KPT-9274 in Patients With Relapsed and Refractory Acute Myeloid Leukemia

NCT04914845 | Completed Phase 1 Results DMC FDA Drug

• 3 other identifiers: 20-2350.ccNCI-2021-08786KPT-9274
• Study Type: interventional
• Target: 16
• Locations: 1 country
• Sites: 1

Brief Summary

This study will evaluate the safety and tolerability of oral KPT-9274 for the treatment of patients with relapsed or refractory acute myeloid leukemia.

Conditions

Acute Myeloid Leukemia, in Relapse; Acute Myeloid Leukemia Refractory; Acute Myeloid Leukemia

Outcome Measures

Primary Outcomes (1)

• Maximum Tolerated Dose (MTD)

  Dose escalation will continue until the MTD is determined. The MTD is defined as the highest dose at which ≤1 patient experiences a DLT in Cycle 1. Count of participants who did not experience a DLT are listed in outcome measure data table.

  28 days

Secondary Outcomes (1)

• Count of Participants Who Did Not Experience a DLT Are Listed in the Outcome Measure Data Table

  28 days

Study Arms (6)

De-escalation Cohort; 20mg

ACTIVE COMPARATOR

For the purposes of dose escalation decisions, a standard 3+3 dose escalation design will be used.The initial cohort, Cohort 1, will consist of 3 enrolled patients who will be treated at 30 mg. If the MTD is exceeded at cohort 1, de-escalation to cohort 0 (20 mg) will occur. If the MTD is not exceeded in cohort 1, dose escalation will continue based on a standard 3+3 design at the dose levels.

Drug: KPT-9274

Cohort 1; 30 mg

ACTIVE COMPARATOR

The initial cohort, Cohort 1, will consist of 3 enrolled patients who will be treated at 30 mg.

Drug: KPT-9274

Cohort 2; 40mg

ACTIVE COMPARATOR

Dose escalation to 40 mg after initial cohort (Cohort 1) after a minimum of 1 cycle of treatment, defined as receiving ≥75% of KPT-9274 doses during Cycle 1 (e.g., ≥9 of 12 doses in the 3 doses/week schedule), or have a DLT within the first cycle of treatment to be evaluable for dose escalation decisions.

Drug: KPT-9274

Cohort 3; 60mg

ACTIVE COMPARATOR

Dose escalation to 60 mg after initial cohort (Cohort 1) after a minimum of 1 cycle of treatment, defined as receiving ≥75% of KPT-9274 doses during Cycle 1 (e.g., ≥9 of 12 doses in the 3 doses/week schedule), or have a DLT within the first cycle of treatment to be evaluable for dose escalation decisions.

Drug: KPT-9274

Cohort 4; 80mg

ACTIVE COMPARATOR

Dose escalation to 80 mg after initial cohort (Cohort 1) after a minimum of 1 cycle of treatment, defined as receiving ≥75% of KPT-9274 doses during Cycle 1 (e.g., ≥9 of 12 doses in the 3 doses/week schedule), or have a DLT within the first cycle of treatment to be evaluable for dose escalation decisions.

Drug: KPT-9274

Cohort 5; 100mg

ACTIVE COMPARATOR

Dose escalation to 100 mg after initial cohort (Cohort 1) after a minimum of 1 cycle of treatment, defined as receiving ≥75% of KPT-9274 doses during Cycle 1 (e.g., ≥9 of 12 doses in the 3 doses/week schedule), or have a DLT within the first cycle of treatment to be evaluable for dose escalation decisions.

Drug: KPT-9274

Interventions

KPT-9274 DRUG

KPT-9274 is a first-in-class orally bioavailable, non-competitive, small molecule, dual modulator of p21 protein (Cdc42/Rac)-activated kinase 4 (PAK4) and nicotinamide phosphoribosyltransferase /PBEF/visfatin (NAMPT). NAMPT is the rate-limiting enzyme in the metabolic scavenging pathway that utilizes nicotinamide to replenish nicotinamide adenine dinucleotide (NAD), an essential metabolic cofactor and second messenger. Recent investigations have shown that in in vitro and in vivo models, NAMPT is uniquely essential for relapsed or refractory AML stem cells. Targeting relapsed AML stem cells, through targeting of NAMPT, may allow for a promising therapeutic opportunity for patients with relapsed or refractory AML.

Cohort 1; 30 mg; Cohort 2; 40mg; Cohort 3; 60mg; Cohort 4; 80mg; Cohort 5; 100mg; De-escalation Cohort; 20mg

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Written informed consent obtained prior to any study related procedures required solely for this research study.
• Age ≥18 years.
• Patients with WHO-confirmed non-APL AML who have not responded to or relapsed after at least one prior therapy and for whom no standard therapy that may provide clinical benefit is available.
• Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2.
• Adequate hepatic function:
• Total bilirubin \< 1.5 times the upper limit of normal (ULN) (except patients with Gilbert's syndrome \[hereditary indirect hyperbilirubinemia\], subjects with Gilbert's syndrome, total bilirubin needs to be ≤ 4 x ULN).
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 times ULN (except patients with known liver involvement of their AML who must have AST and ALT ≤ 5.0 times ULN).
• Adequate renal function: estimated creatinine clearance of ≥ 60 mL/min, calculated using CKD-EPI Creatinine Equation (2021). https://www.kidney.org/content/ckd-epi-creatinine-equation-2021
• Female patients of child-bearing potential must agree to use dual methods of contraception (including one highly effective and one effective method of contraception) and have a negative serum pregnancy test at Screening. For both male and female patients, effective methods of contraception must be used throughout the study and for 3 months following the last dose.
• Fertile female patients must agree to refrain from egg donation from first dose until at least 3 months following the last dose of KPT-9724.
• Women should not breastfeed during treatment with KPT-9724 and for 2 weeks after the last dose.
• \. Male patients must use 2 highly effective methods of contraception if sexually active with a female of child-bearing potential, during treatment with KPT-9724, during a period of 2 weeks (5 half-lives) after the last dose of KPT-9724 plus a period of 3 months. (for 3.5 months after their last dose of KPT-9724). Fertile male patients must agree to refrain from sperm donation from first dose until at least 3.5 months following the last dose of KPT-9724.

You may not qualify if:

• Female patients who are pregnant or lactating.
• Radiation, chemotherapy, immunotherapy or any other anticancer therapy, including investigational anti-cancer therapy ≤ 2 weeks prior to C1D1. Hydroxyurea is not considered an anti-cancer therapy.
• Patients who have not recovered or stabilized (Grade 1 or to their baseline for non-hematologic toxicities) from toxicities related to their previous treatment, except for alopecia.
• Patients with known active central nervous system (CNS) disease
• Clinically significant severe heart disease
• Subjects with uncontrolled systemic fungal, bacterial, viral or other infection despite appropriate antibiotics or other treatment.
• Known, active hepatitis A, B, or C infection; or known to be positive for HCV RNA or HBsAg (HBV surface antigen). Testing is not required.
• Patients with significantly diseased or obstructed gastrointestinal tract or uncontrolled vomiting or diarrhea that could interfere with the absorption of KPT-9274.
• Serious psychiatric or medical conditions that, in the opinion of the Investigator, could interfere with treatment, compliance, or the ability to give consent.

Sponsors & Collaborators

• University of Colorado, Denver: lead
• Karyopharm Therapeutics Inc: collaborator

Study Sites (1)

University of Colorado Hospital

Aurora, Colorado, 80045, United States

Location

Related Publications (1)

• Jones CL, Stevens BM, Pollyea DA, Culp-Hill R, Reisz JA, Nemkov T, Gehrke S, Gamboni F, Krug A, Winters A, Pei S, Gustafson A, Ye H, Inguva A, Amaya M, Minhajuddin M, Abbott D, Becker MW, DeGregori J, Smith CA, D'Alessandro A, Jordan CT. Nicotinamide Metabolism Mediates Resistance to Venetoclax in Relapsed Acute Myeloid Leukemia Stem Cells. Cell Stem Cell. 2020 Nov 5;27(5):748-764.e4. doi: 10.1016/j.stem.2020.07.021. Epub 2020 Aug 20.

  PMID: 32822582 RESULT

MeSH Terms

Conditions

Leukemia, Myeloid, Acute

Interventions

KPT-9274

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases

Results Point of Contact

• Title: Dr. Daniel Pollyea
• Organization: University of Colorado

DANIEL.POLLYEA@CUANSCHUTZ.EDU

(303) 724-9562

Study Officials

• Daniel Pollyea, MD

  University of Colorado, Denver

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: During dose escalation, patients will receive oral KPT-9274 three times a week every other day (Days 1, 3, 5, 8, 10, 12, 15, 17, 19, 22, 24, and 26) during each 28-day cycle, and the first dose cohort will be 30 mg. Subsequent dose escalation cohorts, as well as a de-escalation cohort, will be administered. Dose escalation will continue until the MTD is determined. The MTD is defined as the highest dose at which ≤1 patient experiences a DLT in Cycle 1. A RP2D equal to or less than the MTD will be declared and used for the Dose Expansion Phase, if conducted.

Study Record Dates

• First Submitted: May 25, 2021
• First Posted: June 7, 2021
• Study Start: August 27, 2021
• Primary Completion: July 8, 2025
• Study Completion: October 22, 2025
• Last Updated: January 27, 2026
• Results First Posted: January 27, 2026

Record last verified: 2026-01

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)