KRT-232 + TKI for Chronic Myeloid Leukemia

Recruiting at 25 trial locations

Overseen By Emily Houlihan

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Kartos Therapeutics, Inc.

Must be taking: Tyrosine kinase inhibitors

Must not be taking: MDM2 antagonist therapies

Disqualifiers: CML-BC, T315I mutation, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 6 months

109 Participants Needed

Trial Summary

What is the purpose of this trial?

This study evaluates KRT-232, a novel oral small molecule inhibitor of MDM2, for the treatment of patients with Ph+ Chronic Myeloid Leukemia (CML) who have relapsed or are refractory or intolerant to a Tyrosine Kinase Inhibitor (TKI). This study is a global, open label Phase 1b/2 to determine the efficacy and safety of KRT-232 in patients with chronic phase CML (CML-CP) and accelerated phase (CML-AP) who have failed TKI treatments.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but it does require that you have been resistant or intolerant to at least one Tyrosine Kinase Inhibitor (TKI).

What data supports the effectiveness of the drug combination KRT-232 + TKI for treating Chronic Myeloid Leukemia?

Research shows that tyrosine kinase inhibitors (TKIs) like dasatinib and nilotinib are effective in treating chronic myeloid leukemia (CML) by helping patients achieve a deep molecular response, which is a strong indicator of treatment success. Additionally, studies suggest that optimizing TKI doses can maintain effectiveness while improving patients' quality of life. ^{1 2 3 4 5}

What safety data exists for KRT-232 + TKI treatment in humans?

The safety profiles of TKIs like dasatinib and nilotinib show that they can cause side effects such as cardiovascular issues, fluid retention, and gastrointestinal problems. Asciminib, another treatment option, has a good safety profile but can still cause fatigue, low blood cell counts, and joint pain. It's important to consider individual health conditions when choosing these treatments, as they can affect the likelihood of side effects. ^{6 7 8 9 10}

What makes the drug KRT-232 (Navtemadlin) unique for treating chronic myeloid leukemia?

KRT-232 (Navtemadlin) is unique because it is combined with tyrosine kinase inhibitors (TKIs) to potentially enhance treatment effectiveness for chronic myeloid leukemia, especially in patients who do not respond well to existing TKI therapies. This combination approach aims to address resistance and improve outcomes in patients who have limited options with current treatments. ^{1 3 4 11 12}

Eligibility Criteria

This trial is for adults over 18 with Chronic Myeloid Leukemia who have not responded well to or cannot tolerate Tyrosine Kinase Inhibitor treatments. They must be in the chronic phase (CML-CP) or accelerated phase (CML-AP), without a specific mutation (T315I), and their body should be functioning well enough to participate.

Inclusion Criteria

I have had a cancer treatment that didn't work or I couldn't tolerate it.

I am 18 years old or older.

I can care for myself and am up and about more than 50% of my waking hours.

Exclusion Criteria

My cancer has the T315I mutation.

I cannot tolerate my current TKI medication.

I have chronic myeloid leukemia in the accelerated phase and it's Ph+ and BCR-ABL+.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

KRT-232 is administered orally once daily on Days 1-7 in a 28-day cycle, combined with a Tyrosine Kinase Inhibitor (Dasatinib or Nilotinib) for patients with CML-CP and CML-AP

6 months

Monthly visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

47 months

Treatment Details

Interventions

• Dasatinib
• KRT-232
• Nilotinib

Trial Overview The study tests KRT-232, a new inhibitor targeting MDM2, in combination with existing drugs Dasatinib or Nilotinib, for patients whose leukemia has resisted previous treatments. It's an open-label trial meaning everyone knows what treatment they're getting.

Participant Groups

Group I: Part 2, Arm C (KRT-232 combined with Dasatinib or Nilotinib in patients with CML-AP) Experimental Treatment 3 Interventions

KRT-232 will be administered orally, once daily (QD) on Days 1-7 in a 28-day cycle. Dasatinib or Nilotinib will be administered orally, per locally prescribed dose and schedule.

Group II: Part 2, Arm B (KRT-232 combined with Nilotinib in patients with CML-CP) Experimental Treatment 2 Interventions

KRT-232 will be administered orally, once daily (QD) on Days 1-7 in a 28-day cycle. Nilotinib will be administered orally, per locally prescribed dose and schedule.

Group III: Part 2, Arm A (KRT-232 combined with Dasatinib in patients with CML-CP) Experimental Treatment 2 Interventions

KRT-232 will be administered orally, once daily (QD) on Days 1-7 in a 28-day cycle. Dasastinib will be administered orally, per locally prescribed dose and schedule.

Group IV: Part 1, KRT-232 combined with TKI (Dasatinib or Nilotinib) in patients with CML-CP Experimental Treatment 3 Interventions

KRT-232 will be administered orally, once daily (QD) on Days 1-7 in a 28-day cycle. TKI (dasatinib or nilotinib) will be administered orally, per locally prescribed dose and schedule.

Who Is Running the Clinical Trial?

Kartos Therapeutics, Inc.

Lead Sponsor

Trials

17

Recruited

2,100+

Findings from Research

In a study of 131 patients with chronic myeloid leukemia (CML) treated with tyrosine kinase inhibitors (TKIs), significant cytogenetic and molecular responses were observed, with 95.9% achieving major cytogenetic response after 12 months.

Switching to second-generation TKIs like nilotinib or dasatinib for patients who were resistant or intolerant to imatinib resulted in satisfactory responses, with early molecular responses (BCR-ABLIS levels) at 3 months being strong predictors for achieving deeper molecular remission (MR4.5).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Analysis of Efficacy and Related Factors of Acquired Deep Molecular Response in Chronic Myeloid Leukemia Patients Treated with TKI]. Jing, Y., Yang, L., Liu, DH.[2022]

In a study involving 125 chronic myeloid leukemia (CML) patients, those who underwent low-dose de-escalation of tyrosine kinase inhibitors (TKIs) maintained a high major molecular response (MMR) rate of 88.32% after 12 months, compared to 59.98% in the discontinuation group.

The de-escalation of TKIs not only preserved MMR but also improved patients' quality of life, particularly in emotional functioning and fatigue, suggesting that reducing TKI dosage could be a beneficial new treatment strategy for patients with deep molecular response.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

De-escalation or discontinuation of tyrosine kinase inhibitor in patients with chronic myeloid leukemia: A multicentral, open-label, prospective trial in China. Luo, J., Du, X., Lou, J., et al.[2022]

The introduction of imatinib mesylate has significantly improved survival rates for chronic myeloid leukemia (CML) patients, making their outcomes comparable to those of the healthy population, especially with optimal responses.

For patients who do not respond to first-line imatinib, second-generation tyrosine kinase inhibitors (TKIs) can be beneficial, and about 40-60% of patients achieving deep molecular remission may have a chance for treatment-free remission (TFR).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Contemporary treatment methods of adult patients with BCR/ABL1 positive chronic myeloid leukemia. Slezáková, K., Mistrík, M., Bátorová, A.[2020]

Radotinib is a novel second-generation tyrosine kinase inhibitor (TKI) approved in Korea for treating chronic myeloid leukemia (CML) in both initial and resistant cases, highlighting its potential as a new treatment option.

The review emphasizes radotinib's efficacy and safety in patients with CML, suggesting it may offer significant benefits compared to existing treatments like imatinib and other TKIs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Radotinib and its clinical potential in chronic-phase chronic myeloid leukemia patients: an update. Eskazan, AE., Keskin, D.[2023]

Tyrosine kinase inhibitors (TKIs) have significantly improved the life expectancy of patients with chronic myeloid leukemia (CML), but long-term use can lead to persistent adverse events that negatively affect quality of life.

The review highlights the potential benefits of TKI dose reduction to manage adverse events and maintain effective treatment responses, suggesting that dose modifications could be a viable strategy for both newly diagnosed patients and those experiencing side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dose Optimization of Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia: A New Therapeutic Challenge. Iurlo, A., Cattaneo, D., Bucelli, C., et al.[2021]

The review highlights that the four available BCR-ABL1 tyrosine kinase inhibitors (TKIs) for chronic myeloid leukemia (CML)—imatinib, nilotinib, dasatinib, and bosutinib—have different safety profiles, which are influenced by their specificity and selectivity in targeting the BCR-ABL1 protein.

Understanding the mechanisms behind adverse events, such as cardiovascular toxicity and gastrointestinal issues, is crucial for clinicians when selecting the most appropriate TKI for patients, especially in first-line treatment settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment-, patient-, and disease-related factors and the emergence of adverse events with tyrosine kinase inhibitors for the treatment of chronic myeloid leukemia. Irvine, E., Williams, C.[2022]

Tyrosine kinase inhibitors (TKIs) for chronic myeloid leukemia have similar effectiveness but vary in safety, making it crucial to choose treatments based on individual patient tolerability and adverse event profiles.

Specific TKIs like nilotinib and ponatinib should be avoided in patients with cardiovascular risks, while dasatinib is not recommended for those with lung damage, highlighting the need for personalized treatment plans based on patient comorbidities.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effect of comorbidities on the choice of tyrosine kinase inhibitors in patients with chronic myeloid leukemia. Saydam, G., Ali, R., Demir, AM., et al.[2022]

Asciminib, a new treatment for chronic myeloid leukemia (CML), shows a good safety profile with a lower rate of adverse effects compared to previous tyrosine kinase inhibitors (TKIs), with 55% of patients reporting side effects and only 18% experiencing severe effects.

Despite its unique mechanism of action, asciminib does carry a risk of cross-toxicity with traditional TKIs, particularly for side effects like thrombocytopenia and anemia, indicating careful monitoring is still necessary.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Toxicity of Asciminib in Real Clinical Practice: Analysis of Side Effects and Cross-Toxicity with Tyrosine Kinase Inhibitors. Pérez-Lamas, L., Luna, A., Boque, C., et al.[2023]

A 70-year-old female with chronic myeloid leukemia experienced significant facial edema after starting dasatinib, a tyrosine kinase inhibitor, highlighting a rare but impactful side effect of this treatment.

The patient showed marked improvement using a novel regimen of topical metronidazole and tacrolimus, allowing her to continue dasatinib therapy, suggesting a potential new management strategy for TKI-associated facial edema.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Facial Edema Associated with Dasatinib: Case Report with Successful Treatment. Nyckowski, T., Ambur, A., Vinokurov, A., et al.[2023]

In a study of 450 patients with chronic-phase chronic myeloid leukemia (CML-CP) treated with tyrosine kinase inhibitors (TKIs) from 2004 to 2014, the 5-year overall survival rate was 95.1%, indicating high efficacy of TKIs in this patient population.

Severe adverse events (AEs) during first-line TKI therapy were linked to lower overall survival and event-free survival rates, suggesting that timely modifications to treatment are crucial when patients experience significant AEs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Severe adverse events by tyrosine kinase inhibitors decrease survival rates in patients with newly diagnosed chronic-phase chronic myeloid leukemia. Ota, S., Matsukawa, T., Yamamoto, S., et al.[2022]

Imatinib, a first-line treatment for chronic myeloid leukemia (CML), often leads to intolerance in patients, prompting the need for second- and third-generation tyrosine kinase inhibitors (TKIs) like ponatinib, which is effective against all BCR-ABL1 mutants, including those resistant to other TKIs.

There is a lack of consistent definitions of intolerance across clinical trials, which complicates the assessment of adverse events and their impact on patient quality of life, highlighting the need for better evaluation methods and consideration of ponatinib for patients who cannot tolerate other TKIs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intolerance to tyrosine kinase inhibitors in chronic myeloid leukemia: the possible role of ponatinib. Breccia, M., Efficace, F., Iurlo, A., et al.[2019]

The introduction of affordable generic imatinib allows global access to treatment for all chronic myeloid leukaemia patients, making it a crucial first-line therapy option.

Recent studies indicate that lower doses of tyrosine kinase inhibitors (TKIs), including dose-adjusted ponatinib, are not only effective but also safer, suggesting a shift in treatment strategies towards these lower doses for better patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The influence of drug prices, new availability of inexpensive generic imatinib, new approvals, and post-marketing research on the treatment of chronic myeloid leukaemia in the USA. Kantarjian, H., Paul, S., Thakkar, J., et al.[2022]

References

1. China pubmed.ncbi.nlm.nih.gov

[Analysis of Efficacy and Related Factors of Acquired Deep Molecular Response in Chronic Myeloid Leukemia Patients Treated with TKI]. [2022]

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

De-escalation or discontinuation of tyrosine kinase inhibitor in patients with chronic myeloid leukemia: A multicentral, open-label, prospective trial in China. [2022]

3. Czech Republic pubmed.ncbi.nlm.nih.gov

Contemporary treatment methods of adult patients with BCR/ABL1 positive chronic myeloid leukemia. [2020]

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

Radotinib and its clinical potential in chronic-phase chronic myeloid leukemia patients: an update. [2023]

5. Switzerland pubmed.ncbi.nlm.nih.gov

Dose Optimization of Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia: A New Therapeutic Challenge. [2021]

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

Treatment-, patient-, and disease-related factors and the emergence of adverse events with tyrosine kinase inhibitors for the treatment of chronic myeloid leukemia. [2022]

7. England pubmed.ncbi.nlm.nih.gov

The effect of comorbidities on the choice of tyrosine kinase inhibitors in patients with chronic myeloid leukemia. [2022]

8. Switzerland pubmed.ncbi.nlm.nih.gov

Toxicity of Asciminib in Real Clinical Practice: Analysis of Side Effects and Cross-Toxicity with Tyrosine Kinase Inhibitors. [2023]

9. England pubmed.ncbi.nlm.nih.gov

Facial Edema Associated with Dasatinib: Case Report with Successful Treatment. [2023]

10. England pubmed.ncbi.nlm.nih.gov

Severe adverse events by tyrosine kinase inhibitors decrease survival rates in patients with newly diagnosed chronic-phase chronic myeloid leukemia. [2022]

11. England pubmed.ncbi.nlm.nih.gov

Intolerance to tyrosine kinase inhibitors in chronic myeloid leukemia: the possible role of ponatinib. [2019]

12. England pubmed.ncbi.nlm.nih.gov

The influence of drug prices, new availability of inexpensive generic imatinib, new approvals, and post-marketing research on the treatment of chronic myeloid leukaemia in the USA. [2022]