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

Acute Myeloid Leukemia Clinical Trial

Official title:

A Phase 1 Open-label Study of KPT-9274 in Patients With Relapsed and Refractory Acute Myeloid Leukemia

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04914845
• Other study ID #: 20-2350.cc
• Secondary ID: NCI-2021-08786KP
• Status: Recruiting
• Phase: Phase 1
• Start date: August 27, 2021
• Est. completion date: February 8, 2027

Study information

• Verified date: March 2024
• Source: University of Colorado, Denver
• Contact: Connie Brecl
• Phone: 303-507-8221
• Email: Constance.Brecl[@]CUANSCHUTZ.EDU
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Description:

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 40
• Est. completion date: February 8, 2027
• Est. primary completion date: February 8, 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. Written informed consent obtained prior to any study related procedures required solely for this research study.

2. Age =18 years.

3. 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.

4. Eastern Cooperative Oncology Group (ECOG) performance status of = 2.

5. 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).

6. 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

7. 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.

8. Male patients must use an effective barrier method of contraception if sexually active with a female of child-bearing potential. For both male and female patients, effective methods of contraception must be used throughout the study and for 3 months following the last dose.

Exclusion Criteria:

1. Female patients who are pregnant or lactating.

2. 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.

3. 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.

4. White blood cell count =25x109/L (hydroxyurea or leukapheresis permitted to reduce to below the exclusion criteria threshold and allow eligibility)

5. Patients with known active central nervous system (CNS) disease

6. Clinically significant severe heart disease

7. Subjects with uncontrolled systemic fungal, bacterial, viral or other infection despite appropriate antibiotics or other treatment.

8. 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.

9. Patients with significantly diseased or obstructed gastrointestinal tract or uncontrolled vomiting or diarrhea that could interfere with the absorption of KPT-9274.

10. Serious psychiatric or medical conditions that, in the opinion of the Investigator, could interfere with treatment, compliance, or the ability to give consent.

Related Conditions & MeSH terms

• Acute Myeloid Leukemia
• Acute Myeloid Leukemia Refractory
• Acute Myeloid Leukemia, in Relapse
• Leukemia
• Leukemia, Myeloid
• Leukemia, Myeloid, Acute

Intervention

Drug:
• KPT-9274
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.

Locations

Country	Name	City	State
United States	UCHealth-Metro Denver	Aurora	Colorado
United States	University of Colorado Hospital	Aurora	Colorado

Sponsors (2)

Lead Sponsor	Collaborator
University of Colorado, Denver	Karyopharm Therapeutics Inc

Country where clinical trial is conducted

United States, 

References & 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 Meta — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.	28 days
Secondary	Establish Recommended Phase 2 Dose (RP2D)	A RP2D equal to or less than the MTD will be declared after the MTD is determined and will be used for the Dose Expansion Phase, if conducted. After the RP2D is determined, a dose expansion phase, of up to 10 additional patients, might be conducted, in which a preliminary determination of efficacy will be conducted, using the ELN criteria.	28 days