Acute Myeloid Leukemia, Acute Myeloid Leukemia, in Relapse, Acute Myeloid Leukemia Refractory
Conditions
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.
Detailed 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.
Interventions
DRUGKPT-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.
Sponsors
University of Colorado, Denver
Karyopharm Therapeutics Inc
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
SINGLE (Subject)
Intervention model description
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.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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. 1. 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. 2. Women should not breastfeed during treatment with KPT-9724 and for 2 weeks after the last dose. 8. 8\. 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.
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Tolerated Dose (MTD) | 28 days | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Count of Participants Who Did Not Experience a DLT Are Listed in the Outcome Measure Data Table | 28 days | 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. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORDaniel Pollyea, MD
University of Colorado, Denver
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Customized 18 years of age or older | 16 Participants |
| Age, Customized Under 18 years of age | 0 Participants |
| Race and Ethnicity Not Collected | 0 Participants |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 5 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 |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 0 | 5 / 5 | 6 / 7 | 4 / 4 | 0 / 0 | 0 / 0 |
| other Total, other adverse events | 0 / 0 | 5 / 5 | 7 / 7 | 4 / 4 | 0 / 0 | 0 / 0 |
| serious Total, serious adverse events | 0 / 0 | 2 / 5 | 3 / 7 | 3 / 4 | 0 / 0 | 0 / 0 |
Outcome results
None listed