KPT-9274 for Acute Myeloid Leukemia

Not currently recruiting at 1 trial location

Overseen By Jessica Dell-Martin

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: University of Colorado, Denver

Must not be taking: Radiation, Chemotherapy, Immunotherapy, others

Disqualifiers: Pregnancy, CNS disease, Heart disease, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: Unknown

Duration: 4 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new oral treatment, KPT-9274, to determine its safety and tolerability for people with acute myeloid leukemia (AML) that is unresponsive to or has recurred after previous treatments. AML is a type of blood cancer, and the trial aims to identify the best dose of KPT-9274 through various treatment groups. Candidates may qualify if they have struggled with AML after at least one prior treatment and have no other standard treatment options available. As a Phase 1 trial, this research focuses on understanding how KPT-9274 works in people, offering participants the opportunity to be among the first to receive this new treatment.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, you cannot have had radiation, chemotherapy, immunotherapy, or any other anticancer therapy within 2 weeks before starting the trial, except for hydroxyurea.

Is there any evidence suggesting that KPT-9274 is likely to be safe for humans?

Research has shown that KPT-9274 is being tested for its safety in treating acute myeloid leukemia. Early findings suggest that KPT-9274 is generally well-tolerated in people, though some side effects have been observed. In earlier animal studies, KPT-9274 caused stomach and kidney problems, as well as anemia (a condition with fewer red blood cells than normal), especially in female mice.

In ongoing human trials, researchers are collecting early safety data, but detailed results are not yet available. Since this study is in its early stages, the main goal is to determine the drug's safety at different doses. Researchers continue to monitor for any side effects as more people take the drug. It is important to consult healthcare providers to understand the benefits and risks before joining a trial. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

KPT-9274 is unique because it targets cancer cells in a way that’s different from typical treatments for acute myeloid leukemia (AML), like chemotherapy or targeted therapies such as FLT3 inhibitors. Most AML treatments aim to kill rapidly dividing cells, but KPT-9274 works by inhibiting a specific protein called PAK4, which plays a role in cancer cell survival and proliferation. This could potentially lead to a new avenue of treatment with fewer side effects. Researchers are excited about KPT-9274 because it might offer a more targeted approach, reducing damage to healthy cells and improving patient outcomes.

What evidence suggests that KPT-9274 might be an effective treatment for acute myeloid leukemia?

Research has shown that KPT-9274 may help treat acute myeloid leukemia (AML). In studies, KPT-9274 reduced the growth of cancer cell groups and helped transform cancer cells into less harmful forms. It also lowered the number of cells that initiate the disease, which are crucial to its progression. Additionally, when combined with another drug, KPT-9274 led to increased cancer cell death, indicating its potential effectiveness. While these findings are promising, they primarily come from early research. More studies are needed to confirm these results in humans. Participants in this trial will receive different dosages of KPT-9274 to evaluate its safety and effectiveness at various levels. ^{1 2 3 5 6}

Who Is on the Research Team?

Daniel Pollyea, MD

Principal Investigator

University of Colorado, Denver

Are You a Good Fit for This Trial?

Adults with acute myeloid leukemia that's come back or hasn't responded to treatment, and no other beneficial therapy is available. They must be able to perform daily activities with some limitations (ECOG ≤ 2), have good liver and kidney function, not be pregnant or breastfeeding, agree to use contraception, and not have had cancer treatment in the last 2 weeks.

Inclusion Criteria

My AML has not improved or has returned after treatment, and no standard treatments are likely to help.

Adequate hepatic function: Total bilirubin < 1.5 times the upper limit of normal (ULN) (except patients with Gilbert's syndrome [hereditary indirect hyperbilirubinemia]; in the case of Gilbert's syndrome the direct bilirubin must be ≤2.0 times the 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 the formula of Cockroft and Gault (140-Age) • Mass (kg)/(72 • creatinine mg/dL); multiply by 0.85 if female, 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, 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

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

Exclusion Criteria

I don't have severe GI issues that could affect medication absorption.

I have an infection that hasn't improved with treatment.

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

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive oral KPT-9274 in a dose-escalation study to determine the Maximum Tolerated Dose (MTD)

4 weeks

Weekly visits for dose administration and monitoring

Dose Expansion

After determining the MTD, additional patients may be enrolled to further evaluate safety and preliminary efficacy

4 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• KPT-9274

Trial Overview The trial tests KPT-9274 taken orally for safety and effectiveness in patients with relapsed or refractory acute myeloid leukemia. It aims to see how well patients tolerate this drug as a potential new treatment option.

How Is the Trial Designed?

Group I: De-escalation Cohort; 20mg Active Control 1 Intervention

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.

Group II: Cohort 2; 40mg Active Control 1 Intervention

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.

Group III: Cohort 3; 60mg Active Control 1 Intervention

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.

Group IV: Cohort 1; 30 mg Active Control 1 Intervention

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

Group V: Cohort 4; 80mg Active Control 1 Intervention

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.

Group VI: Cohort 5; 100mg Active Control 1 Intervention

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.

Who Is Running the Clinical Trial?

University of Colorado, Denver

Lead Sponsor

Trials

1,842

Recruited

3,028,000+

Karyopharm Therapeutics Inc

Industry Sponsor

Trials

89

Recruited

7,200+

Richard Paulson

Karyopharm Therapeutics Inc

Chief Executive Officer since 2021

MBA from the University of Toronto's Rotman School of Management

Reshma Rangwala

Karyopharm Therapeutics Inc

Chief Medical Officer since 2023

MD, PhD

Published Research Related to This Trial

In a study of 190 newly diagnosed acute myeloid leukaemia (AML) patients, those with KMT2A gene rearrangements (KMT2Ar) were generally younger and had a higher rate of additional cytogenetic abnormalities compared to those with KMT2A partial tandem duplications (KMT2A-PTD), indicating distinct biological profiles between the two subtypes.

Both KMT2Ar and KMT2A-PTD subtypes were associated with poor outcomes, particularly in patients over 60 years, with specific gene mutations like KRAS in KMT2Ar and DNMT3A non-R882 in KMT2A-PTD identified as adverse prognostic factors affecting overall survival.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cytogenetic and molecular genetic characterization of KMT2A-PTD positive acute myeloid leukemia in comparison to KMT2A-Rearranged acute myeloid leukemia. Vetro, C., Haferlach, T., Meggendorfer, M., et al.[2021]

In a study of 90 pediatric patients with KMT2A-rearranged acute myeloid leukemia (AML) who underwent allogeneic hematopoietic stem cell transplantation (HSCT), the 3-year overall survival rate was 52.1%, indicating that HSCT can be a curative option for this high-risk group.

The study found that achieving complete remission before HSCT significantly improved survival outcomes, and treatment-related mortality was notably lower when HSCT was performed using HLA-matched related donors compared to haploidentical donors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hematopoietic stem cell transplantation for pediatric acute myeloid leukemia patients with KMT2A rearrangement; A nationwide retrospective analysis in Japan. Miyamura, T., Kudo, K., Tabuchi, K., et al.[2020]

In younger patients with acute myeloid leukemia (AML), combination chemotherapy using anthracycline and cytarabine has shown very good disease control, especially with recent trials suggesting that increasing the dose of anthracycline during induction therapy can enhance outcomes.

While intensive postremission therapy has been effective in improving survival rates, the addition of the targeted therapy gemtuzumab ozogamicin has not led to better results, indicating a need for further research into newer agents that target specific molecular abnormalities in leukemic cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New trends in the standard of care for initial therapy of acute myeloid leukemia. Fernandez, HF.[2016]

In a study of 967 pediatric AML patients, 24.9% had KMT2A rearrangements (KMT2A-r), which are linked to specific characteristics like high white blood cell counts and younger age at diagnosis.

While KMT2A-r did not affect overall survival rates across the entire cohort, certain subgroups showed varied outcomes, with some patients having less than 50% survival and others achieving 100% survival, highlighting the importance of subgroup analysis in prognosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of KMT2A Rearrangement and CSPG4 Expression in Pediatric Acute Myeloid Leukemia. Hoffmeister, LM., Orhan, E., Walter, C., et al.[2021]

Acute myeloid leukemia (AML) is becoming more common, especially in older populations, and traditional chemotherapy treatments are often ineffective for most patients, highlighting the need for more personalized approaches.

Recent advancements in molecular technologies have identified new genetic mutations and changes in AML, which can help tailor more effective, individualized treatment strategies that combine targeted therapies with conventional methods.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acute Myeloid Leukemia: Biologic, Prognostic, and Therapeutic Insights. Khaled, S., Al Malki, M., Marcucci, G.[2021]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6373756/

Selective targeting of NAMPT by KPT-9274 in acute myeloid ... KPT-9274 exposure reduced colony formation, increased blast differentiation, and diminished the frequency of leukemia-initiating cells from ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8243474/

Anti-tumor NAMPT inhibitor, KPT-9274, mediates gender ... KPT-9274 treatment caused gender-dependent stomach and kidney injuries and anemia. Female mice treated with KPT-9274 had EPO deficiency and associated impaired ...

3. sciencedirect.com sciencedirect.com/science/article/pii/S2772892725000483

PAK4 Phosphorylates and Stabilizes MYC to Promote ... Combining the PAK4 inhibitor KPT-9274 with the MCL-1 antagonist S63845 induces synergistic lethality in AML cells. These findings provide the ...

4. cell.com cell.com/cell-stem-cell/fulltext/S1934-5909(21)00274-5

Nicotinamide phosphoribosyltransferase inhibitors ... Our results indicate that AML cells including LSCs upregulate the expression of SREBP-regulated genes in response to KPT-9274 treatment.

5. cancer.gov cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2021-08786

KPT-9274 for the Treatment of Recurrent and Refractory ... This phase I trial evaluates the safety and tolerability of an oral PAK4/NAMPT inhibitor ATG-019 (KPT-9274) for the treatment of patients with acute myeloid ...

6. ashpublications.org ashpublications.org/bloodneoplasia/article/2/3/100119/537332/NAMPT-haploinsufficiency-is-a-collateral-lethal

NAMPT haploinsufficiency is a collateral lethal therapeutic ... NAMPT is a therapeutic vulnerability that can be pharmacologically targeted in high-risk, TP53-deficient −7/del(7q) myeloid malignancies.