NHL, Solid Tumors
Conditions
Keywords
PAK4, KPT-9274, Karyopharm, NHL, Solid Tumors, NAMPT, Melanoma
Brief summary
This study will evaluate the safety, tolerability, and efficacy of oral KPT-9274 for the treatment of patients with advanced solid malignancies or non-Hodgkin's lymphoma (NHL).
Detailed description
This is a first-in-human, multi-center, open-label clinical study with separate Dose Escalation and Expansion Phases to assess preliminary safety, tolerability, and efficacy of KPT-9274, a dual inhibitor of PAK4 and NAMPT, in patients with advanced solid malignancies (including sarcoma, colon, lung, melanoma, etc.) or NHL for which all standard therapeutic options considered useful by the investigator have been exhausted.
Sponsors
Karyopharm Therapeutics Inc
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Participants must meet all of the following inclusion criteria to be eligible to enroll in the Part C of this study. 1. Should have unresectable advanced, recurrent or metastatic melanoma and must have objective and measurable melanoma by RECIST 1.1 after disease progression on a prior anti-PD-1 or anti-PD-L1 therapy. 2. ECOG performance status of ≤ 2. 3. Life expectancy of ≥ 3 months. 4. Adequate hepatic function: * Total bilirubin \< 1.5 times the ULN (except participants with Gilbert's syndrome \[hereditary indirect hyperbilirubinemia\] who must have a total bilirubin of ≤ 3 times ULN), * AST and ALT ≤ 2.5 times ULN (except participants with known liver involvement of their advanced solid malignancy who must have an AST and ALT ≤ 5.0 times ULN). 5. Adequate renal function: * Estimated creatinine clearance of ≥ 60 mL/min, calculated using the formula of Cockroft and Gault (140-Age) Mass (kg)/(72 creatinine mg/dL); multiply by 0.85 if female. 6. Adequate hematopoietic function: * Total WBC count ≥ 1500/mm³, ANC ≥ 1000/mm³, Hb ≥ 10.0 g/dL, platelet count ≥ 100,000/mm³
Exclusion criteria
Participants meeting any of the following
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Duration of Response (DOR) | Up to 44 weeks | The DOR was defined as the duration of time from the first meeting CR or PR measurement criteria (whichever occurs first) until the first date diseases progression. |
| Percentage of Participants With Overall Response Rate (ORR) | From date of randomization up to 44 weeks | The ORR was defined as percentage of participants who had a response of partial response (PR) or complete response (CR). The PR was achieved when a participant had at least a 30 percent (%) decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. The CR was achieved in a participant when all target lesions disappeared. Any pathological lymph nodes (whether target or non target) must have reduction in the short axis to \<10 millimeter (mm). |
| Percentage of Participants With Disease Control Rate (DCR) | From date of the first study treatment up to 44 weeks | The DCR was defined as percentage of participants who have a response of CR, PR, and stable disease (SD) \>= 16 weeks, DCR = CR + PR+ SD. The PR was achieved when a participant had at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. The CR was achieved in a participant when all target lesions disappeared. Any pathological lymph nodes (whether target or non-target) must have reduction in the short axis to \<10mm. The SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD). |
| Progression-free Survival (PFS) | From the date of first study treatment until the first date of PD, or death due (up to 44 weeks) | The PFS was defined as the duration of time from date of the first study treatment until the first date that PD is objectively documented or death due to any cause. The PD is 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 5mm. Appearance of one or more new lesions will also constitute PD. |
| Overall Survival (OS) | From date of the first study treatment until death (up to 44 weeks) | The OS was defined as the duration of time from date of the first study treatment until death from any cause. |
| Time to Progression (TTP) | From date of the first study treatment until the first date of PD or death (up to 44 weeks) | The TTP was defined as the duration of time from date of the first study treatment until the first date that PD was objectively documented or death due to PD. |
| Maximum Tolerated Dose (MTD) for KPT-9274 | From start of study drug administration up to 44 weeks | The MTD was defined as the highest dose at which less than or equal to (\<=) 1 participant experienced a dose limiting toxicity (DLT) in Cycle 1. A DLT was defined as an adverse event (AE) or abnormal laboratory value occurring within the first 28 days of treatment of KPT-9274, excluding those clearly caused by underlying disease, disease progression, or external factors. |
| Number of Dose Limiting Toxicities (DLT) Experienced by Participants | At Cycle 1 only (28-day cycle) | A DLT was defined as an AE or abnormal laboratory value occurring within the first 28 days of KPT-9274 treatment, excluding those clearly caused by underlying disease, disease progression, or extraneous causes, and meets any of the criteria for defining dose limiting toxicities. |
| Number of Participants With Adverse Event (AE) of Severity Grade >= 3 or 4, Serious AEs, and AEs Leading to Treatment Discontinuation | From start of study drug administration up to 49 weeks | The AE severity was graded on a scale from 1 to 4 using the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 4.03; any events not specifically listed in the scale were defined as: Grade 1 is mild; Grade 2 is moderate; Grade 3 is severe or medically significant; Grade 4 is life-threatening. An SAE was any untoward medical occurrence that at any dose met one, more of the following criteria: results in death, life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent, significant disability/incapacity, a congenital abnormality/birth defect, an important medical event. The AE leading to treatment discontinuation in the study. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time-to-peak Plasma Concentration (Tmax) in Participants Who Received KPT-9274 | Cycle 1 and 2: Pre-dose, 3, 6, 8, 24, and 48 hours post-dose (each cycle =28 days) | Time taken by KPT-9274 to achieve maximum plasma concentration after the first dose administration. |
| Terminal Half-life (T1/2) in Participants Who Received KPT-9274 | Cycle 1 and 2: Pre-dose, 3, 6, 8, 24, and 48 hours post-dose (each cycle =28 days) | The T1/2 was defied as the time it takes for the concentration of KPT-9274 in the plasma to be reduced by 50%. |
| Volume of Distribution (Vd/F) in Participants Who Received KPT-9274 | Cycle 1 and 2: Pre-dose, 3, 6, 8, 24, and 48 hours post-dose (each cycle =28 days) | The Vd/F was defined as MRT\*CL/F, where MRT is the mean residence time (calculated as AUMC\[0-tau\]/AUC\[0-tau\], where AUMC\[0-tau\] is the area under the first moment curve determined as the area under the concentration\*time versus time curve). |
| Apparent Plasma Clearance (CL/F) in Participants Who Received KPT-9274 | Cycle 1 and 2: Pre-dose, 3, 6, 8, 24, and 48 hours post-dose (each cycle =28 days) | The CL/F was calculated as the KPT-9274 dose administered divided by the area-under-the-curve of KPT-9274 plasma concentration versus (vs) time. |
| Maximum Plasma Concentration (Cmax) in Participants Who Received KPT-9274 | Cycle 1 and 2: Pre-dose, 3, 6, 8, 24, and 48 hours post-dose (each cycle =28 days) | Cmax achieved by the KPT-9274 after the first dose administrations. |
Countries
Canada, United States
Participant flow
Recruitment details
This study was conducted at 8 investigative sites in the United States and Canada from 08 Jun 2016 to 26 Jan 2021.
Pre-assignment details
A total of 60 participants were enrolled and randomized to receive treatment in 2 phases, Dose Escalation (Part A \[23 participants\] and Part B \[27 participants\]; and Dose Expansion Phases (Part C \[10 participants\]). Study was terminated prematurely due to a lack of efficacy during primary analysis and therefore, efficacy, pharmacokinetic (PK) and pharmacodynamics (PDn) assessments were not determined.
Participants by arm
| Arm | Count |
|---|---|
| Part A: KPT-9274 10mg Participants received 10mg of oral tablets of KPT-9274 three times a week every other day during each 28 day cycle. | 3 |
| Part A: KPT-9274 20mg Participants received 20mg of oral tablets of KPT-9274 three times a week every other day during each 28 day cycle. | 3 |
| Part A: KPT-9274 30mg Participants received 30mg of oral tablets of KPT-9274 three times a week every other day during each 28 day cycle. | 5 |
| Part A: KPT-9274 40mg Participants received 40mg of oral tablets of KPT-9274 three times a week every other day during each 28 day cycle. | 7 |
| Part A: KPT-9274 40mg BIW Participants received KPT-9274 40mg of oral tablet BIW during each 28-day cycle. | 5 |
| Part B: KPT-9274 30mg + Niacin 500mg Participants received KPT-9274 30mg of oral tablet along with a starting dose of 500mg niacin extended release (ER) orally three times a week every other day during each 28-day cycle. | 3 |
| Part B: KPT-9274 40mg + Niacin 500mg Participants received KPT-9274 40mg of oral tablet along with a starting dose of 500mg niacin ER orally three times a week every other day during each 28-day cycle. | 4 |
| Part B: KPT-9274 60mg + Niacin 500mg Participants received KPT-9274 60mg of oral tablet along with a starting dose of 500mg niacin ER orally three times a week every other day during each 28-day cycle. | 12 |
| Part B: KPT-9274 80mg + Niacin 500mg Participants received KPT-9274 80mg of oral tablet along with a starting dose of 500mg niacin ER orally three times a week every other day during each 28-day cycle. | 7 |
| Part B: KPT-9274 100mg + Niacin 500mg Participants received KPT-9274 100mg of oral tablet along with a starting dose of 500mg niacin ER orally three times a week every other day during each 28-day cycle | 1 |
| Part C: KPT-9274 20mg + Nivolumab 480mg Participants received KPT-9274 20mg of oral tablet three times a week every other day during each 28-day cycle along with 480mg of nivolumab intravenous infusion on Day 1 of each cycle (once every 4-week cycle). | 1 |
| Part C: KPT-9274 30mg + Nivolumab 480mg Participants received KPT-9274 30mg of oral tablet three times a week every other day during each 28-day cycle along with 480mg of nivolumab intravenous infusion on Day 1 of each cycle (once every 4-week cycle). | 5 |
| Part C: KPT-9274 40mg + Nivolumab 480mg Participants received KPT-9274 40mg of oral tablet three times a week every other day during each 28-day cycle along with 480mg of nivolumab intravenous infusion on Day 1 of each cycle (once every 4-week cycle). | 4 |
| Total | 60 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 | FG009 | FG010 | FG011 | FG012 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 1 | 2 | 1 | 0 | 1 | 0 | 2 | 0 | 0 | 0 | 1 |
| Overall Study | Clinical progression | 0 | 0 | 2 | 1 | 0 | 2 | 1 | 4 | 0 | 0 | 1 | 2 | 0 |
| Overall Study | Disease progression | 3 | 3 | 2 | 4 | 4 | 1 | 2 | 8 | 5 | 1 | 0 | 3 | 2 |
| Overall Study | Other | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Total | Part A: KPT-9274 10mg | Part A: KPT-9274 20mg | Part A: KPT-9274 30mg | Part A: KPT-9274 40mg | Part A: KPT-9274 40mg BIW | Part B: KPT-9274 30mg + Niacin 500mg | Part B: KPT-9274 40mg + Niacin 500mg | Part B: KPT-9274 60mg + Niacin 500mg | Part B: KPT-9274 80mg + Niacin 500mg | Part B: KPT-9274 100mg + Niacin 500mg | Part C: KPT-9274 20mg + Nivolumab 480mg | Part C: KPT-9274 30mg + Nivolumab 480mg | Part C: KPT-9274 40mg + Nivolumab 480mg |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 59.8 Years STANDARD_DEVIATION 12.26 | 55.3 Years STANDARD_DEVIATION 16.62 | 63.7 Years STANDARD_DEVIATION 3.21 | 56.6 Years STANDARD_DEVIATION 6.77 | 59.6 Years STANDARD_DEVIATION 17.17 | 68.8 Years STANDARD_DEVIATION 4.66 | 44.0 Years STANDARD_DEVIATION 14.73 | 65.0 Years STANDARD_DEVIATION 4.55 | 61.8 Years STANDARD_DEVIATION 9.69 | 55.0 Years STANDARD_DEVIATION 15 | 38.0 Years | 67.0 Years | 63.6 Years STANDARD_DEVIATION 14.36 | 62.0 Years STANDARD_DEVIATION 10.2 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 49 Participants | 3 Participants | 3 Participants | 4 Participants | 5 Participants | 5 Participants | 2 Participants | 4 Participants | 8 Participants | 5 Participants | 0 Participants | 1 Participants | 5 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 9 Participants | 0 Participants | 0 Participants | 1 Participants | 2 Participants | 0 Participants | 1 Participants | 0 Participants | 2 Participants | 2 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 5 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 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 | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 47 Participants | 2 Participants | 3 Participants | 3 Participants | 5 Participants | 4 Participants | 2 Participants | 4 Participants | 10 Participants | 5 Participants | 1 Participants | 1 Participants | 4 Participants | 3 Participants |
| Sex: Female, Male Female | 26 Participants | 1 Participants | 0 Participants | 3 Participants | 2 Participants | 1 Participants | 1 Participants | 3 Participants | 6 Participants | 2 Participants | 0 Participants | 0 Participants | 5 Participants | 2 Participants |
| Sex: Female, Male Male | 34 Participants | 2 Participants | 3 Participants | 2 Participants | 5 Participants | 4 Participants | 2 Participants | 1 Participants | 6 Participants | 5 Participants | 1 Participants | 1 Participants | 0 Participants | 2 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 | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk | EG010 affected / at risk | EG011 affected / at risk | EG012 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 2 / 3 | 2 / 3 | 3 / 5 | 5 / 7 | 1 / 5 | 3 / 3 | 3 / 4 | 6 / 12 | 4 / 7 | 1 / 1 | 1 / 1 | 2 / 5 | 3 / 4 |
| other Total, other adverse events | 3 / 3 | 2 / 3 | 5 / 5 | 7 / 7 | 5 / 5 | 3 / 3 | 4 / 4 | 12 / 12 | 7 / 7 | 1 / 1 | 1 / 1 | 5 / 5 | 4 / 4 |
| serious Total, serious adverse events | 0 / 3 | 2 / 3 | 2 / 5 | 3 / 7 | 0 / 5 | 1 / 3 | 1 / 4 | 6 / 12 | 1 / 7 | 1 / 1 | 1 / 1 | 2 / 5 | 2 / 4 |
Outcome results
Primary
Duration of Response (DOR)
The DOR was defined as the duration of time from the first meeting CR or PR measurement criteria (whichever occurs first) until the first date diseases progression.
Time frame: Up to 44 weeks
Population: Study was terminated prematurely due to a lack of efficacy during primary analysis stage. Data for this outcome measure was not collected or analyzed as per planned analysis.
Primary
Maximum Tolerated Dose (MTD) for KPT-9274
The MTD was defined as the highest dose at which less than or equal to (\<=) 1 participant experienced a dose limiting toxicity (DLT) in Cycle 1. A DLT was defined as an adverse event (AE) or abnormal laboratory value occurring within the first 28 days of treatment of KPT-9274, excluding those clearly caused by underlying disease, disease progression, or external factors.
Time frame: From start of study drug administration up to 44 weeks
Population: Study was terminated prematurely due to a lack of efficacy. Therefore, the data were not determined due to insufficient number of participants with events.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part A: KPT-9274 10mg | Maximum Tolerated Dose (MTD) for KPT-9274 | NA Participants |
| Part A: KPT-9274 20mg | Maximum Tolerated Dose (MTD) for KPT-9274 | NA Participants |
| Part A: KPT-9274 30mg | Maximum Tolerated Dose (MTD) for KPT-9274 | NA Participants |
| Part A: KPT-9274 40mg | Maximum Tolerated Dose (MTD) for KPT-9274 | NA Participants |
| Part A: KPT-9274 40mg BIW | Maximum Tolerated Dose (MTD) for KPT-9274 | NA Participants |
| Part B: KPT-9274 30mg + Niacin 500mg | Maximum Tolerated Dose (MTD) for KPT-9274 | NA Participants |
| Part B: KPT-9274 40mg + Niacin 500mg | Maximum Tolerated Dose (MTD) for KPT-9274 | NA Participants |
| Part B: KPT-9274 60mg + Niacin 500mg | Maximum Tolerated Dose (MTD) for KPT-9274 | NA Participants |
| Part B: KPT-9274 80mg + Niacin 500mg | Maximum Tolerated Dose (MTD) for KPT-9274 | NA Participants |
| Part B: KPT-9274 100mg + Niacin 500mg | Maximum Tolerated Dose (MTD) for KPT-9274 | NA Participants |
| Part C: KPT-9274 20mg + Nivolumab 480mg | Maximum Tolerated Dose (MTD) for KPT-9274 | NA Participants |
| Part C: KPT-9274 30mg + Nivolumab 480mg | Maximum Tolerated Dose (MTD) for KPT-9274 | NA Participants |
| Part C: KPT-9274 40mg + Nivolumab 480mg | Maximum Tolerated Dose (MTD) for KPT-9274 | NA Participants |
Primary
Number of Dose Limiting Toxicities (DLT) Experienced by Participants
A DLT was defined as an AE or abnormal laboratory value occurring within the first 28 days of KPT-9274 treatment, excluding those clearly caused by underlying disease, disease progression, or extraneous causes, and meets any of the criteria for defining dose limiting toxicities.
Time frame: At Cycle 1 only (28-day cycle)
Population: The safety population consisted of all participants who had received at least 1 dose of the study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part A: KPT-9274 10mg | Number of Dose Limiting Toxicities (DLT) Experienced by Participants | 0 Number of DLTs |
| Part A: KPT-9274 20mg | Number of Dose Limiting Toxicities (DLT) Experienced by Participants | 0 Number of DLTs |
| Part A: KPT-9274 30mg | Number of Dose Limiting Toxicities (DLT) Experienced by Participants | 0 Number of DLTs |
| Part A: KPT-9274 40mg | Number of Dose Limiting Toxicities (DLT) Experienced by Participants | 1 Number of DLTs |
| Part A: KPT-9274 40mg BIW | Number of Dose Limiting Toxicities (DLT) Experienced by Participants | 0 Number of DLTs |
| Part B: KPT-9274 30mg + Niacin 500mg | Number of Dose Limiting Toxicities (DLT) Experienced by Participants | 0 Number of DLTs |
| Part B: KPT-9274 40mg + Niacin 500mg | Number of Dose Limiting Toxicities (DLT) Experienced by Participants | 0 Number of DLTs |
| Part B: KPT-9274 60mg + Niacin 500mg | Number of Dose Limiting Toxicities (DLT) Experienced by Participants | 0 Number of DLTs |
| Part B: KPT-9274 80mg + Niacin 500mg | Number of Dose Limiting Toxicities (DLT) Experienced by Participants | 2 Number of DLTs |
| Part B: KPT-9274 100mg + Niacin 500mg | Number of Dose Limiting Toxicities (DLT) Experienced by Participants | 0 Number of DLTs |
| Part C: KPT-9274 20mg + Nivolumab 480mg | Number of Dose Limiting Toxicities (DLT) Experienced by Participants | 0 Number of DLTs |
| Part C: KPT-9274 30mg + Nivolumab 480mg | Number of Dose Limiting Toxicities (DLT) Experienced by Participants | 0 Number of DLTs |
| Part C: KPT-9274 40mg + Nivolumab 480mg | Number of Dose Limiting Toxicities (DLT) Experienced by Participants | 0 Number of DLTs |
Primary
Number of Participants With Adverse Event (AE) of Severity Grade >= 3 or 4, Serious AEs, and AEs Leading to Treatment Discontinuation
The AE severity was graded on a scale from 1 to 4 using the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 4.03; any events not specifically listed in the scale were defined as: Grade 1 is mild; Grade 2 is moderate; Grade 3 is severe or medically significant; Grade 4 is life-threatening. An SAE was any untoward medical occurrence that at any dose met one, more of the following criteria: results in death, life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent, significant disability/incapacity, a congenital abnormality/birth defect, an important medical event. The AE leading to treatment discontinuation in the study.
Time frame: From start of study drug administration up to 49 weeks
Population: The safety population consisted of all participants who had received at least 1 dose of the study treatment.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part A: KPT-9274 10mg | Number of Participants With Adverse Event (AE) of Severity Grade >= 3 or 4, Serious AEs, and AEs Leading to Treatment Discontinuation | Maximum Grade 3/4 AEs | 1 Participants |
| Part A: KPT-9274 10mg | Number of Participants With Adverse Event (AE) of Severity Grade >= 3 or 4, Serious AEs, and AEs Leading to Treatment Discontinuation | AEs Leading to Study Treatment Discontinuation | 0 Participants |
| Part A: KPT-9274 10mg | Number of Participants With Adverse Event (AE) of Severity Grade >= 3 or 4, Serious AEs, and AEs Leading to Treatment Discontinuation | Maximum Grade 4 AEs | 0 Participants |
| Part A: KPT-9274 10mg | Number of Participants With Adverse Event (AE) of Severity Grade >= 3 or 4, Serious AEs, and AEs Leading to Treatment Discontinuation | Serious AEs | 0 Participants |
| Part A: KPT-9274 20mg | Number of Participants With Adverse Event (AE) of Severity Grade >= 3 or 4, Serious AEs, and AEs Leading to Treatment Discontinuation | Maximum Grade 3/4 AEs | 2 Participants |
| Part A: KPT-9274 20mg | Number of Participants With Adverse Event (AE) of Severity Grade >= 3 or 4, Serious AEs, and AEs Leading to Treatment Discontinuation | Serious AEs | 2 Participants |
| Part A: KPT-9274 20mg | Number of Participants With Adverse Event (AE) of Severity Grade >= 3 or 4, Serious AEs, and AEs Leading to Treatment Discontinuation | Maximum Grade 4 AEs | 0 Participants |
| Part A: KPT-9274 20mg | Number of Participants With Adverse Event (AE) of Severity Grade >= 3 or 4, Serious AEs, and AEs Leading to Treatment Discontinuation | AEs Leading to Study Treatment Discontinuation | 0 Participants |
| Part A: KPT-9274 30mg | Number of Participants With Adverse Event (AE) of Severity Grade >= 3 or 4, Serious AEs, and AEs Leading to Treatment Discontinuation | Serious AEs | 2 Participants |
| Part A: KPT-9274 30mg | Number of Participants With Adverse Event (AE) of Severity Grade >= 3 or 4, Serious AEs, and AEs Leading to Treatment Discontinuation | AEs Leading to Study Treatment Discontinuation | 1 Participants |
| Part A: KPT-9274 30mg | Number of Participants With Adverse Event (AE) of Severity Grade >= 3 or 4, Serious AEs, and AEs Leading to Treatment Discontinuation | Maximum Grade 3/4 AEs | 5 Participants |
| Part A: KPT-9274 30mg | Number of Participants With Adverse Event (AE) of Severity Grade >= 3 or 4, Serious AEs, and AEs Leading to Treatment Discontinuation | Maximum Grade 4 AEs | 1 Participants |
| Part A: KPT-9274 40mg | Number of Participants With Adverse Event (AE) of Severity Grade >= 3 or 4, Serious AEs, and AEs Leading to Treatment Discontinuation | Serious AEs | 3 Participants |
| Part A: KPT-9274 40mg | Number of Participants With Adverse Event (AE) of Severity Grade >= 3 or 4, Serious AEs, and AEs Leading to Treatment Discontinuation | AEs Leading to Study Treatment Discontinuation | 2 Participants |
| Part A: KPT-9274 40mg | Number of Participants With Adverse Event (AE) of Severity Grade >= 3 or 4, Serious AEs, and AEs Leading to Treatment Discontinuation | Maximum Grade 4 AEs | 3 Participants |
| Part A: KPT-9274 40mg | Number of Participants With Adverse Event (AE) of Severity Grade >= 3 or 4, Serious AEs, and AEs Leading to Treatment Discontinuation | Maximum Grade 3/4 AEs | 7 Participants |
| Part A: KPT-9274 40mg BIW | Number of Participants With Adverse Event (AE) of Severity Grade >= 3 or 4, Serious AEs, and AEs Leading to Treatment Discontinuation | Maximum Grade 3/4 AEs | 3 Participants |
| Part A: KPT-9274 40mg BIW | Number of Participants With Adverse Event (AE) of Severity Grade >= 3 or 4, Serious AEs, and AEs Leading to Treatment Discontinuation | Serious AEs | 0 Participants |
| Part A: KPT-9274 40mg BIW | Number of Participants With Adverse Event (AE) of Severity Grade >= 3 or 4, Serious AEs, and AEs Leading to Treatment Discontinuation | Maximum Grade 4 AEs | 0 Participants |
| Part A: KPT-9274 40mg BIW | Number of Participants With Adverse Event (AE) of Severity Grade >= 3 or 4, Serious AEs, and AEs Leading to Treatment Discontinuation | AEs Leading to Study Treatment Discontinuation | 1 Participants |
| Part B: KPT-9274 30mg + Niacin 500mg | Number of Participants With Adverse Event (AE) of Severity Grade >= 3 or 4, Serious AEs, and AEs Leading to Treatment Discontinuation | Maximum Grade 3/4 AEs | 2 Participants |
| Part B: KPT-9274 30mg + Niacin 500mg | Number of Participants With Adverse Event (AE) of Severity Grade >= 3 or 4, Serious AEs, and AEs Leading to Treatment Discontinuation | Maximum Grade 4 AEs | 1 Participants |
| Part B: KPT-9274 30mg + Niacin 500mg | Number of Participants With Adverse Event (AE) of Severity Grade >= 3 or 4, Serious AEs, and AEs Leading to Treatment Discontinuation | AEs Leading to Study Treatment Discontinuation | 0 Participants |
| Part B: KPT-9274 30mg + Niacin 500mg | Number of Participants With Adverse Event (AE) of Severity Grade >= 3 or 4, Serious AEs, and AEs Leading to Treatment Discontinuation | Serious AEs | 1 Participants |
| Part B: KPT-9274 40mg + Niacin 500mg | Number of Participants With Adverse Event (AE) of Severity Grade >= 3 or 4, Serious AEs, and AEs Leading to Treatment Discontinuation | Maximum Grade 3/4 AEs | 3 Participants |
| Part B: KPT-9274 40mg + Niacin 500mg | Number of Participants With Adverse Event (AE) of Severity Grade >= 3 or 4, Serious AEs, and AEs Leading to Treatment Discontinuation | Maximum Grade 4 AEs | 0 Participants |
| Part B: KPT-9274 40mg + Niacin 500mg | Number of Participants With Adverse Event (AE) of Severity Grade >= 3 or 4, Serious AEs, and AEs Leading to Treatment Discontinuation | Serious AEs | 1 Participants |
| Part B: KPT-9274 40mg + Niacin 500mg | Number of Participants With Adverse Event (AE) of Severity Grade >= 3 or 4, Serious AEs, and AEs Leading to Treatment Discontinuation | AEs Leading to Study Treatment Discontinuation | 1 Participants |
| Part B: KPT-9274 60mg + Niacin 500mg | Number of Participants With Adverse Event (AE) of Severity Grade >= 3 or 4, Serious AEs, and AEs Leading to Treatment Discontinuation | Serious AEs | 6 Participants |
| Part B: KPT-9274 60mg + Niacin 500mg | Number of Participants With Adverse Event (AE) of Severity Grade >= 3 or 4, Serious AEs, and AEs Leading to Treatment Discontinuation | Maximum Grade 4 AEs | 0 Participants |
| Part B: KPT-9274 60mg + Niacin 500mg | Number of Participants With Adverse Event (AE) of Severity Grade >= 3 or 4, Serious AEs, and AEs Leading to Treatment Discontinuation | AEs Leading to Study Treatment Discontinuation | 0 Participants |
| Part B: KPT-9274 60mg + Niacin 500mg | Number of Participants With Adverse Event (AE) of Severity Grade >= 3 or 4, Serious AEs, and AEs Leading to Treatment Discontinuation | Maximum Grade 3/4 AEs | 10 Participants |
| Part B: KPT-9274 80mg + Niacin 500mg | Number of Participants With Adverse Event (AE) of Severity Grade >= 3 or 4, Serious AEs, and AEs Leading to Treatment Discontinuation | Serious AEs | 1 Participants |
| Part B: KPT-9274 80mg + Niacin 500mg | Number of Participants With Adverse Event (AE) of Severity Grade >= 3 or 4, Serious AEs, and AEs Leading to Treatment Discontinuation | Maximum Grade 3/4 AEs | 7 Participants |
| Part B: KPT-9274 80mg + Niacin 500mg | Number of Participants With Adverse Event (AE) of Severity Grade >= 3 or 4, Serious AEs, and AEs Leading to Treatment Discontinuation | AEs Leading to Study Treatment Discontinuation | 2 Participants |
| Part B: KPT-9274 80mg + Niacin 500mg | Number of Participants With Adverse Event (AE) of Severity Grade >= 3 or 4, Serious AEs, and AEs Leading to Treatment Discontinuation | Maximum Grade 4 AEs | 0 Participants |
| Part B: KPT-9274 100mg + Niacin 500mg | Number of Participants With Adverse Event (AE) of Severity Grade >= 3 or 4, Serious AEs, and AEs Leading to Treatment Discontinuation | AEs Leading to Study Treatment Discontinuation | 0 Participants |
| Part B: KPT-9274 100mg + Niacin 500mg | Number of Participants With Adverse Event (AE) of Severity Grade >= 3 or 4, Serious AEs, and AEs Leading to Treatment Discontinuation | Maximum Grade 3/4 AEs | 1 Participants |
| Part B: KPT-9274 100mg + Niacin 500mg | Number of Participants With Adverse Event (AE) of Severity Grade >= 3 or 4, Serious AEs, and AEs Leading to Treatment Discontinuation | Maximum Grade 4 AEs | 1 Participants |
| Part B: KPT-9274 100mg + Niacin 500mg | Number of Participants With Adverse Event (AE) of Severity Grade >= 3 or 4, Serious AEs, and AEs Leading to Treatment Discontinuation | Serious AEs | 1 Participants |
| Part C: KPT-9274 20mg + Nivolumab 480mg | Number of Participants With Adverse Event (AE) of Severity Grade >= 3 or 4, Serious AEs, and AEs Leading to Treatment Discontinuation | Serious AEs | 1 Participants |
| Part C: KPT-9274 20mg + Nivolumab 480mg | Number of Participants With Adverse Event (AE) of Severity Grade >= 3 or 4, Serious AEs, and AEs Leading to Treatment Discontinuation | AEs Leading to Study Treatment Discontinuation | 0 Participants |
| Part C: KPT-9274 20mg + Nivolumab 480mg | Number of Participants With Adverse Event (AE) of Severity Grade >= 3 or 4, Serious AEs, and AEs Leading to Treatment Discontinuation | Maximum Grade 4 AEs | 0 Participants |
| Part C: KPT-9274 20mg + Nivolumab 480mg | Number of Participants With Adverse Event (AE) of Severity Grade >= 3 or 4, Serious AEs, and AEs Leading to Treatment Discontinuation | Maximum Grade 3/4 AEs | 1 Participants |
| Part C: KPT-9274 30mg + Nivolumab 480mg | Number of Participants With Adverse Event (AE) of Severity Grade >= 3 or 4, Serious AEs, and AEs Leading to Treatment Discontinuation | AEs Leading to Study Treatment Discontinuation | 0 Participants |
| Part C: KPT-9274 30mg + Nivolumab 480mg | Number of Participants With Adverse Event (AE) of Severity Grade >= 3 or 4, Serious AEs, and AEs Leading to Treatment Discontinuation | Maximum Grade 4 AEs | 0 Participants |
| Part C: KPT-9274 30mg + Nivolumab 480mg | Number of Participants With Adverse Event (AE) of Severity Grade >= 3 or 4, Serious AEs, and AEs Leading to Treatment Discontinuation | Maximum Grade 3/4 AEs | 4 Participants |
| Part C: KPT-9274 30mg + Nivolumab 480mg | Number of Participants With Adverse Event (AE) of Severity Grade >= 3 or 4, Serious AEs, and AEs Leading to Treatment Discontinuation | Serious AEs | 2 Participants |
| Part C: KPT-9274 40mg + Nivolumab 480mg | Number of Participants With Adverse Event (AE) of Severity Grade >= 3 or 4, Serious AEs, and AEs Leading to Treatment Discontinuation | Maximum Grade 4 AEs | 1 Participants |
| Part C: KPT-9274 40mg + Nivolumab 480mg | Number of Participants With Adverse Event (AE) of Severity Grade >= 3 or 4, Serious AEs, and AEs Leading to Treatment Discontinuation | Serious AEs | 2 Participants |
| Part C: KPT-9274 40mg + Nivolumab 480mg | Number of Participants With Adverse Event (AE) of Severity Grade >= 3 or 4, Serious AEs, and AEs Leading to Treatment Discontinuation | Maximum Grade 3/4 AEs | 3 Participants |
| Part C: KPT-9274 40mg + Nivolumab 480mg | Number of Participants With Adverse Event (AE) of Severity Grade >= 3 or 4, Serious AEs, and AEs Leading to Treatment Discontinuation | AEs Leading to Study Treatment Discontinuation | 1 Participants |
Primary
Overall Survival (OS)
The OS was defined as the duration of time from date of the first study treatment until death from any cause.
Time frame: From date of the first study treatment until death (up to 44 weeks)
Population: Study was terminated prematurely due to a lack of efficacy during primary analysis stage. Data for this outcome measure was not collected or analyzed as per planned analysis.
Primary
Percentage of Participants With Disease Control Rate (DCR)
The DCR was defined as percentage of participants who have a response of CR, PR, and stable disease (SD) \>= 16 weeks, DCR = CR + PR+ SD. The PR was achieved when a participant had at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. The CR was achieved in a participant when all target lesions disappeared. Any pathological lymph nodes (whether target or non-target) must have reduction in the short axis to \<10mm. The SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD).
Time frame: From date of the first study treatment up to 44 weeks
Population: Study was terminated prematurely due to a lack of efficacy during primary analysis stage. Data for this outcome measure was not collected or analyzed as per planned analysis.
Primary
Percentage of Participants With Overall Response Rate (ORR)
The ORR was defined as percentage of participants who had a response of partial response (PR) or complete response (CR). The PR was achieved when a participant had at least a 30 percent (%) decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. The CR was achieved in a participant when all target lesions disappeared. Any pathological lymph nodes (whether target or non target) must have reduction in the short axis to \<10 millimeter (mm).
Time frame: From date of randomization up to 44 weeks
Population: Study was terminated prematurely due to a lack of efficacy during primary analysis stage. Data for this outcome measure was not collected or analyzed as per planned analysis.
Primary
Progression-free Survival (PFS)
The PFS was defined as the duration of time from date of the first study treatment until the first date that PD is objectively documented or death due to any cause. The PD is 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 5mm. Appearance of one or more new lesions will also constitute PD.
Time frame: From the date of first study treatment until the first date of PD, or death due (up to 44 weeks)
Population: Study was terminated prematurely due to a lack of efficacy during primary analysis stage. Data for this outcome measure was not collected or analyzed as per planned analysis.
Primary
Time to Progression (TTP)
The TTP was defined as the duration of time from date of the first study treatment until the first date that PD was objectively documented or death due to PD.
Time frame: From date of the first study treatment until the first date of PD or death (up to 44 weeks)
Population: Study was terminated prematurely due to a lack of efficacy during primary analysis stage. Data for this outcome measure was not collected or analyzed as per planned analysis.
Secondary
Apparent Plasma Clearance (CL/F) in Participants Who Received KPT-9274
The CL/F was calculated as the KPT-9274 dose administered divided by the area-under-the-curve of KPT-9274 plasma concentration versus (vs) time.
Time frame: Cycle 1 and 2: Pre-dose, 3, 6, 8, 24, and 48 hours post-dose (each cycle =28 days)
Population: Study was terminated prematurely due to a lack of efficacy during primary analysis stage. Data for this outcome measure was not collected or analyzed as per planned analysis.
Secondary
Maximum Plasma Concentration (Cmax) in Participants Who Received KPT-9274
Cmax achieved by the KPT-9274 after the first dose administrations.
Time frame: Cycle 1 and 2: Pre-dose, 3, 6, 8, 24, and 48 hours post-dose (each cycle =28 days)
Population: Study was terminated prematurely due to a lack of efficacy during primary analysis stage. Data for this outcome measure was not collected or analyzed as per planned analysis.
Secondary
Terminal Half-life (T1/2) in Participants Who Received KPT-9274
The T1/2 was defied as the time it takes for the concentration of KPT-9274 in the plasma to be reduced by 50%.
Time frame: Cycle 1 and 2: Pre-dose, 3, 6, 8, 24, and 48 hours post-dose (each cycle =28 days)
Population: Study was terminated prematurely due to a lack of efficacy during primary analysis stage. Data for this outcome measure was not collected or analyzed as per planned analysis.
Secondary
Time-to-peak Plasma Concentration (Tmax) in Participants Who Received KPT-9274
Time taken by KPT-9274 to achieve maximum plasma concentration after the first dose administration.
Time frame: Cycle 1 and 2: Pre-dose, 3, 6, 8, 24, and 48 hours post-dose (each cycle =28 days)
Population: Study was terminated prematurely due to a lack of efficacy during primary analysis stage. Data for this outcome measure was not collected or analyzed as per planned analysis.
Secondary
Volume of Distribution (Vd/F) in Participants Who Received KPT-9274
The Vd/F was defined as MRT\*CL/F, where MRT is the mean residence time (calculated as AUMC\[0-tau\]/AUC\[0-tau\], where AUMC\[0-tau\] is the area under the first moment curve determined as the area under the concentration\*time versus time curve).
Time frame: Cycle 1 and 2: Pre-dose, 3, 6, 8, 24, and 48 hours post-dose (each cycle =28 days)
Population: Study was terminated prematurely due to a lack of efficacy during primary analysis stage. Data for this outcome measure was not collected or analyzed as per planned analysis.