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First-in-Human Phase I Study of KPT-9274, a First-in-Class Dual Inhibitor of PAK4 and NAMPT, in Patients with
Albiruni Razak1, Amit Mahipal2, Jennifer R Diamond3
1Princess Margaret Hospital, Toronto, ON, Canada. Albiruni.Razak@uhn.ca.
Background:
KPT-9274, a potentially first-in-class, dual NAMPT/PAK4 inhibitor, has shown single-agent anticancer activity in hematologic and solid tumor cell lines and xenografts. KPT-9274 has shown anti-tumor activity in combination with nivolumab in nonclinical models.
Objective:
KCP-9274-901 was a first-in-human, multi-center, open-label clinical study to assess preliminary safety, tolerability, and efficacy of KPT-9274 in patients with advanced solid tumors.
Patients And Methods:
This study was conducted in three parts. A two-part (A, B) dose escalation phase to determine the recommended phase II dose and maximum tolerated dose (MTD) of KPT-9274 alone and with niacin. Part 3 (C) was a dose-finding and expansion phase in patients with melanoma treated with KPT-9274 plus nivolumab.
Results:
A total of 60 patients were enrolled (part A and B n = 50; part C n = 10). Three dose-limiting toxicities (DLTs) were observed in the 40-mg (n = 1) and 80-mg plus niacin (n = 2) cohorts. MTD was not reached in parts A and B and was 60 mg plus nivolumab in part C. The most frequently reported TEAEs (≥30%) were anemia (82.6%), arthralgia (52.2%), and fatigue (43.5%). Patient enrollment was halted prematurely due to a lack of observable efficacy in all parts of the study.
Conclusions:
The MTD of KPT-9274 was not reached in a dose escalation study conducted in patients with advanced solid tumors. Clinical activity was not observed at study doses in combination with niacin or nivolumab. Further investigation into potential therapeutic areas where KPT-9274 may serve as a targeted agent is warranted.
Trial Registry:
Clinical trial registration: www.
Clinicaltrials:
gov , NCT02702492.
Insights
The dual NAMPT/PAK4 inhibitor KPT-9274 showed no observable efficacy in advanced solid tumors, even with niacin or nivolumab. Further research is needed to identify potential therapeutic uses for this targeted agent.
Area of Science:
- Oncology
- Pharmacology
- Clinical Trials
Background:
- KPT-9274 is a novel dual NAMPT/PAK4 inhibitor with preclinical anticancer activity.
- Previous studies indicated anti-tumor effects of KPT-9274 in combination with nivolumab in nonclinical models.
Purpose of the Study:
- To evaluate the safety, tolerability, and preliminary efficacy of KPT-9274 in patients with advanced solid tumors.
- To determine the recommended Phase II dose (RP2D) and maximum tolerated dose (MTD) of KPT-9274.
Main Methods:
- A first-in-human, multi-center, open-label study (NCT02702492) involving dose escalation and expansion phases.
- Part 1 and 2 involved dose escalation of KPT-9274 alone and with niacin.
- Part 3 assessed KPT-9274 in combination with nivolumab in melanoma patients.
Main Results:
- Sixty patients were enrolled; dose-limiting toxicities were observed at higher doses.
- The MTD was not reached in dose escalation alone or with niacin, but was determined as 60 mg with nivolumab.
- Frequent adverse events included anemia, arthralgia, and fatigue. Enrollment was halted due to lack of efficacy.
Conclusions:
- The MTD of KPT-9274 was not established in this study of advanced solid tumors.
- No clinical activity was observed when KPT-9274 was combined with niacin or nivolumab.
- Further investigation is warranted to explore potential targeted therapeutic applications for KPT-9274.
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