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).
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.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
60
UCLA Health
Los Angeles, California, United States
University of Colorado Cancer Center
Aurora, Colorado, United States
Georgetown University, Lombardi Comprehensive Cancer Center
Washington D.C., District of Columbia, United States
Mayo Clinic Rochester
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
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)
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
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).
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Rochester, Minnesota, United States
NYU-Laura & Isaac Perlmutter Cancer Center
New York, New York, United States
Vanderbilt-Ingram Cancer Center
Nashville, Tennessee, United States
MD Anderson Cancer Center
Houston, Texas, United States
Princess Margaret Hospital
Toronto, Ontario, Canada
Time frame: From date of randomization up to 44 weeks
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
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)
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)
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)
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
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)
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)
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)
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)
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)