KPT-9274 for Acute Myeloid Leukemia

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

40 Participants Needed

Trial Summary

What is the purpose of this trial?

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

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.

What makes the drug KPT-9274 unique for treating acute myeloid leukemia?

KPT-9274 is unique because it targets specific molecular abnormalities in cancer cells, which is different from the traditional 'one-size-fits-all' chemotherapy approach used for acute myeloid leukemia. This drug represents a move towards more personalized treatment options that focus on the unique genetic makeup of the cancer. ^{1 2 3 4 5}

Research Team

Daniel Pollyea, MD

Principal Investigator

University of Colorado, Denver

Eligibility Criteria

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

I am 18 years old or older.

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

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

Treatment Details

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.

Participant Groups

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

Findings from Research

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]

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]

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]

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]

References

1. Switzerland pubmed.ncbi.nlm.nih.gov

Impact of KMT2A Rearrangement and CSPG4 Expression in Pediatric Acute Myeloid Leukemia. [2021]

2. United States 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. [2021]

3. United States pubmed.ncbi.nlm.nih.gov

Acute Myeloid Leukemia: Biologic, Prognostic, and Therapeutic Insights. [2021]

4. England pubmed.ncbi.nlm.nih.gov

Hematopoietic stem cell transplantation for pediatric acute myeloid leukemia patients with KMT2A rearrangement; A nationwide retrospective analysis in Japan. [2020]

5. United States pubmed.ncbi.nlm.nih.gov

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