance (CL/F) of Selinexor | 0.20 liter per hour per kilogram | — |
| Arm B (Gynecological Cancer) | Apparent Total Body Clearance (CL/F) of Selinexor | 0.18 liter per hour per kilogram | Geometric Coefficient of Variation 7.9 |
| Arm C (Squamous Cell Cancer) | Apparent Total Body Clearance (CL/F) of Selinexor | 0.19 liter per hour per kilogram | Geometric Coefficient of Variation 16 |
| Arm D (Castrate-resistant Prostate Cancer) | Apparent Total Body Clearance (CL/F) of Selinexor | 0.20 liter per hour per kilogram | — |
| Arm E (Glioblastoma Multiforme) | Apparent Total Body Clearance (CL/F) of Selinexor | 0.19 liter per hour per kilogram | Geometric Coefficient of Variation 27 |
| Arm F (Melanoma) | Apparent Total Body Clearance (CL/F) of Selinexor | 0.19 liter per hour per kilogram | Geometric Coefficient of Variation 26.1 |
| Arm G (Other Solid Tumors) | Apparent Total Body Clearance (CL/F) of Selinexor | 0.18 liter per hour per kilogram | — |
| Selinexor Dose: 30 mg/m^2 | Apparent Total Body Clearance (CL/F) of Selinexor | 0.17 liter per hour per kilogram | Geometric Coefficient of Variation 16.8 |
| Selinexor Dose: 35 mg/m^2 | Apparent Total Body Clearance (CL/F) of Selinexor | 0.20 liter per hour per kilogram | Geometric Coefficient of Variation 26.7 |
| Selinexor Dose: 39 mg/m^2 | Apparent Total Body Clearance (CL/F) of Selinexor | 0.20 liter per hour per kilogram | Geometric Coefficient of Variation 12.5 |
| Selinexor Dose: 40 mg/m^2 | Apparent Total Body Clearance (CL/F) of Selinexor | 0.19 liter per hour per kilogram | Geometric Coefficient of Variation 24.4 |
| Selinexor Dose: 45 mg/m^2 | Apparent Total Body Clearance (CL/F) of Selinexor | 0.27 liter per hour per kilogram | — |
| Selinexor Dose: 50 mg/m^2 | Apparent Total Body Clearance (CL/F) of Selinexor | 0.18 liter per hour per kilogram | Geometric Coefficient of Variation 10.6 |
| Selinexor Dose: 55 mg/m^2 | Apparent Total Body Clearance (CL/F) of Selinexor | 0.20 liter per hour per kilogram | Geometric Coefficient of Variation 17.1 |
| Selinexor Dose: 58 mg/m^2 | Apparent Total Body Clearance (CL/F) of Selinexor | 0.20 liter per hour per kilogram | Geometric Coefficient of Variation 17 |
| Selinexor Dose: 65 mg/m^2 | Apparent Total Body Clearance (CL/F) of Selinexor | 0.15 liter per hour per kilogram | Geometric Coefficient of Variation 32.7 |
| Selinexor Dose: 80 mg/m^2 | Apparent Total Body Clearance (CL/F) of Selinexor | 0.22 liter per hour per kilogram | — |
| Selinexor Dose: 85 mg/m^2 | Apparent Total Body Clearance (CL/F) of Selinexor | 0.18 liter per hour per kilogram | Geometric Coefficient of Variation 4.1 |
Secondary
Apparent Volume of Distribution of Selinexor (Vd/F)
Vd/F was calculated as Dose/(kel \* AUC0-inf), uncorrected for fraction absorbed; reported normalized by participant body weight (kilogram).
Time frame: Cycle1, Day1: Pre-dose, 30, 60, 120, 240, 480 minutes
Population: PK population consisted of all participants who received selinexor, and had evaluable PK for at least one dosing occasion. Data for the PK parameters were planned and analyzed based on doses and % coefficient of variation was not evaluable for arms with single participant. Here, 'Overall number of participants analyzed' signifies participants with available data for the outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Arm A (Colorectal Cancer) | Apparent Volume of Distribution of Selinexor (Vd/F) | 1.8 liter per kilogram | — |
| Arm B (Gynecological Cancer) | Apparent Volume of Distribution of Selinexor (Vd/F) | 1.4 liter per kilogram | Geometric Coefficient of Variation 12.5 |
| Arm C (Squamous Cell Cancer) | Apparent Volume of Distribution of Selinexor (Vd/F) | 1.4 liter per kilogram | Geometric Coefficient of Variation 22.5 |
| Arm D (Castrate-resistant Prostate Cancer) | Apparent Volume of Distribution of Selinexor (Vd/F) | 1.6 liter per kilogram | — |
| Arm E (Glioblastoma Multiforme) | Apparent Volume of Distribution of Selinexor (Vd/F) | 1.6 liter per kilogram | Geometric Coefficient of Variation 20.9 |
| Arm F (Melanoma) | Apparent Volume of Distribution of Selinexor (Vd/F) | 1.6 liter per kilogram | Geometric Coefficient of Variation 21.2 |
| Arm G (Other Solid Tumors) | Apparent Volume of Distribution of Selinexor (Vd/F) | 1.5 liter per kilogram | — |
| Selinexor Dose: 30 mg/m^2 | Apparent Volume of Distribution of Selinexor (Vd/F) | 1.6 liter per kilogram | Geometric Coefficient of Variation 6.6 |
| Selinexor Dose: 35 mg/m^2 | Apparent Volume of Distribution of Selinexor (Vd/F) | 1.6 liter per kilogram | Geometric Coefficient of Variation 26.6 |
| Selinexor Dose: 39 mg/m^2 | Apparent Volume of Distribution of Selinexor (Vd/F) | 1.5 liter per kilogram | Geometric Coefficient of Variation 26.1 |
| Selinexor Dose: 40 mg/m^2 | Apparent Volume of Distribution of Selinexor (Vd/F) | 1.9 liter per kilogram | Geometric Coefficient of Variation 31.1 |
| Selinexor Dose: 45 mg/m^2 | Apparent Volume of Distribution of Selinexor (Vd/F) | 2.8 liter per kilogram | — |
| Selinexor Dose: 50 mg/m^2 | Apparent Volume of Distribution of Selinexor (Vd/F) | 1.9 liter per kilogram | Geometric Coefficient of Variation 14.3 |
| Selinexor Dose: 55 mg/m^2 | Apparent Volume of Distribution of Selinexor (Vd/F) | 1.9 liter per kilogram | Geometric Coefficient of Variation 24.7 |
| Selinexor Dose: 58 mg/m^2 | Apparent Volume of Distribution of Selinexor (Vd/F) | 1.8 liter per kilogram | Geometric Coefficient of Variation 15.4 |
| Selinexor Dose: 65 mg/m^2 | Apparent Volume of Distribution of Selinexor (Vd/F) | 1.5 liter per kilogram | Geometric Coefficient of Variation 31.8 |
| Selinexor Dose: 80 mg/m^2 | Apparent Volume of Distribution of Selinexor (Vd/F) | 1.8 liter per kilogram | — |
| Selinexor Dose: 85 mg/m^2 | Apparent Volume of Distribution of Selinexor (Vd/F) | 1.4 liter per kilogram | Geometric Coefficient of Variation 22.7 |
Secondary
Area Under the Concentration Time Curve From the Time of Dosing Extrapolated to Infinity (AUC0-inf) of Selinexor
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.
Time frame: Cycle1, Day1: Pre-dose, 30, 60, 120, 240, 480 minutes
Population: PK population consisted of all participants who received selinexor, and had evaluable PK for at least one dosing occasion. Data for the PK parameters were planned and analyzed based on doses and % coefficient of variation was not evaluable for arms with single participant. Here, 'Overall number of participants analyzed' signifies participants with available data for the outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Arm A (Colorectal Cancer) | Area Under the Concentration Time Curve From the Time of Dosing Extrapolated to Infinity (AUC0-inf) of Selinexor | 355 nanogram hour per milliliter | — |
| Arm B (Gynecological Cancer) | Area Under the Concentration Time Curve From the Time of Dosing Extrapolated to Infinity (AUC0-inf) of Selinexor | 808 nanogram hour per milliliter | Geometric Coefficient of Variation 5.2 |
| Arm C (Squamous Cell Cancer) | Area Under the Concentration Time Curve From the Time of Dosing Extrapolated to Infinity (AUC0-inf) of Selinexor | 1613 nanogram hour per milliliter | Geometric Coefficient of Variation 21.4 |
| Arm D (Castrate-resistant Prostate Cancer) | Area Under the Concentration Time Curve From the Time of Dosing Extrapolated to Infinity (AUC0-inf) of Selinexor | 1455 nanogram hour per milliliter | — |
| Arm E (Glioblastoma Multiforme) | Area Under the Concentration Time Curve From the Time of Dosing Extrapolated to Infinity (AUC0-inf) of Selinexor | 2269 nanogram hour per milliliter | Geometric Coefficient of Variation 27.2 |
| Arm F (Melanoma) | Area Under the Concentration Time Curve From the Time of Dosing Extrapolated to Infinity (AUC0-inf) of Selinexor | 3332 nanogram hour per milliliter | Geometric Coefficient of Variation 17.3 |
| Arm G (Other Solid Tumors) | Area Under the Concentration Time Curve From the Time of Dosing Extrapolated to Infinity (AUC0-inf) of Selinexor | 3936 nanogram hour per milliliter | — |
| Selinexor Dose: 30 mg/m^2 | Area Under the Concentration Time Curve From the Time of Dosing Extrapolated to Infinity (AUC0-inf) of Selinexor | 3961 nanogram hour per milliliter | Geometric Coefficient of Variation 12.1 |
| Selinexor Dose: 35 mg/m^2 | Area Under the Concentration Time Curve From the Time of Dosing Extrapolated to Infinity (AUC0-inf) of Selinexor | 4585 nanogram hour per milliliter | Geometric Coefficient of Variation 18.2 |
| Selinexor Dose: 39 mg/m^2 | Area Under the Concentration Time Curve From the Time of Dosing Extrapolated to Infinity (AUC0-inf) of Selinexor | 5014 nanogram hour per milliliter | Geometric Coefficient of Variation 18 |
| Selinexor Dose: 40 mg/m^2 | Area Under the Concentration Time Curve From the Time of Dosing Extrapolated to Infinity (AUC0-inf) of Selinexor | 5294 nanogram hour per milliliter | Geometric Coefficient of Variation 24 |
| Selinexor Dose: 45 mg/m^2 | Area Under the Concentration Time Curve From the Time of Dosing Extrapolated to Infinity (AUC0-inf) of Selinexor | 3395 nanogram hour per milliliter | — |
| Selinexor Dose: 50 mg/m^2 | Area Under the Concentration Time Curve From the Time of Dosing Extrapolated to Infinity (AUC0-inf) of Selinexor | 5688 nanogram hour per milliliter | Geometric Coefficient of Variation 0.6 |
| Selinexor Dose: 55 mg/m^2 | Area Under the Concentration Time Curve From the Time of Dosing Extrapolated to Infinity (AUC0-inf) of Selinexor | 5894 nanogram hour per milliliter | Geometric Coefficient of Variation 24.8 |
| Selinexor Dose: 58 mg/m^2 | Area Under the Concentration Time Curve From the Time of Dosing Extrapolated to Infinity (AUC0-inf) of Selinexor | 6567 nanogram hour per milliliter | Geometric Coefficient of Variation 12.8 |
| Selinexor Dose: 65 mg/m^2 | Area Under the Concentration Time Curve From the Time of Dosing Extrapolated to Infinity (AUC0-inf) of Selinexor | 10265 nanogram hour per milliliter | Geometric Coefficient of Variation 31.4 |
| Selinexor Dose: 80 mg/m^2 | Area Under the Concentration Time Curve From the Time of Dosing Extrapolated to Infinity (AUC0-inf) of Selinexor | 9025 nanogram hour per milliliter | — |
| Selinexor Dose: 85 mg/m^2 | Area Under the Concentration Time Curve From the Time of Dosing Extrapolated to Infinity (AUC0-inf) of Selinexor | 11830 nanogram hour per milliliter | Geometric Coefficient of Variation 20.1 |
Secondary
Area Under the Concentration Time Curve From the Time of Dosing to Time in Plasma (AUC0-t) of Selinexor
AUC0-t was defined as area under the concentration-time curve from time zero to the last non-zero concentration.
Time frame: Cycle1, Day1: Pre-dose, 30, 60, 120, 240, 480 minutes
Population: PK population consisted of all participants who received selinexor, and had evaluable PK for at least one dosing occasion. Data for the PK parameters were planned and analyzed based on doses and % coefficient of variation was not evaluable for arms with single participant. Here, 'Overall number of participants analyzed' signifies participants with available data for the outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Arm A (Colorectal Cancer) | Area Under the Concentration Time Curve From the Time of Dosing to Time in Plasma (AUC0-t) of Selinexor | 333 nanogram hour per milliliter | — |
| Arm B (Gynecological Cancer) | Area Under the Concentration Time Curve From the Time of Dosing to Time in Plasma (AUC0-t) of Selinexor | 707 nanogram hour per milliliter | Geometric Coefficient of Variation 13.6 |
| Arm C (Squamous Cell Cancer) | Area Under the Concentration Time Curve From the Time of Dosing to Time in Plasma (AUC0-t) of Selinexor | 1578 nanogram hour per milliliter | Geometric Coefficient of Variation 21 |
| Arm D (Castrate-resistant Prostate Cancer) | Area Under the Concentration Time Curve From the Time of Dosing to Time in Plasma (AUC0-t) of Selinexor | 1369 nanogram hour per milliliter | — |
| Arm E (Glioblastoma Multiforme) | Area Under the Concentration Time Curve From the Time of Dosing to Time in Plasma (AUC0-t) of Selinexor | 2446 nanogram hour per milliliter | Geometric Coefficient of Variation 23.3 |
| Arm F (Melanoma) | Area Under the Concentration Time Curve From the Time of Dosing to Time in Plasma (AUC0-t) of Selinexor | 3387 nanogram hour per milliliter | Geometric Coefficient of Variation 17.7 |
| Arm G (Other Solid Tumors) | Area Under the Concentration Time Curve From the Time of Dosing to Time in Plasma (AUC0-t) of Selinexor | 3106 nanogram hour per milliliter | Geometric Coefficient of Variation 31 |
| Selinexor Dose: 30 mg/m^2 | Area Under the Concentration Time Curve From the Time of Dosing to Time in Plasma (AUC0-t) of Selinexor | 3861 nanogram hour per milliliter | Geometric Coefficient of Variation 16.6 |
| Selinexor Dose: 35 mg/m^2 | Area Under the Concentration Time Curve From the Time of Dosing to Time in Plasma (AUC0-t) of Selinexor | 3691 nanogram hour per milliliter | Geometric Coefficient of Variation 25 |
| Selinexor Dose: 39 mg/m^2 | Area Under the Concentration Time Curve From the Time of Dosing to Time in Plasma (AUC0-t) of Selinexor | 4885 nanogram hour per milliliter | Geometric Coefficient of Variation 15.3 |
| Selinexor Dose: 40 mg/m^2 | Area Under the Concentration Time Curve From the Time of Dosing to Time in Plasma (AUC0-t) of Selinexor | 5255 nanogram hour per milliliter | Geometric Coefficient of Variation 24.4 |
| Selinexor Dose: 45 mg/m^2 | Area Under the Concentration Time Curve From the Time of Dosing to Time in Plasma (AUC0-t) of Selinexor | 4390 nanogram hour per milliliter | Geometric Coefficient of Variation 24.9 |
| Selinexor Dose: 50 mg/m^2 | Area Under the Concentration Time Curve From the Time of Dosing to Time in Plasma (AUC0-t) of Selinexor | 5490 nanogram hour per milliliter | Geometric Coefficient of Variation 3.1 |
| Selinexor Dose: 55 mg/m^2 | Area Under the Concentration Time Curve From the Time of Dosing to Time in Plasma (AUC0-t) of Selinexor | 5803 nanogram hour per milliliter | Geometric Coefficient of Variation 23.5 |
| Selinexor Dose: 58 mg/m^2 | Area Under the Concentration Time Curve From the Time of Dosing to Time in Plasma (AUC0-t) of Selinexor | 5888 nanogram hour per milliliter | Geometric Coefficient of Variation 18.9 |
| Selinexor Dose: 65 mg/m^2 | Area Under the Concentration Time Curve From the Time of Dosing to Time in Plasma (AUC0-t) of Selinexor | 8482 nanogram hour per milliliter | Geometric Coefficient of Variation 44.8 |
| Selinexor Dose: 70 mg/m^2 | Area Under the Concentration Time Curve From the Time of Dosing to Time in Plasma (AUC0-t) of Selinexor | 7210 nanogram hour per milliliter | — |
| Selinexor Dose: 80 mg/m^2 | Area Under the Concentration Time Curve From the Time of Dosing to Time in Plasma (AUC0-t) of Selinexor | 9838 nanogram hour per milliliter | Geometric Coefficient of Variation 12.7 |
| Selinexor Dose: 85 mg/m^2 | Area Under the Concentration Time Curve From the Time of Dosing to Time in Plasma (AUC0-t) of Selinexor | 11485 nanogram hour per milliliter | Geometric Coefficient of Variation 20.1 |
Secondary
Duration of Stable Disease (SD)
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).
Time frame: From first dose of study drug administration to first documented evidence of disease recurrence or progression (maximum duration of 45 months)
Population: Efficacy Population included all participants registered to the study who had either completed 1 cycle of treatment or discontinued treatment prior to completing the first cycle due to documented disease progression, death related to disease, or treatment-related toxicity. As pre-specified in the study Protocol data were not collected per dose level. The limited data available based on cancer stratification as pre-specified in the protocol is presented.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A (Colorectal Cancer) | Duration of Stable Disease (SD) | 53 Days |
| Arm B (Gynecological Cancer) | Duration of Stable Disease (SD) | 119 Days |
| Arm C (Squamous Cell Cancer) | Duration of Stable Disease (SD) | 52 Days |
| Arm D (Castrate-resistant Prostate Cancer) | Duration of Stable Disease (SD) | 133 Days |
| Arm E (Glioblastoma Multiforme) | Duration of Stable Disease (SD) | 43 Days |
| Arm F (Melanoma) | Duration of Stable Disease (SD) | 52 Days |
| Arm G (Other Solid Tumors) | Duration of Stable Disease (SD) | 134 Days |
Secondary
Elimination Half-Life (t1/2) of Selinexor
t1/2 was defined as elimination half-life, it was calculated as ln(2)/kel, where In = natural logarithm and kel = elimination rate constant.
Time frame: Cycle1, Day1: Pre-dose, 30, 60, 120, 240, 480 minutes
Population: PK population consisted of all participants who received selinexor, and had evaluable PK for at least one dosing occasion. Data for the PK parameters were planned and analyzed based on doses and full range was not evaluable for arms with single participant. Here, 'Overall number of participants analyzed' signifies participants with available data for the outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A (Colorectal Cancer) | Elimination Half-Life (t1/2) of Selinexor | 6.2 hours |
| Arm B (Gynecological Cancer) | Elimination Half-Life (t1/2) of Selinexor | 5.6 hours |
| Arm C (Squamous Cell Cancer) | Elimination Half-Life (t1/2) of Selinexor | 5.0 hours |
| Arm D (Castrate-resistant Prostate Cancer) | Elimination Half-Life (t1/2) of Selinexor | 5.7 hours |
| Arm E (Glioblastoma Multiforme) | Elimination Half-Life (t1/2) of Selinexor | 5.6 hours |
| Arm F (Melanoma) | Elimination Half-Life (t1/2) of Selinexor | 5.8 hours |
| Arm G (Other Solid Tumors) | Elimination Half-Life (t1/2) of Selinexor | 5.7 hours |
| Selinexor Dose: 30 mg/m^2 | Elimination Half-Life (t1/2) of Selinexor | 6.5 hours |
| Selinexor Dose: 35 mg/m^2 | Elimination Half-Life (t1/2) of Selinexor | 6.0 hours |
| Selinexor Dose: 39 mg/m^2 | Elimination Half-Life (t1/2) of Selinexor | 5.9 hours |
| Selinexor Dose: 40 mg/m^2 | Elimination Half-Life (t1/2) of Selinexor | 6.9 hours |
| Selinexor Dose: 45 mg/m^2 | Elimination Half-Life (t1/2) of Selinexor | 7.3 hours |
| Selinexor Dose: 50 mg/m^2 | Elimination Half-Life (t1/2) of Selinexor | 7.3 hours |
| Selinexor Dose: 55 mg/m^2 | Elimination Half-Life (t1/2) of Selinexor | 6.2 hours |
| Selinexor Dose: 58 mg/m^2 | Elimination Half-Life (t1/2) of Selinexor | 6.5 hours |
| Selinexor Dose: 65 mg/m^2 | Elimination Half-Life (t1/2) of Selinexor | 6.9 hours |
| Selinexor Dose: 80 mg/m^2 | Elimination Half-Life (t1/2) of Selinexor | 5.7 hours |
| Selinexor Dose: 85 mg/m^2 | Elimination Half-Life (t1/2) of Selinexor | 5.3 hours |
Secondary
Maximum Observed Plasma Concentration (Cmax) of Selinexor
Cmax was defined as maximum observed concentration, taken directly from the plasma concentration data.
Time frame: Cycle1, Day1: Pre-dose, 30, 60, 120, 240, 480 minutes
Population: Pharmacokinetic (PK) population consisted of all participants who received selinexor, and had evaluable PK for at least one dosing occasion. Data for the PK parameters were planned and analyzed based on doses and % coefficient of variation was not evaluable for arms where single participant was analyzed. Here, 'Overall number of participants analyzed' signifies participants with available data for the outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Arm A (Colorectal Cancer) | Maximum Observed Plasma Concentration (Cmax) of Selinexor | 30 nanogram per milliliter | — |
| Arm B (Gynecological Cancer) | Maximum Observed Plasma Concentration (Cmax) of Selinexor | 75 nanogram per milliliter | Geometric Coefficient of Variation 38.2 |
| Arm C (Squamous Cell Cancer) | Maximum Observed Plasma Concentration (Cmax) of Selinexor | 149 nanogram per milliliter | Geometric Coefficient of Variation 32 |
| Arm D (Castrate-resistant Prostate Cancer) | Maximum Observed Plasma Concentration (Cmax) of Selinexor | 168 nanogram per milliliter | — |
| Arm E (Glioblastoma Multiforme) | Maximum Observed Plasma Concentration (Cmax) of Selinexor | 220 nanogram per milliliter | Geometric Coefficient of Variation 44.5 |
| Arm F (Melanoma) | Maximum Observed Plasma Concentration (Cmax) of Selinexor | 308 nanogram per milliliter | Geometric Coefficient of Variation 12.1 |
| Arm G (Other Solid Tumors) | Maximum Observed Plasma Concentration (Cmax) of Selinexor | 293 nanogram per milliliter | Geometric Coefficient of Variation 58.3 |
| Selinexor Dose: 30 mg/m^2 | Maximum Observed Plasma Concentration (Cmax) of Selinexor | 413 nanogram per milliliter | Geometric Coefficient of Variation 46.7 |
| Selinexor Dose: 35 mg/m^2 | Maximum Observed Plasma Concentration (Cmax) of Selinexor | 349 nanogram per milliliter | Geometric Coefficient of Variation 25.4 |
| Selinexor Dose: 39 mg/m^2 | Maximum Observed Plasma Concentration (Cmax) of Selinexor | 528 nanogram per milliliter | Geometric Coefficient of Variation 12.5 |
| Selinexor Dose: 40 mg/m^2 | Maximum Observed Plasma Concentration (Cmax) of Selinexor | 442 nanogram per milliliter | Geometric Coefficient of Variation 63.6 |
| Selinexor Dose: 45 mg/m^2 | Maximum Observed Plasma Concentration (Cmax) of Selinexor | 390 nanogram per milliliter | Geometric Coefficient of Variation 25.3 |
| Selinexor Dose: 50 mg/m^2 | Maximum Observed Plasma Concentration (Cmax) of Selinexor | 507 nanogram per milliliter | Geometric Coefficient of Variation 57.8 |
| Selinexor Dose: 55 mg/m^2 | Maximum Observed Plasma Concentration (Cmax) of Selinexor | 505 nanogram per milliliter | Geometric Coefficient of Variation 18.2 |
| Selinexor Dose: 58 mg/m^2 | Maximum Observed Plasma Concentration (Cmax) of Selinexor | 561 nanogram per milliliter | Geometric Coefficient of Variation 45.4 |
| Selinexor Dose: 65 mg/m^2 | Maximum Observed Plasma Concentration (Cmax) of Selinexor | 896 nanogram per milliliter | Geometric Coefficient of Variation 71.7 |
| Selinexor Dose: 70 mg/m^2 | Maximum Observed Plasma Concentration (Cmax) of Selinexor | 521 nanogram per milliliter | — |
| Selinexor Dose: 80 mg/m^2 | Maximum Observed Plasma Concentration (Cmax) of Selinexor | 765 nanogram per milliliter | Geometric Coefficient of Variation 6.6 |
| Selinexor Dose: 85 mg/m^2 | Maximum Observed Plasma Concentration (Cmax) of Selinexor | 1371 nanogram per milliliter | Geometric Coefficient of Variation 31.1 |
Secondary
Number of Participants With Best Overall Response (BOR)
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.
Time frame: Up to maximum duration of 45 months
Population: Efficacy Population included all participants registered to the study who had either completed 1 cycle of treatment or discontinued treatment prior to completing the first cycle due to documented disease progression, death related to disease, or treatment-related toxicity. As pre-specified in the study Protocol data were not collected per dose level. The limited data available based on cancer stratification as pre-specified in the protocol is presented.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm A (Colorectal Cancer) | Number of Participants With Best Overall Response (BOR) | Not Evaluable | 9 Participants |
| Arm A (Colorectal Cancer) | Number of Participants With Best Overall Response (BOR) | Partial Response | 1 Participants |
| Arm A (Colorectal Cancer) | Number of Participants With Best Overall Response (BOR) | Progression (Objective) | 28 Participants |
| Arm A (Colorectal Cancer) | Number of Participants With Best Overall Response (BOR) | Complete Response | 0 Participants |
| Arm A (Colorectal Cancer) | Number of Participants With Best Overall Response (BOR) | Stable Disease | 15 Participants |
| Arm A (Colorectal Cancer) | Number of Participants With Best Overall Response (BOR) | Progressive Disease due to symptomatic deterioration | 4 Participants |
| Arm B (Gynecological Cancer) | Number of Participants With Best Overall Response (BOR) | Complete Response | 0 Participants |
| Arm B (Gynecological Cancer) | Number of Participants With Best Overall Response (BOR) | Progression (Objective) | 6 Participants |
| Arm B (Gynecological Cancer) | Number of Participants With Best Overall Response (BOR) | Not Evaluable | 2 Participants |
| Arm B (Gynecological Cancer) | Number of Participants With Best Overall Response (BOR) | Partial Response | 3 Participants |
| Arm B (Gynecological Cancer) | Number of Participants With Best Overall Response (BOR) | Progressive Disease due to symptomatic deterioration | 0 Participants |
| Arm B (Gynecological Cancer) | Number of Participants With Best Overall Response (BOR) | Stable Disease | 9 Participants |
| Arm C (Squamous Cell Cancer) | Number of Participants With Best Overall Response (BOR) | Progressive Disease due to symptomatic deterioration | 3 Participants |
| Arm C (Squamous Cell Cancer) | Number of Participants With Best Overall Response (BOR) | Stable Disease | 5 Participants |
| Arm C (Squamous Cell Cancer) | Number of Participants With Best Overall Response (BOR) | Not Evaluable | 5 Participants |
| Arm C (Squamous Cell Cancer) | Number of Participants With Best Overall Response (BOR) | Progression (Objective) | 8 Participants |
| Arm C (Squamous Cell Cancer) | Number of Participants With Best Overall Response (BOR) | Complete Response | 0 Participants |
| Arm C (Squamous Cell Cancer) | Number of Participants With Best Overall Response (BOR) | Partial Response | 0 Participants |
| Arm D (Castrate-resistant Prostate Cancer) | Number of Participants With Best Overall Response (BOR) | Progressive Disease due to symptomatic deterioration | 0 Participants |
| Arm D (Castrate-resistant Prostate Cancer) | Number of Participants With Best Overall Response (BOR) | Complete Response | 0 Participants |
| Arm D (Castrate-resistant Prostate Cancer) | Number of Participants With Best Overall Response (BOR) | Partial Response | 0 Participants |
| Arm D (Castrate-resistant Prostate Cancer) | Number of Participants With Best Overall Response (BOR) | Stable Disease | 11 Participants |
| Arm D (Castrate-resistant Prostate Cancer) | Number of Participants With Best Overall Response (BOR) | Progression (Objective) | 5 Participants |
| Arm D (Castrate-resistant Prostate Cancer) | Number of Participants With Best Overall Response (BOR) | Not Evaluable | 3 Participants |
| Arm E (Glioblastoma Multiforme) | Number of Participants With Best Overall Response (BOR) | Progression (Objective) | 5 Participants |
| Arm E (Glioblastoma Multiforme) | Number of Participants With Best Overall Response (BOR) | Partial Response | 0 Participants |
| Arm E (Glioblastoma Multiforme) | Number of Participants With Best Overall Response (BOR) | Progressive Disease due to symptomatic deterioration | 0 Participants |
| Arm E (Glioblastoma Multiforme) | Number of Participants With Best Overall Response (BOR) | Not Evaluable | 1 Participants |
| Arm E (Glioblastoma Multiforme) | Number of Participants With Best Overall Response (BOR) | Stable Disease | 0 Participants |
| Arm E (Glioblastoma Multiforme) | Number of Participants With Best Overall Response (BOR) | Complete Response | 0 Participants |
| Arm F (Melanoma) | Number of Participants With Best Overall Response (BOR) | Stable Disease | 3 Participants |
| Arm F (Melanoma) | Number of Participants With Best Overall Response (BOR) | Progression (Objective) | 4 Participants |
| Arm F (Melanoma) | Number of Participants With Best Overall Response (BOR) | Partial Response | 1 Participants |
| Arm F (Melanoma) | Number of Participants With Best Overall Response (BOR) | Progressive Disease due to symptomatic deterioration | 1 Participants |
| Arm F (Melanoma) | Number of Participants With Best Overall Response (BOR) | Complete Response | 1 Participants |
| Arm F (Melanoma) | Number of Participants With Best Overall Response (BOR) | Not Evaluable | 4 Participants |
| Arm G (Other Solid Tumors) | Number of Participants With Best Overall Response (BOR) | Stable Disease | 20 Participants |
| Arm G (Other Solid Tumors) | Number of Participants With Best Overall Response (BOR) | Partial Response | 1 Participants |
| Arm G (Other Solid Tumors) | Number of Participants With Best Overall Response (BOR) | Not Evaluable | 14 Participants |
| Arm G (Other Solid Tumors) | Number of Participants With Best Overall Response (BOR) | Progression (Objective) | 10 Participants |
| Arm G (Other Solid Tumors) | Number of Participants With Best Overall Response (BOR) | Progressive Disease due to symptomatic deterioration | 1 Participants |
| Arm G (Other Solid Tumors) | Number of Participants With Best Overall Response (BOR) | Complete Response | 0 Participants |
Secondary
Overall Survival (OS)
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.
Time frame: From first dose of study drug administration to date of death (maximum duration of 45 months)
Population: Efficacy Population included all participants registered to the study who had either completed 1 cycle of treatment or discontinued treatment prior to completing the first cycle due to documented disease progression, death related to disease, or treatment-related toxicity. As pre-specified in the study Protocol data were not collected per dose level. The limited data available based on cancer stratification as pre-specified in the protocol is presented.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A (Colorectal Cancer) | Overall Survival (OS) | 136 Days |
| Arm B (Gynecological Cancer) | Overall Survival (OS) | 491 Days |
| Arm C (Squamous Cell Cancer) | Overall Survival (OS) | 161 Days |
| Arm D (Castrate-resistant Prostate Cancer) | Overall Survival (OS) | 354 Days |
| Arm E (Glioblastoma Multiforme) | Overall Survival (OS) | 103 Days |
| Arm F (Melanoma) | Overall Survival (OS) | NA Days |
| Arm G (Other Solid Tumors) | Overall Survival (OS) | 290 Days |
Secondary
Percentage of Participants With Objective Response
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.
Time frame: Up to maximum duration of 45 months
Population: Efficacy Population included all participants registered to the study who had either completed 1 cycle of treatment or discontinued treatment prior to completing the first cycle due to documented disease progression, death related to disease, or treatment-related toxicity. As pre-specified in the study Protocol data were not collected per dose level. The limited data available based on cancer stratification as pre-specified in the protocol is presented.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A (Colorectal Cancer) | Percentage of Participants With Objective Response | 1.8 percentage of participants |
| Arm B (Gynecological Cancer) | Percentage of Participants With Objective Response | 15.0 percentage of participants |
| Arm C (Squamous Cell Cancer) | Percentage of Participants With Objective Response | 0 percentage of participants |
| Arm D (Castrate-resistant Prostate Cancer) | Percentage of Participants With Objective Response | 0 percentage of participants |
| Arm E (Glioblastoma Multiforme) | Percentage of Participants With Objective Response | 0 percentage of participants |
| Arm F (Melanoma) | Percentage of Participants With Objective Response | 14.3 percentage of participants |
| Arm G (Other Solid Tumors) | Percentage of Participants With Objective Response | 2.2 percentage of participants |
Secondary
Progression-free Survival (PFS)
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.
Time frame: From start of study drug administration until PD or discontinuation from the study or death (maximum duration of 45 months)
Population: Efficacy Population included all participants registered to the study who had either completed 1 cycle of treatment or discontinued treatment prior to completing the first cycle due to documented disease progression, death related to disease, or treatment-related toxicity. As pre-specified in the study Protocol data were not collected per dose level. The limited data available based on cancer stratification as pre-specified in the protocol is presented.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A (Colorectal Cancer) | Progression-free Survival (PFS) | 53 Days |
| Arm B (Gynecological Cancer) | Progression-free Survival (PFS) | 119 Days |
| Arm C (Squamous Cell Cancer) | Progression-free Survival (PFS) | 52 Days |
| Arm D (Castrate-resistant Prostate Cancer) | Progression-free Survival (PFS) | 127 Days |
| Arm E (Glioblastoma Multiforme) | Progression-free Survival (PFS) | 41 Days |
| Arm F (Melanoma) | Progression-free Survival (PFS) | 52 Days |
| Arm G (Other Solid Tumors) | Progression-free Survival (PFS) | 88 Days |
Secondary
Time of Maximum Observed Concentration in Plasma (Tmax) of Selinexor
Tmax was defined as time of first observation of Cmax, taken directly from the plasma concentration data.
Time frame: Cycle1, Day1: Pre-dose, 30, 60, 120, 240, 480 minutes
Population: PK population consisted of all participants who received selinexor, and had evaluable PK for at least one dosing occasion. Data for the PK parameters were planned and analyzed based on doses and full range data was not evaluable for arms with single participant. Here, 'Overall number of participants analyzed' signifies participants with available data for the outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A (Colorectal Cancer) | Time of Maximum Observed Concentration in Plasma (Tmax) of Selinexor | 1 hours |
| Arm B (Gynecological Cancer) | Time of Maximum Observed Concentration in Plasma (Tmax) of Selinexor | 2.1 hours |
| Arm C (Squamous Cell Cancer) | Time of Maximum Observed Concentration in Plasma (Tmax) of Selinexor | 2.0 hours |
| Arm D (Castrate-resistant Prostate Cancer) | Time of Maximum Observed Concentration in Plasma (Tmax) of Selinexor | 2.1 hours |
| Arm E (Glioblastoma Multiforme) | Time of Maximum Observed Concentration in Plasma (Tmax) of Selinexor | 2.3 hours |
| Arm F (Melanoma) | Time of Maximum Observed Concentration in Plasma (Tmax) of Selinexor | 2.1 hours |
| Arm G (Other Solid Tumors) | Time of Maximum Observed Concentration in Plasma (Tmax) of Selinexor | 3.1 hours |
| Selinexor Dose: 30 mg/m^2 | Time of Maximum Observed Concentration in Plasma (Tmax) of Selinexor | 2.9 hours |
| Selinexor Dose: 35 mg/m^2 | Time of Maximum Observed Concentration in Plasma (Tmax) of Selinexor | 3.8 hours |
| Selinexor Dose: 39 mg/m^2 | Time of Maximum Observed Concentration in Plasma (Tmax) of Selinexor | 3.1 hours |
| Selinexor Dose: 40 mg/m^2 | Time of Maximum Observed Concentration in Plasma (Tmax) of Selinexor | 3.9 hours |
| Selinexor Dose: 45 mg/m^2 | Time of Maximum Observed Concentration in Plasma (Tmax) of Selinexor | 4.2 hours |
| Selinexor Dose: 50 mg/m^2 | Time of Maximum Observed Concentration in Plasma (Tmax) of Selinexor | 3.0 hours |
| Selinexor Dose: 55 mg/m^2 | Time of Maximum Observed Concentration in Plasma (Tmax) of Selinexor | 3.8 hours |
| Selinexor Dose: 58 mg/m^2 | Time of Maximum Observed Concentration in Plasma (Tmax) of Selinexor | 3.1 hours |
| Selinexor Dose: 65 mg/m^2 | Time of Maximum Observed Concentration in Plasma (Tmax) of Selinexor | 2.0 hours |
| Selinexor Dose: 70 mg/m^2 | Time of Maximum Observed Concentration in Plasma (Tmax) of Selinexor | 8.0 hours |
| Selinexor Dose: 80 mg/m^2 | Time of Maximum Observed Concentration in Plasma (Tmax) of Selinexor | 3.9 hours |
| Selinexor Dose: 85 mg/m^2 | Time of Maximum Observed Concentration in Plasma (Tmax) of Selinexor | 3.9 hours |